Review ArticleSurveillance Phagocytosis and Inflammation HowNever-Resting Microglia Influence Adult HippocampalNeurogenesis
Amanda Sierra123 Sol Beccari23 Irune Diaz-Aparicio23 Juan M Encinas123
Samuel Comeau45 and Marie-Egraveve Tremblay45
1 Ikerbasque Foundation 48011 Bilbao Spain2 Achucarro Basque Center for Neuroscience Bizkaia Science and Technology Park 48170 Zamudio Spain3 Department of Neurosciences University of the Basque Country 48940 Leioa Spain4Centre de Recherche du CHU de Quebec Axe Neurosciences Canada G1P 4C75Departement de Medecine Moleculaire Universite Laval Canada G1V 4G2
Correspondence should be addressed to Amanda Sierra asierraikerbasqueorgand Marie-Eve Tremblay TremblayMarie-Evecrchudequebeculavalca
Received 10 December 2013 Accepted 11 February 2014 Published 19 March 2014
Academic Editor Carlos Fitzsimons
Copyright copy 2014 Amanda Sierra et alThis is an open access article distributed under the Creative Commons Attribution Licensewhich permits unrestricted use distribution and reproduction in any medium provided the original work is properly cited
Microglia cells are the major orchestrator of the brain inflammatory response As such they are traditionally studied in variouscontexts of trauma injury and disease where they are well-known for regulating a wide range of physiological processes by theirrelease of proinflammatory cytokines reactive oxygen species and trophic factors among other crucial mediators In the lastfew years however this classical view of microglia was challenged by a series of discoveries showing their active and positivecontribution to normal brain functions In light of these discoveries surveillant microglia are now emerging as an importanteffector of cellular plasticity in the healthy brain alongside astrocytes and other types of inflammatory cells Here we will reviewthe roles of microglia in adult hippocampal neurogenesis and their regulation by inflammation during chronic stress agingand neurodegenerative diseases with a particular emphasis on their underlying molecular mechanisms and their functionalconsequences for learning and memory
1 Microglia The Resident ImmuneCells of the Brain
Microglia were first described in 1919 by the Spanish neu-roanatomist Pıo del Rıo Hortega a disciple of the renownedSantiago Ramon y Cajal almost half a century later thanneurons and astrocytes and just before oligodendrocytes[1] This delayed appearance into the neuroscience arena isstill apparent today as microglia remain one of the leastunderstood cell types of the brain Traditionally microgliawere simply considered as ldquobrain macrophagesrdquo controllingthe inflammatory response during acute insults and neurode-generative conditions and only recently was their uniqueorigin revealed Indeed microglia were shown to derive from
primitive myeloid progenitors of the yolk sac that invadethe central nervous system (CNS) during early embryonicdevelopment (reviewed in [2]) In contrast circulatingmono-cytes and lymphocytes as well as most tissue macrophagesderive from hematopoietic stem cells located initially in thefoetal liver and later in the bone marrow [3] In the adultbrain the microglial population is maintained exclusively byself-renewal during normal physiological conditions [2] Asa consequence microglia are the only immune cells whichpermanently reside in theCNS parenchyma alongside neuraltube-derived neurons astrocytes and oligodendrocytes
These past few years unprecedented insights were alsoprovided into their extreme dynamism and functionalbehaviour in health as much as in disease Indeed microglia
Hindawi Publishing CorporationNeural PlasticityVolume 2014 Article ID 610343 15 pageshttpdxdoiorg1011552014610343
2 Neural Plasticity
were revealed to be exceptional sensors of their environmentresponding on a time scale of minutes to even subtle vari-ations of their milieu by undergoing concerted changes inmorphology and gene expression [4 5] During pathologicalinsults ldquoactivatedrdquo microglia were particularly shown tothicken and retract their processes extend filopodia prolif-erate and migrate release factors and compounds influenc-ing neuronal survival (such as proinflammatory cytokinestrophic factors reactive oxygen species (ROS) etc) andphagocytose pathogens degenerating cells and debris thusproviding better understanding of their roles in orchestratingthe inflammatory response [6] These abilities as immunecells are also recruited during normal physiological condi-tions where ldquosurveillantrdquo microglia further participate inthe remodeling of neuronal circuits by their phagocyticelimination of synapses and their regulation of glutamater-gic receptors maturation and synaptic transmission amongother previously unexpected roles [7ndash9] in addition totheir crucial involvement in the phagocytic elimination ofnewborn cells in the context of adult neurogenesis [10]
Our review will discuss the emerging roles of microgliain adult hippocampal neurogenesis and their regulation byinflammation during chronic stress aging and neurode-generative diseases with a particular emphasis on theirunderlying molecular mechanisms and their functional con-sequences for learning and memory (Figure 1)
2 A Brief Overview ofAdult Hippocampal Neurogenesis
Adult hippocampal neurogenesis is continuously maintainedby the proliferation of neural stem cells located in thesubgranular zone (SGZ) [11ndash13] These neuroprogenitorshave been named ldquoradial glia-like cellsrdquo (rNSCs) or type 1cells since they morphologically and functionally resemblethe embryonic radial glia They have also been defined asldquoquiescent neuroprogenitorsrdquo because only a small percentageof the population is actively dividing during normal phys-iological conditions The lineage of these cells is frequentlytraced by using analogs of the nucleotide thymidine suchas bromodeoxyuridine (BrdU) which gets incorporated intothe DNA of dividing cells during the S phase and can bedetected by immunofluorescence Alternatively their lineagecan be traced by labeling with fluorescent reporters which aredelivered to dividing cells by retroviral vectors or expressedby specific cell type promoters via inducible transgenic mice(for a review of the methods commonly used to study adultneurogenesis see [14]) The daughter cells of rNSCs alsocalled type 2 cells or amplifying neuroprogenitors (ANPs)rapidly expand their pool by proliferating before becomingpostmitotic neuroblasts Within a month these neuroblastsdifferentiate and integrate as mature neurons into the hip-pocampal circuitry [15] They however display unique elec-trophysiological characteristics during several months beingmore excitable than mature neurons [16] and constitute aspecial cell population that is particularly inclined to undergosynaptic remodeling and activity-dependent plasticity [17]
These unique properties of the newborn neurons andthe neurogenic cascade in general suggested that adulthippocampal neurogenesis could play an important rolein hippocampal-dependent functions that require exten-sive neuroplasticity such as learning and memory Indeedactivity-dependent plasticity and learning are long knownfor modulating adult neurogenesis in a complex yet specificmanner with adult hippocampal neurogenesis being influ-enced by learning tasks which depend on the hippocam-pus [44 45] For instance hippocampal-dependent learningparadigms were found to regulate the survival of newbornneurons in a positive manner that depends on the timingbetween their birth and the phases of learning [46 47] Young(15ndash2 months old) newborn neurons were also shown tobe preferentially activated during memory recall in a watermaze task compared to mature neurons as determined bycolabeling of BrdU with immediate early genes such as c-Fos and Arc in which expression correlates with neuronalfiring [48] Nonetheless it has only been in the last fewyears that loss-of-function and gain-of-function approacheswith inducible transgenic mice were able to confirm thatadult hippocampal neurogenesis is necessary for synaptictransmission and plasticity including the induction of long-term potentiation (LTP) and long-term depression [49] aswell as trace learning in conditioned protocols [50] memoryretention in spatial learning tasks [51 52] and encoding ofoverlapping input patterns that is pattern separation [53]
Adult hippocampal neurogenesis and its functionalimplications for learning and memory are however influ-enced negatively by a variety of conditions that are commonlyassociatedwithmicroglial activation and inflammation in thebrain such as chronic stress aging and neurodegenerativediseases as we will review herein Indeed inflammationcaused by irradiation produces a sustained inhibition ofneurogenesis notably by decreasing the proliferation andneuronal differentiation of the progenitors and thereforeexposure to therapeutic doses of cranial irradiation has beenwidely used for modulating neurogenesis experimentallybefore the development of more specific approaches [54]
3 Regulation of Adult HippocampalNeurogenesis by Inflammation
Inflammation is a natural bodily response to damage orinfection that is generally mediated by proinflammatorycytokines such as interleukin 1 beta (IL-1120573) interleukin 6 (IL-6) and tumour necrosis factor alpha (TNF120572) in additionto lipidic mediators such as prostaglandins and leukotrienesOftentimes it is associated with an increased production ofROS as well as nitric oxide (NO) Together these proin-flammatory mediators lead to an increase in local bloodflow adhesion and extravasation of circulating monocytesneutrophils and lymphocytes [55] In the brainmicroglia arethe main orchestrator of the neuroinflammatory responsebut other resident cell types including astrocytes endothelialcells mast cells perivascular and meningeal macrophagesand even neurons can produce proinflammatory mediatorsthough perhaps not to the same extent as microglia [56]
Figure 1 The effects of surveillant and inflammatory microglia on the adult hippocampal neurogenic cascade During physiologicalconditions surveillant microglia effectively phagocytose the excess of apoptotic newborn cells and may release antineurogenic factorssuch as TGF120573 This anti-inflammatory state is maintained by neuronal (tethered or released) fractalkine Enriched environment drivesmicroglia towards a phenotype supportive of neurogenesis via the production of IGF-1 In contrast inflammatory challenge triggered byLPS irradiation aging or AD induces the production of proinflammatory cytokines such as IL-1120573 TNF120572 and IL-6 by microglia as well asresident astrocytes and infiltrating monocytes neutrophils and lymphocytes These cytokines have profound detrimental effects on adultneurogenesis by reducing the proliferation survival integration and differentiation of the newborn neurons and decreasing their recallduring learning and memory paradigms
In addition peripheral immune cells invading the CNSduring inflammation can further produce proinflammatorymediators but the respective contribution ofmicroglia versusother cell types in the inflammatory response of the brain ispoorly understood
The harmful effects of inflammation are also widelydetermined by the actual levels of proinflammatory media-tors released rather than the occurrence or absence of aninflammatory response in itself For instance TNF120572 regulatessynaptic plasticity by potentiating the cell surface expressionof AMPA glutamatergic receptors thus resulting in a homeo-static scaling following prolonged blockage of neuronal activ-ity during visual system development [57] However TNF120572also produces differential effects at higher concentrationsranging from an inhibition of long-term potentiation to anenhancement of glutamate-mediated excitotoxicity in vitro[58] Inflammation induced by chronic ventricular infusionof bacterial lipopolysaccharides (LPS a main componentof the outer membrane of Gram-negative bacteria) that isthe most widely used method for inducing an inflammatorychallenge also increases ex vivo the hippocampal levels ofTNF120572 and IL-1120573 thereby impairing novel place recognitionspatial learning and memory formation but all these cog-nitive deficits can be restored by pharmacological treatment
with a TNF120572 protein synthesis inhibitor a novel analog ofthalidomide 361015840-dithiothalidomide [59]
The impact of inflammation on adult hippocampal neu-rogenesis was originally discovered by Olle Lindvall andTheo Palmerrsquos groups in 2003 showing that systemic orintrahippocampal administration of LPS reduces the for-mation of newborn neurons in the adult hippocampus aneffect that is prevented by indomethacin a nonsteroidal anti-inflammatory drug (NSAID) which inhibits the synthesis ofproinflammatory prostaglandins [60 61] Similarly inflam-mation can determine the increase in neurogenesis that isdriven by seizures a context in which neurogenesis can beprevented by LPS and increased by the anti-inflammatoryantibiotic minocycline [60] In these studies hippocampalproliferation remained unaffected by LPS orminocycline andthus it is likely that inflammation targeted the survival ofnewborn cells [60 61] as LPS is known to increase SGZapoptosis [62] Inflammation also has further downstreameffects on the neurogenic cascade For instance LPS increasesthe number of thin dendritic spines and the expressionof the excitatory synapses marker ldquopostsynaptic densityprotein of 95kDardquo (PSD95) in newborn neurons LPS inaddition increases the expression ofGABAA receptors at earlystages of synapse formation leading to suggesting a possible
4 Neural Plasticity
imbalance of excitatory and inhibitory neurotransmissionin these young neurons [63] Finally LPS also prevents theintegration of newborn neurons into behaviourally relevantnetworks including most notably their activation duringspatial exploration as determined by the percentage of BrdUcells colabeled with the immediate early gene Arc [64]
Importantly none of these manipulations is specific tomicroglia and may directly or indirectly affect other braincells involved in the inflammatory response of the brain Forinstance both LPS andminocycline affect astrocytic functionin vitro and in vivo [65ndash69] Furthermore LPS is knownto drive infiltration of monocytes and neutrophils into thebrain parenchyma [70] Monocytes and neutrophils producemajor proinflammatorymediators and could therefore act onthe neurogenic cascade as well The implication of microgliain LPS-induced decrease in neurogenesis is nonethelesssupported in vivo by the negative correlation between thenumber of newborn neurons (BrdU+ NeuN+ cells) andthe number of ldquoactivatedrdquo microglia (ie expressing ED1)[60] ED1 also called CD68 or macrosialin is a lysosomalprotein which is overexpressed during inflammatory chal-lenge While the location of ED1 previously suggested itsinvolvement in phagocytosis its loss of function did not resultin phagocytosis deficits and thus its function still remainsunknown (reviewed in [10]) The number of ED1-positivemicroglia also negatively correlates with neurogenesis duringinflammation provoked by cranial irradiation [61] Whilecorrelation does not involve causation nor can pinpoint tothe underlying mechanism these experiments were the firstto reveal a potential role for ldquoactivatedrdquo microglia in theregulation of adult hippocampal neurogenesis More directevidence of microglial mediation in LPS deleterious effectswas obtained from in vitro experiments as it was shown thatconditionedmedia fromLPS-challengedmicroglia containedIL-6 which in turn caused apoptosis of neuroblasts [61]Nonetheless astrocytes can also release IL-6 when stimulatedwith TNF120572 or IL-1120573 [71] and chronic astrocytic releaseof IL-6 in transgenic mice reduced proliferation survivaland differentiation of newborn cells thus resulting in anet decrease in neurogenesis [72] In summary while thedetrimental impact of inflammation on neurogenesis is wellestablished more work is needed to define the specific rolesplayed by the various inflammatory cells populating thebrain
4 Inflammation Associated withChronic Stress
Across health and disease the most prevalent condi-tion that is associated with neuroinflammation is ldquochronicstressrdquo which commonly refers to the repeated or sus-tained inability to cope with stressful environmental socialand psychological constraints Chronic stress is character-ized by an imbalanced secretion of glucocorticoids by thehypothalamic-pituitary-adrenal (HPA) axis (most notablycortisol in humans and corticosterone in rodents) whichleads to an altered brain remodelingmassive loss of synapsesand compromised cognitive function [73] In particular an
impairment of spatial learning working memory noveltyseeking and decision making has been associated withchronic stress [74] Glucocorticoids are well known fortheir anti-inflammatory properties as they interfere withNF-120581B-mediated cytokine transcription ultimately delayingwound healing [75] They are also potent anti-inflammatorymediators in vivo [76] and in purified microglia cultures[77] Recently repeated administration of high doses ofglucocorticoids by intraperitoneal injection to mimic theirrelease by chronic stress was also shown to induce a lossof dendritic spines in the motor cortex while impairinglearning of a motor task A transcription-dependent pathwayacting downstream of the glucocorticoid receptor GR wasproposed [78 79] but the particular cell types involved werenot identified
Microglia are considered to be a direct target of the gluco-corticoids as they were shown to express GR during normalphysiological conditions in vivo [77] In fact transgenic micelacking GR in microglia and macrophages show an increasedproduction of proinflammatory mediators (including TNF120572and IL-1120573) and greater neuronal damage in response to anintraparenchymal injection of LPS compared to wild-typemice [80] In contrast glucocorticoids are considered to beproinflammatory in the chronically stressed brain [81] whereamong other changes they can promote inflammation oxida-tive stress neurodegeneration andmicroglial activation [82]For example repeated restraint stress induces microglialproliferation and morphological changes including a hyper-ramification of their processes in the adult hippocampusfollowing restraint stress [83] but a nearly complete lossof processes in the context of social defeat [84] Prenatalrestraint stress also causes an increase in the basal levels ofTNF120572 and IL-1120573 while increasing the proportion ofmicrogliashowing a reactive morphology in the adult hippocampus[85] Similarly social defeat leads to an enhanced responseto the inflammatory challenge induced by intraperitonealinjection of LPS including an increased production of TNF120572and IL-1120573 and expression of inducible NO synthase (iNOS)by microglia accompanied by an increased infiltration ofcirculating monocytes [84 86] Therefore microglia are astrong candidate for mediating some of the effects of stresson adult neurogenesis as will be discussed below in synergywith other types of inflammatory cells
Chronic stress is well known for its negative effects onhippocampal neurogenesis (reviewed in [87 88]) althoughnot all stress paradigms are equally effective [89] Severalstress paradigms can decrease neuroprogenitors proliferationin the tree shrew [90] and inmice [91 92] although this effectseems to be compensated by an increased survival of newbornneurons [92] and whether stress results in a net increaseor decrease in neurogenesis remains controversial (reviewedin [87 88]) The effects of stress on adult neurogenesisseem to be mediated at least partially by glucocorticoidsbecause mice lacking a single copy of the GR gene showbehavioural symptoms of depression including learned help-lessness neuroendocrine alterations of the HPA axis andimpaired neurogenesis [93] In parallel chronic stress isassociated with an increased inflammatory response whichmay inhibit neurogenesis as well For instance serum levels
Neural Plasticity 5
of IL-1120573 and IL-6 are significantly increased in depressedpatients [94] In mice restraint stress leads to a widespreadactivation of NF-120581B in the hippocampus including at thelevel of neuroprogenitors [95] and increased protein levels ofIL-1120573 [96] In addition to the direct role of glucocorticoidsIL-1120573 also seems to mediate some of the effects of mildchronic stress because in vivomanipulations that block IL-1120573(either pharmacologically or in null transgenic mice) preventthe anhedonic stress response and the antineurogenic effectof stress [91 96]Moreover the corticoids and IL-1120573 pathwaysmay regulate each other in a bidirectional manner becausethe administration of a GR antagonist can blunt the LPS-induced production of hippocampal IL-1120573 in stressed mice[97] whereas mice knockout for the IL-1120573 receptor (IL-1R1)fail to display the characteristic elevation of corticosteroneinduced by mild chronic stress [96] Another stress-relatedcytokine IL-6 induces depressive phenotypes and preventsthe antidepressant actions of fluoxetinewhen administered tomice in vivo [98] So far the effects of stress on neurogenesisvia corticosteroids and inflammation have been assumed tobe cell autonomous as neuroprogenitors express both GR[99] and IL-1R1 [95] The potential participation of microgliais yet to be determined but there are some reports of adirect effect of stress on microglial activation For instancemicroglia acutely isolated frommice subjected to acute stress(by inescapable tail shock) showed a primed response to LPSchallenge by producing higher levels of IL-1120573mRNA ex vivo[100] and the specific loss of expression of GR in microglialeads to a blunted inflammatory response in vitro and to adecreased neuronal damage in vivo in response to LPS [80]In stress paradigms these enhanced responses of microgliato inflammatory challenges are similar to their age-relatedldquoprimingrdquo which has been associated with and is possiblydue to an increased basal production of proinflammatorymediators However whether microglia express increasedlevels of IL-1120573 and other proinflammatory cytokines inresponse to stressful events is presently unclear [101] It is thuspossible that some of the antineurogenic effects of stress areexerted bymeans of microglial-dependent inflammation butthis hypothesis remains to be experimentally tested
5 Inflammation Associated with Aging andNeurodegenerative Diseases
Inflammation is also commonly associated with normalaging and neurodegenerative diseases and therefore couldrepresent a putative underlying mechanism that explainstheir decrease in hippocampal neurogenesis Nonethelessinflammation is also associated with neurological diseasessuch as epilepsy or stroke where neurogenesis is thought tobe increased although the data from rodents and humans issomewhat conflictive [102] Neurogenesis is well known todecline throughout adulthood and normal aging in rodentsand humans [103 104] but the decay ismore pronounced andoccurs later in life in mice than in humans [105] The aging-associated decrease in neurogenesis has been shown to occurmainly as a consequence of exhaustion of the rNSC popula-tion which after being recruited and activated undergo three
rounds of mitosis in average and then terminally differentiateinto astrocytes [12 106] In addition a reduced mitoticcapacity of the neuroprogenitors could further contribute todecreasing neurogenesis [106] and moreover an age-relatedincrease in the levels of proinflammatory cytokines couldalso hinder neurogenesis in the aging brain Serum levelsof IL-1120573 IL-6 and TNF120572 are elevated in elderly patients[107 108] Aged microglia express higher levels of theseproinflammatory cytokines and show a greater response toLPS inflammatory challenge that is a ldquoprimedrdquo responsethan their younger counterparts [109] The origin of thislow-grade age-related inflammation (ldquoinflamm-agingrdquo [110])remains unknown and may be related to both aging anddamage to the surrounding neurons as well as aging of theimmune system per se
At the cellular level stress to the endoplasmic reticulum(ER) caused by various perturbations such as nutrient deple-tion disturbances in calcium or redox status or increasedlevels of misfolded proteins can induce a cell-autonomousinflammatory response to neurons Stress to the ER a mul-tifunctional organelle which is involved in protein foldinglipid biosynthesis and calcium storage triggers a homeostaticresponse mechanism named the unfolding protein response(UPR) aiming to clear the unfolded proteins in order torestore normal ER homeostasis [111] However if the ERstress cannot be resolved theUPR also initiates inflammatoryand apoptotic pathways via activation of the transcriptionfactor NF-120581B which controls the expression of most proin-flammatory cytokines [112] In the brain ER stress is ofteninitiated by the formation of abnormal protein aggregatesin several neurodegenerative diseases such as Alzheimerrsquosdisease (AD) Parkinsonrsquos disease (PD) amyotrophic lateralsclerosis (ALS) Huntingtonrsquos disease (HD) and prion-relateddisorders [113] This neurodegeneration-associated ER stressis assumed to occur mostly in neurons but there aresome examples of microglial protein misfolding as well Forinstance both microglia and neurons overexpress CHOP(CEBP homologous protein) a transcription factor whichis activated during ER stress in human patients and mousemodels of ALS [114] Inflammation has been speculated tobe a main negative contributor to the pathology of ALS[115] but a direct microglial involvement in mediating theinflammatory response to abnormal protein aggregation inALS and other neurodegenerative conditions remains to betested Finally ER stress has been linked to a variety of inflam-matory conditions [116 117] including chronic stress diet-induced obesity and drug abuse as well as atherosclerosisand arthritis [118ndash120] During normal aging a progressivedecline in expression and activity of key ER molecularchaperones and folding enzymes could also compromise theadaptive response of the UPR thereby contributing to theage-associated decline in cellular functions [118] Thereforeaging is strongly associated with a chronic ER stress whichleads to increased activation of NF-120581B [112] however thecontribution of the different brain cell types to ldquoinflamm-agingrdquo is still poorly understood The detrimental effects onneurogenesis of increased proinflammatory cytokines in theaging brain are not necessarily related to microglia but alsoto stressed neurons Furthermore ER stress may also cause a
6 Neural Plasticity
cell-autonomous response in neural stem cells [121] althoughits impact on neurogenesis remains to be experimentallydetermined
In addition aging is accompanied by an increased levelof mitochondrial oxidative stress which in turn activatesthe ldquoInflammasomerdquo [122] a group of multimeric proteinscomprising the interleukin 1 converting enzyme (ICE cas-pase 1) which serves to release the active form of thecytokine [123] IL-1120573 may act directly on rNSCs (visualisedby labeling with the Sox2 marker) as they express IL-1R1 in the adult hippocampus [91] Treatment with IL-1120573decreases hippocampal proliferation in young mice [91] andpharmacological inhibition of ICE partially restores the num-ber of newborn neurons in aged mice without significantlyaffecting their differentiation rate [124] Transgenic IL-1120573overexpression results in chronic inflammation and deple-tion of doublecortin-labeled neuroblasts thus mimickingthe aging-associated depletion of neurogenesis [125] Theactual mechanism of action of IL-1120573 on neurogenesis inaged mice including decreased proliferation of rNSCsANPsand survival of newborn neurons remains undeterminedMicroglia are a main source of IL-1120573 in the aging brain butthe hypothesis that microglia-derived IL-1120573 is responsiblefor depleting neurogenesis in the aging brain remains to bedirectly tested
The regulation of neurogenesis by IL-1120573 in the agingbrain has been further linked to the activity of anothercytokine the chemokine fractalkine or CX3CL1 Fractalkinehas soluble and membrane-tethered forms and is exclu-sively expressed by neurons while the fractalkine receptor(CX3CR1) is expressed in the brain by microglia alone [126]Thismodule forms a unique neuron-microglia signalling unitthat controls the extent of microglial inflammation in severalneurodegenerative conditions including PD ALS [127] orAD [128] In fact CX3CR1 blocking antibodies increasethe production of hippocampal IL-1120573 when administeredto young adult rats [129] Importantly chronic treatmentwith fractalkine increases hippocampal proliferation and thenumber of neuroblasts in aged (22 months old) but notyoung (3 months old) or middle-aged rats (12 months old)whereas an antagonists of CX3CR1 has the opposite effectsin young but not in middle-aged nor old rats [129] Sincefractalkine expression is decreased during aging [129] areduced neuron-microglia signalling might be releasing thebrake on microglial contribution to inflammatory responsesalthough increased levels of fractalkine were instead reportedin aged rat hippocampus by other studies [68] Additionalinsights into the role of fractalkine signalling come fromknock-in mice in which the endogenous CX3CR1 locus isreplaced by the fluorescent reporter GFP [126] The initialstudies suggested that CX3CR1GFPGFP (ie CX3CR1minusminus)mice have no significant differences in brain development andfunctions [130] but more systematic investigations recentlyrevealed a long list of hippocampal-dependent changes inyoung (3 months old) CX3CR1GFPGFP and CX3CR1GFP+mice compared to wild-type mice These changes notablyincluded decreased neuroprogenitors proliferation and neu-roblasts number impaired LTP performance in contextual
fear conditioning and water maze spatial learning and mem-ory and importantly increased IL-1120573 protein levels [131]Thesignalling pathway of fractalkine-IL-1120573 is functionally rele-vant because IL-1R1 antagonists rescued LTP and cognitivefunction in CX3CR1GFPGFP mice [131] In sum even thoughneuronal fractalkine seems to be sufficient for restrainingthe inflammatory activity of microglia in young rats itsdownregulation during aging could activate the microglialinflammatory response and thereby subsequently reduce theproliferation of remaining neuroprogenitors
In AD inflammatory cytokines such as IL-1120573 are over-expressed in the microglia associated with the amyloid beta(A120573) plaques of postmortem samples [132] and in transgenicmice modeling the disease [133] The loss of synapses (fromhippocampus to frontal cortex) is one of the main patho-logical substrates in this disease but adult neurogenesis isalso severely reduced in most mouse models of AD possiblydue to a decreased proliferation of neuroprogenitors and adecreased survival of newborn cells even though the putativechanges in the neurogenic cascade in postmortem samplesremain controversial (reviewed in [102]) This lack of agree-ment is possibly explained by the fact that the vast majorityof AD cases have a late onset over 65 years of age when littleneurogenesis remains In contrast in most transgenic ADmouse models the A120573 accumulation cognitive deficits andchanges in neurogenesis are already detectable in young ani-mals (2-3 months old) The study of AD is further hinderedby the difficulty in comparing the time course and pathologyacross different mouse models For instance early treatmentwith minocycline can improve cognition and reduce A120573burden in mice expressing the human amyloid precursorprotein (APP) [134] In contrast in mice expressing APP anda mutated form of presenilin 1 (PS1) which is part of the 120574secretase pathway that cleaves A120573 inflammation is reducedwithout any detectable changes in A120573 plaques deposition[135] Concomitantly with a decrease in tissue inflamma-tory cytokines and number of microglial cells minocyclinerestores neurogenesis and hippocampus-dependent memorydeficits in these APPPS1 mice [135] indirectly suggestingthat cognitive decay in AD may be at least in part relatedto a detrimental effect of inflammation on hippocampalneurogenesis Direct evidence that neurogenesis is associatedwith the cognitive performance in AD is still lacking Furtherresearch is also necessary to determine the neurogenic targetsof AD-related inflammation One central open questionfor future therapies aiming at increasing neurogenesis andcognition in AD is whether neuroprogenitors are spared orwhether their age-induced loss becomes accelerated Ratherthan increasing the proliferation and neurogenic output ofthe few rNSCs remaining in an old AD brain it may be morerelevant to develop strategies that prevent the age-related lossof neuroprogenitors in presymptomatic patients
In summary inflammation associated with a wide varietyof experimental models of disease produces strong detri-mental effects on hippocampal neurogenesis These effectson human neurogenesis are however not so well describedand in vitro IL-1120573 increases the proliferation of hip-pocampal embryonic neuroprogenitors but decreases their
Neural Plasticity 7
differentiation into neurons [136] Novel methods to assesshippocampal neurogenesis in the living human brain frommetabolomics of neuroprogenitors to hippocampal bloodbrain volume (reviewed in [102]) will help to determine thecontribution of inflammation to adult neurogenesis in thehealthy and diseased human brain during aging
6 Normal Physiological Conditions
In the healthy mature brain microglia are an essential com-ponent of the neurogenic SGZ niche where they physicallyintermingle with neuroprogenitors neuroblasts and new-born neurons [62] Here surveillant microglia effectively andrapidly phagocytose the excess of newborn cells undergoingapoptosis [62] Importantly microglial phagocytosis in theadult SGZ is not disturbed by inflammation associated withaging or by LPS challenge as the phagocytic index (iethe proportion of apoptotic cells completely engulfed bymicroglia) is maintained over 90 in these conditions [62]Nonetheless the consequences of microglial phagocytosis onadult hippocampal neurogenesis remain elusive Treatment ofmice with annexin V which binds to the phosphatidylserine(PS) receptor and prevents the recognition of PS on thesurface of apoptotic cells presumably blocking phagocytosisincreases the number of apoptotic cells in the SGZ [40] Con-comitantly annexin V reduces neurogenesis by decreasingthe survival of neuroblasts without affecting neuroprogeni-tors proliferation [40] Similar results were obtained in trans-genic mice knock-out for ELMO1 a cytoplasm protein whichpromotes the internalization of apoptotic cells althoughthe effects on neurogenesis were ascribed to a decreasedphagocytic activity of neuroblasts [40]The actual phagocytictarget of the neuroblasts remains undetermined but thenewborn apoptotic cells in the adult SGZ are exclusivelyphagocytosed by microglia at least in physiological condi-tions [62] Nevertheless none of the above manipulationshas specifically tested the role of microglial phagocytosisin hippocampal-dependent learning and memory and thusthe functional impact of microglial phagocytosis in adultneurogenic niches during normal physiological conditionsremains to be elucidated
Microglial phagocytosis of apoptotic cells is activelyanti-inflammatory at least in vitro and thus it has beenhypothesized that anti-inflammatory cytokines produced byphagocytic microglia may further regulate neurogenesis [10]For instance transforming growth factor beta (TGF120573) whichis produced by phagocytic microglia in vitro [137] inhibitsthe proliferation of SGZ neuroprogenitors [138] Microgliaare further able to produce proneurogenic factors in vitro[139] When primed with cytokines associated with T helpercells such as interleukin 4 (IL-4) or low doses of interferongamma (IFN120574) culturedmicroglia support neurogenesis andoligodendrogenesis through decreased production of TNF120572and increased production of insulin-like growth factor 1(IGF-1) [139] an inducer of neuroprogenitor proliferation[26] A list of potential factors produced by microgliaand known to act on neuroprogenitor proliferation can
be found in Table 1 In addition recent observations sug-gest that neuroprogenitor cells may not only regulate theirown environment but also influence microglial functionsFor instance vascular endothelial growth factor (VEGF)produced by cultured neuroprecursor cells directly affectsmicroglial proliferation migration and phagocytosis [20]More potential factors produced by neuroprogenitors shownto be influencing microglial activity and function can befound in Table 2 However it has to be taken into accountthat most of these observations were obtained in culture andthat further research is needed in order to elucidate whetherthose factors are also secreted and have the same regulatoryresponses in vivo
In addition microglial capacity to remodel and eliminatesynaptic structures during normal physiological conditionshas suggested that microglia could also control the synap-tic integration of the newborn neurons generated duringadult hippocampal neurogenesis [140] Three main mech-anisms were proposed (1) the phagocytic elimination ofnonapoptotic axon terminals and dendritic spines (2) theproteolytic remodeling of the perisynaptic environmentand (3) the concomitant structural remodeling of dendriticspines [7 140] Indeed microglial contacts with synapticelements are frequently observed in the cortex during normalphysiological conditions sometimes accompanied by theirengulfment and phagocytic elimination [141ndash143] as in thedeveloping retinogeniculate system [144] Microglial cells aredistinctively surrounded by pockets of extracellular spacecontrarily to all the other cellular elements [142] suggestingthat microglia could remodel the volume and geometryof the extracellular space and thus the concentration ofvarious ions neurotransmitters and signalling moleculesin the synaptic environment Whether microglia create thepockets of extracellular space themselves or not remainsunknown but these pockets could result from microglialrelease of extracellular proteases such as metalloproteinasesand cathepsins [145] which are well known for influencingthe formation structural remodeling and elimination ofdendritic spines in situ and also experience-dependent plas-ticity in vivo [7 146] More recently microglial phagocytosisof synaptic components was also observed in the developinghippocampus in the unique time window of synaptogenesisa process which is notably regulated by fractalkine-CX3CR1signalling [147] Therefore the attractive hypothesis thatmicroglial sculpts the circuitry of newborn cells in the adulthippocampus deserves further attention
Lastly microglia were also involved in increasing adulthippocampal neurogenesis in the enriched environment(EE) experimental paradigm EE is a paradigm mimick-ing some features of the normal living circumstances ofwild animals as it gives them access to social interactionstoys running wheels and edible treats EE has long beenknown to enhance neurogenesis by acting on newborncells survival resulting ultimately in an enlargement ofthe dentate gyrus [148] Functionally these changes areaccompanied by enhanced spatial learning and memoryformation with the water maze paradigm [149] Similarincreases in neurogenesis are obtained by subjecting miceto voluntary running paradigms although in this case the
8 Neural Plasticity
Table 1 Summary of factors secreted by microglia and the potential effect they have on neuroprogenitors in vitro
Microglia secreted factors Reference Modulation of neural progenitor cells ReferenceBDNF [18] Differentiation [19]EGF [20] Survival expansion proliferation differentiation [21]FGF120573 [22] Survival and expansion [23]GDNF [24] Survival migration and differentiation [25]IGF-1 [21] Proliferation [26]IL-1120573 [27] Reduction in migration [27]IL-6 [28] Inhibition of neurogenesis [29]IL-7 [20] Differentiation [30]IL-11 [20] Differentiation [30]NT-4 [24] Differentiation [31]PDGF [32] Expansion and differentiation [33]TGF120573 [34] Inhibition of proliferation [19]
Table 2 Summary of factors secreted by neuroprogenitors and the potential effect they have on microglia in vitro
NPC secreted factors Reference Modulation of microglia ReferenceBDNF [18] Proliferation and induction of phagocytic activity [35]Haptoglobin [24] Neuroprotection [36]IL-1120573 [37] Intracellular Ca+2 elevation and proliferation [22]IL-6 [37] Increase in proliferation [38]M-CSF [20] Mitogen [39]NGF [40] Decrease in LPS-induced NO [41]TGF120573 [37] Inhibition of TNF120572 secretion [42]TNF120572 [37] Upregulation of IL-10 secretion [43]VEGF [20] Induction of chemotaxis and proliferation [20]
effect is mediated by increased neuroprogenitor proliferation[150] During inflammatory conditions EE is antiapoptoticand neuroprotective [151] and it limits the hippocampalresponse to LPS challenge by decreasing the expression ofseveral cytokines and chemokines including IL1-120573 andTNF120572[152] In fact EE is believed to counteract the inflammatoryenvironment and rescue the decreased number of neuroblastsin CX3CR1GFPGFP mice compared to wild-type mice [153]The effects of EE are independent of the IL-1120573 signallingpathway as it increases neurogenesis in mice that are nullfor IL-1R1 [154] EE also induces microglial proliferation andexpression of the proneurogenic IGF-1 [155] but the fullphenotype of microglia in EE compared to standard housingand its impact on the neurogenic cascade remains to bedetermined
The mechanisms behind the anti-inflammatory actionsof EE are unknown but they were suggested to involvemicroglial interactions with T lymphocytes through anincreased expression of themajor histocompatibility complexof class II (MHC-II) during EE [155] MHC-II is responsiblefor presenting the phagocytosed and degraded antigens tothe antibodies expressed on the surface of a subtype ofT lymphocytes (T helper or CD4+ cells) thus initiatingtheir activation and production of antigen-specific antibod-ies Severe combined immunodeficient (SCID) mice lackingeither T and B lymphocytes or nude mice lacking only Tcells have impaired proliferation and neurogenesis in normal
and EE housing compared to wild-type mice [155] as wellas impaired performance in the water maze [156] Similarlyantibody-based depletion of T helper lymphocytes impairsbasal and exercise-induced proliferation and neurogenesis[157] Furthermore a genetic study in heterogeneous stockmice which descend from eight inbred progenitor strainshas found a significant positive correlation between geneticloci associated to hippocampal proliferation and to theproportion of CD4+ cells among blood CD3+ lymphocytes[158] Additional experiments are needed to fully determinethe possible interactions between microglia and T cellsin neurogenesis because at least in normal physiologicalconditions (1) T cell surveillance of the brain parenchymais minimal (2) microglia are poor antigen presenting cellsand (3) antigen presentation by means of MHC-II family ofmolecules is thought to occur outside the brain that is in themeninges and choroid plexus [159] In fact during voluntaryexercise there are no significant changes in T cell surveillanceof the hippocampus nor a direct interaction between T cellsand microglia nor any changes in the gene expression profileof microglia including that of IGF-1 IL-1120573 and TNF120572 [160]The number of microglia is also inversely correlated withthe number of hippocampal proliferating cells rNSCs andneuroblasts in aged (8 months) mice subjected to voluntaryrunning as well as in vitro cocultures of microglia andneuroprogenitors which has been interpreted as resultingfrom an overall inhibitory effect of microglia on adult
Neural Plasticity 9
neurogenesis [161] Even though EE is clearly a more com-plex environmental factor than voluntary running furtherresearch is necessary to disregard nonspecific or indirecteffects of genetic or antibody-based T cells depletion onmicroglia and other brain cell populations including rNSCsFor instance adoptive transfer of T helper cells treated withglatiramer acetate a synthetic analog of myelin basic protein(MBP) approved for the treatment of multiple sclerosis pro-duces a bystander effect on resident astrocytes and microgliaby increasing their expression of anti-inflammatory cytokinessuch as TGF120573 [162] Alternatively it has been suggested thatT cells may mediate an indirect effect on adult hippocampalneurogenesis by increasing the production of brain-derivedneurotrophic factor (BDNF) [157] which is involved in theproneurogenic actions of EE [163] Whether BDNF cancounteract the detrimental effects of T cell depletion on neu-rogenesis remains unknownOverall the roles ofmicroglia inEE and running-induced neurogenesis are unclear and haveto be addressed with more precise experimental designs Insummary surveillant microglia are part of the physical nichesurrounding the neural stem cells and newborn neurons ofthe mature hippocampus where they continuously phagocy-tose the excess of newborn cellsMicroglia were also linked tothe proneurogenic and anti-inflammatory effects of voluntaryrunning and EE but direct evidence is missing The overallcontribution of microglia to neurogenesis and learning andmemory in normal physiological conditions remains largelyunexplored at this early stage in the field
7 Conclusion
In light of these observations microglia are now emergingas important effector cells during normal brain developmentand functions including adult hippocampal neurogenesisMicroglia can exert a positive or negative influence onthe proliferation survival or differentiation of newborncells depending on the inflammatory context For instancemicroglia can compromise the neurogenic cascade duringchronic stress aging and neurodegenerative diseases bytheir release of proinflammatory cytokines such as IL-1120573IL-6 and TNF120572 A reduced fractalkine signalling betweenneurons and microglia could also be involved during normalaging However microglia are not necessarily the only celltype implicated because astrocytes endothelial cells mastcells perivascular and meningeal macrophages and to alesser extent neurons and invading peripheral immune cellscould further contribute by releasing proinflammatorymedi-ators
Additionally microglia were shown to phagocytose theexcess of newborn neurons undergoing apoptosis in thehippocampal neurogenic niche during normal physiologicalconditions while a similar role in the synaptic integrationof newborn cells was also proposed in light of their capacityto phagocytose synaptic elements Lastly microglial interac-tions with T cells leading to the release of anti-inflammatorycytokines neurotrophic factors and other proneurogenicmediators (notably during EE and voluntary running) couldcounteract the detrimental effects of inflammation on adult
hippocampal neurogenesis and their functional implicationsfor learning and memory
However further research is necessary to assess the rela-tive contribution of microglia versus other types of residentand infiltrating inflammatory cells and to determine thenature of the effector cytokines and other inflammatorymediators involved as well as their cellular andmolecular tar-gets in the neurogenic cascade Such research will undoubt-edly help to develop novel strategies aiming at protecting theneurogenic potential and ultimately its essential contributionto learning and memory
The authors declare that there is no conflict of interestsregarding the publication of this paper
Acknowledgments
This work was supported by grants from the Spanish Min-istry of Economy and Competitiveness to Amanda Sierra(BFU2012-32089) and Juan M Encinas (SAF2012-40085)from Basque Government (Saiotek S-PC 12UN014) and Iker-basque start-up funds to JuanM Encinas andAmanda Sierraand fromTheBanting Research Foundation the Scottish RiteCharitable Foundation of Canada and start-up funds fromUniversite Laval andCentre de recherche duCHUdeQuebecto Marie-Eve Tremblay
References
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[2] F Ginhoux S Lim G Hoeffel D Low and T Huber ldquoOriginand differentiation of microgliardquo Frontiers in Cellular Neuro-science vol 7 article 45 2013
[3] E Gomez Perdiguero C Schulz and F Geissmann ldquoDevelop-ment and homeostasis of ldquoresidentrdquomyeloid cells the case of themicrogliardquo GLIA vol 61 no 1 pp 112ndash120 2013
[4] H Kettenmann F Kirchhoff and A Verkhratsky ldquoMicroglianew roles for the synaptic stripperrdquo Neuron vol 77 no 1 pp10ndash18 2013
[5] A Aguzzi B A Barres and M L Bennett ldquoMicroglia scape-goat saboteur or something elserdquo Science vol 339 no 6116 pp156ndash161 2013
[6] K Helmut U K Hanisch M Noda and A VerkhratskyldquoPhysiology of microgliardquo Physiological Reviews vol 91 no 2pp 461ndash553 2011
[7] M E Tremblay B Stevens A Sierra H Wake A Bessis andA Nimmerjahn ldquoThe role of microglia in the healthy brainrdquoJournal of Neuroscience vol 31 no 45 pp 16064ndash16069 2011
[8] A Miyamoto H Wake A J Moorhouse and J NabekuraldquoMicroglia and synapse interactions fine tuaning neural circuitsand candidate moleculesrdquo Frontiers in Cellular Neurosciencevol 7 article 70 2013
[9] C Bechade Y Cantaut-Belarif and A Bessis ldquoMicroglialcontrol of neuronal activityrdquo Frontiers in Cellular Neurosciencevol 7 article 32 2013
[10] A Sierra O Abiega A Shahraz and H Neumann ldquoJanus-faced microglia beneficial and detrimental consequences ofmicroglial phagocytosisrdquo Frontiers in Cellular Neuroscience vol7 article 6 2013
[11] G Kempermann S Jessberger B Steiner and G KronenbergldquoMilestones of neuronal development in the adult hippocam-pusrdquo Trends in Neurosciences vol 27 no 8 pp 447ndash452 2004
[12] J M Encinas T V Michurina N Peunova et al ldquoDivision-coupled astrocytic differentiation and age-related depletion ofneural stem cells in the adult hippocampusrdquo Cell Stem Cell vol8 no 5 pp 566ndash579 2011
[13] M A Bonaguidi M A Wheeler J S Shapiro et al ldquoIn vivoclonal analysis reveals self-renewing and multipotent adultneural stem cell characteristicsrdquo Cell vol 145 no 7 pp 1142ndash1155 2011
[14] J J Breunig J I Arellano J D Macklis and P RakicldquoEverything that glitters isnrsquot gold a critical review of postnatalneural precursor analysesrdquo Cell Stem Cell vol 1 no 6 pp 612ndash627 2007
[15] L S Overstreet-Wadiche and G L Westbrook ldquoFunctionalmaturation of adult-generated granule cellsrdquoHippocampus vol16 no 3 pp 208ndash215 2006
[16] S Ge C H Yang K S Hsu G L Ming andH Song ldquoA criticalperiod for enhanced synaptic plasticity in newly generatedneurons of the adult brainrdquo Neuron vol 54 no 4 pp 559ndash5662007
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[19] M Krampert S R Chirasani F P Wachs et al ldquoSmad7regulates the adult neural stemprogenitor cell pool in a trans-forming growth factor 120573- and bone morphogenetic protein-independent mannerrdquo Molecular and Cellular Biology vol 30no 14 pp 3685ndash3694 2010
[20] K I Mosher R H Andres T Fukuhara et al ldquoNeural pro-genitor cells regulate microglia functions and activityrdquo NatureNeuroscience vol 15 no 11 pp 1485ndash1487 2012
[21] V Tropepe M Sibilia B G Ciruna J Rossant E F Wagnerand D van der Kooy ldquoDistinct neural stem cells proliferatein response to EGF and FGF in the developing mouse telen-cephalonrdquo Developmental Biology vol 208 no 1 pp 166ndash1881999
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[23] B A Reynolds and R L Rietze ldquoNeural stem cells andneurospheresmdashre-evaluating the relationshiprdquoNatureMethodsvol 2 no 5 pp 333ndash336 2005
[24] K Satake Y Matsuyama M Kamiya et al ldquoUp-regulation ofglial cell line-derived neurotrophic factor (GDNF) followingtraumatic spinal cord injuryrdquo NeuroReport vol 11 no 17 pp3877ndash3881 2000
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Neural Plasticity 11
[27] K Striedinger and E Scemes ldquoInterleukin-1120573 affects calciumsignaling and in vitro cell migration of astrocyte progenitorsrdquoJournal of Neuroimmunology vol 196 no 1-2 pp 116ndash123 2008
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[30] M F Mehler R Rozental M Dougherty D C Spray and JA Kessler ldquoCytokine regulation of neuronal differentiation ofhippocampal progenitor cellsrdquo Nature vol 362 no 6415 pp62ndash65 1993
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[33] F C Mansergh M A Wride and D E Rancourt ldquoNeuronsfrom stem cells implications for understanding nervous systemdevelopment and repairrdquo Biochemistry and Cell Biology vol 78no 5 pp 613ndash628 2000
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[35] S Elkabes E M DiCicco-Bloom and I B Black ldquoBrainmicrogliamacrophages express neurotrophins that selectivelyregulate microglial proliferation and functionrdquo Journal of Neu-roscience vol 16 no 8 pp 2508ndash2521 1996
[36] U K Hanisch and H Kettenmann ldquoMicroglia active sensorand versatile effector cells in the normal and pathologic brainrdquoNature Neuroscience vol 10 no 11 pp 1387ndash1394 2007
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[38] W J Streit S D Hurley T S McGraw and S L Semple-Rowland ldquoComparative evaluation of cytokine profiles andreactive gliosis supports a critical role for interleukin-6 inneuron-glia signaling during regenerationrdquo Journal of Neuro-science Research vol 61 no 1 pp 10ndash20 2000
[39] A Suzumura M Sawada H Yamamoto and T MarunouchildquoEffects of colony stimulating factors on isolated microglia invitrordquo Journal of Neuroimmunology vol 30 no 2-3 pp 111ndash1201990
[40] Z Lu M R Elliott Y Chen et al ldquoPhagocytic activity ofneuronal progenitors regulates adult neurogenesisrdquoNature CellBiology vol 13 no 9 pp 1076ndash1084 2011
[41] K Nakajima Y Kikuchi E Ikoma et al ldquoNeurotrophinsregulate the function of cultured microgliardquo GLIA vol 24 no3 pp 272ndash289 1998
[42] P A Lodge and S Sriram ldquoRegulation of microglial activationby TGF-120573 IL-10 and CSF-1rdquo Journal of Leukocyte Biology vol60 no 4 pp 502ndash508 1996
[43] W S Sheng S Hu F H Kravitz P K Peterson and C C ChaoldquoTumor necrosis factor alpha upregulates humanmicroglial cell
production of interleukin-10 in vitrordquo Clinical and DiagnosticLaboratory Immunology vol 2 no 5 pp 604ndash608 1995
[44] G LMing andH Song ldquoAdult neurogenesis in themammalianbrain significant answers and significant questionsrdquo Neuronvol 70 no 4 pp 687ndash702 2011
[45] E Bruel-Jungerman S Davis C Rampon and S LarocheldquoLong-term potentiation enhances neurogenesis in the adultdentate gyrusrdquo Journal of Neuroscience vol 26 no 22 pp 5888ndash5893 2006
[46] E Drapeau M F Montaron S Aguerre and D N AbrousldquoLearning-induced survival of new neurons depends on thecognitive status of aged ratsrdquo Journal of Neuroscience vol 27no 22 pp 6037ndash6044 2007
[47] A Mouret G Gheusi M M Gabellec F De Chaumont J COlivo-Marin and P M Lledo ldquoLearning and survival of newlygenerated neurons when timemattersrdquo Journal of Neurosciencevol 28 no 45 pp 11511ndash11516 2008
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[49] F Massa M Koelh T Wiesner et al ldquoConditional reduction ofadult neurogenesis impairs bidirectional hippocampal synapticplasticityrdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 108 no 16 pp 6644ndash6649 2011
[50] T J Shors G Miesegaes A Beylin M Zhao T Rydel and EGould ldquoNeurogenesis in the adult is involved in the formationof tracememoriesrdquoNature vol 410 no 6826 pp 372ndash376 2001
[51] W Deng M D Saxe I S Gallina and F H Gage ldquoAdult-born hippocampal dentate granule cells undergoingmaturationmodulate learning and memory in the brainrdquo Journal of Neuro-science vol 29 no 43 pp 13532ndash13542 2009
[52] M Arruda-Carvalho M Sakaguchi K G Akers S A Josselynand P W Frankland ldquoPosttraining ablation of adult-generatedneurons degrades previously acquired memoriesrdquo Journal ofNeuroscience vol 31 no 42 pp 15113ndash15127 2011
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[56] H K Jeong K Ji K Min and E H Joe ldquoBrain inflammationand microglia facts and misconceptionsrdquo Experimental Neuro-biology vol 22 no 2 pp 59ndash67 2013
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12 Neural Plasticity
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[81] S F Sorrells J R Caso C DMunhoz and RM Sapolsky ldquoThestressed CNS when glucocorticoids aggravate inflammationrdquoNeuron vol 64 no 1 pp 33ndash39 2009
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[84] E S Wohleb N D Powell J P Godbout and J F SheridanldquoStress-induced recruitment of bone marrow-derived mono-cytes to the brain promotes anxiety-like behaviorrdquo The Journalof Neuroscience vol 33 no 34 pp 13820ndash13833 2013
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Neural Plasticity 13
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[110] C FranceschiM Bonafe S Valensin et al ldquoInflamm-aging Anevolutionary perspective on immunosenescencerdquo Annals of theNew York Academy of Sciences vol 908 pp 244ndash254 2000
[111] R Sano and J C Reed ldquoER stress-induced cell death mecha-nismsrdquoBiochimica et BiophysicaActa vol 1833 no 12 pp 3460ndash3470 2013
[112] S Z Hasnain R Lourie I Das A C H Chen and MA McGuckin ldquoThe interplay between endoplasmic reticulumstress and inflammationrdquo Immunology and Cell Biology vol 90no 3 pp 260ndash270 2012
[113] S Matus L H Glimcher and C Hetz ldquoProtein folding stressin neurodegenerative diseases a glimpse into the ERrdquo CurrentOpinion in Cell Biology vol 23 no 2 pp 239ndash252 2011
[114] Y Ito M Yamada H Tanaka et al ldquoInvolvement of CHOP anER-stress apoptotic mediator in both human sporadic ALS andALS model micerdquo Neurobiology of Disease vol 36 no 3 pp470ndash476 2009
[115] D Papadimitriou V Le Verche A Jacquier B Ikiz S Przed-borski and D B Re ldquoInflammation in ALS and SMA sortingout the good from the evilrdquo Neurobiology of Disease vol 37 no3 pp 493ndash502 2010
[116] A R Johnson J J Milner and LMakowski ldquoThe inflammationhighway metabolism accelerates inflammatory traffic in obe-sityrdquo Immunological Reviews vol 249 no 1 pp 218ndash238 2012
[117] S Buch H Yao M Guo et al ldquoCocaine and HIV-1 interplayin CNS cellular and molecular mechanismsrdquo Current HIVResearch vol 10 no 5 pp 425ndash428 2012
[118] M K Brown and N Naidoo ldquoThe endoplasmic reticulumstress response in aging and age-related diseasesrdquo Frontiers inPhysiology vol 3 article 263 2012
[119] G Castro C Areias MF L Weissmann et al ldquoDiet-inducedobesity induces endoplasmic reticulum stress and insulin resis-tance in the amygdala of ratsrdquo FEBS Open Bio vol 3 pp 443ndash449 2013
[120] A A Pavlovsky D Boehning D Li Y Zhang X Fan andT A Green ldquoPsychological stress cocaine and natural rewardeach induce endoplasmic reticulum stress genes in rat brainrdquoNeuroscience vol 246 pp 160ndash169 2013
[121] G GargiuloM CesaroniM Serresi et al ldquoIn vivo RNAi screenfor BMI1 targets identifies TGF-betaBMP-ER stress pathwaysas key regulators of neural- and malignant glioma-stem cellhomeostasisrdquo Cancer Cell vol 23 no 5 pp 660ndash676 2013
[122] A Salminen K Kaarniranta and A Kauppinen ldquoInflammag-ing disturbed interplay between autophagy and inflamma-somesrdquo Aging vol 4 no 3 pp 166ndash175 2012
[123] E Latz T S Xiao andA Stutz ldquoActivation and regulation of theinflammasomesrdquoNature Reviews Immunology vol 13 no 6 pp397ndash411 2013
[124] C Gemma A D Bachstetter M J Cole M Fister C Hudsonand P C Bickford ldquoBlockade of caspase-1 increases neurogene-sis in the aged hippocampusrdquo European Journal of Neurosciencevol 26 no 10 pp 2795ndash2803 2007
[125] M D Wu A M Hein M J Moravan S S Shaftel J AOlschowka and M K OrsquoBanion ldquoAdult murine hippocampal
14 Neural Plasticity
neurogenesis is inhibited by sustained IL-1120573 and not rescued byvoluntary runningrdquo Brain Behavior and Immunity vol 26 no2 pp 292ndash300 2012
[126] Y Wolf S Yona K W Kim and S Jung ldquoMicroglia seen fromthe CX3CR1 anglerdquo Frontiers in Cellular Neuroscience vol 7article 26 2013
[127] A E Cardona E P Pioro M E Sasse et al ldquoControl ofmicroglial neurotoxicity by the fractalkine receptorrdquo NatureNeuroscience vol 9 no 7 pp 917ndash924 2006
[128] K Bhaskar M Konerth O N Kokiko-Cochran A Cardona RM Ransohoff and B T Lamb ldquoRegulation of tau pathology bythe microglial fractalkine receptorrdquo Neuron vol 68 no 1 pp19ndash31 2010
[129] A D Bachstetter J M Morganti J Jernberg et al ldquoFractalkineand CX3CR1 regulate hippocampal neurogenesis in adult andaged ratsrdquo Neurobiology of Aging vol 32 no 11 pp 2030ndash20442011
[130] S Jung J Aliberti P Graemmel et al ldquoAnalysis of fractalkinereceptor CX3CR1 function by targeted deletion and greenfluorescent protein reporter gene insertionrdquo Molecular andCellular Biology vol 20 no 11 pp 4106ndash4114 2000
[131] J T Rogers J M Morganti A D Bachstetter et al ldquoCX3CR1deficiency leads to impairment of hippocampal cognitive func-tion and synaptic plasticityrdquo Journal of Neuroscience vol 31 no45 pp 16241ndash16250 2011
[132] W S T Griffin L C Stanley C Ling et al ldquoBrain interleukin1 and S-100 immunoreactivity are elevated in Down syndromeand Alzheimer diseaserdquo Proceedings of the National Academy ofSciences of the United States of America vol 86 no 19 pp 7611ndash7615 1989
[133] W C Benzing J RWujek E KWard et al ldquoEvidence for glial-mediated inflammation in aged APP(SW) transgenic micerdquoNeurobiology of Aging vol 20 no 6 pp 581ndash589 1999
[134] T J Seabrook L Jiang M Maier and C A Lemere ldquoMinocy-cline affects microglia activation A120573 deposition and behaviorin APP-tg micerdquo GLIA vol 53 no 7 pp 776ndash782 2006
[135] B Biscaro O Lindvall G Tesco C T Ekdahl and RM NitschldquoInhibition of microglial activation protects hippocampal neu-rogenesis and improves cognitive deficits in a transgenic mousemodel for Alzheimerrsquos diseaserdquoNeurodegenerative Diseases vol9 no 4 pp 187ndash198 2012
[136] P A Zunszain C Anacker A Cattaneo et al ldquoInterleukin-1120573a new regulator of the kynurenine pathway affecting humanhippocampal neurogenesisrdquo Neuropsychopharmacology vol 37no 4 pp 939ndash949 2012
[137] R De Simone M Antonietta Ajmone-Cat P Tirassa and LMinghetti ldquoApoptotic PC12 cells exposing phosphatidylserinepromote the production of anti-inflammatory and neuropro-tective molecules bymicroglial cellsrdquo Journal of Neuropathologyand Experimental Neurology vol 62 no 2 pp 208ndash216 2003
[138] M S Buckwalter M Yamane B S Coleman et al ldquoChroni-cally increased transforming growth factor-1205731 strongly inhibitshippocampal neurogenesis in aged micerdquo American Journal ofPathology vol 169 no 1 pp 154ndash164 2006
[139] O Butovsky Y Ziv A Schwartz et al ldquoMicroglia activatedby IL-4 or IFN-120574 differentially induce neurogenesis and oligo-dendrogenesis from adult stemprogenitor cellsrdquoMolecular andCellular Neuroscience vol 31 no 1 pp 149ndash160 2006
[140] C T Ekdahl ldquoMicroglial activationmdashtuning and pruning adultneurogenesisrdquo Frontiers in Pharmacology vol 3 article 41 2012
[141] HWakeA JMoorhouse S Jinno S Kohsaka and JNabekuraldquoResting microglia directly monitor the functional state ofsynapses in vivo and determine the fate of ischemic terminalsrdquoJournal of Neuroscience vol 29 no 13 pp 3974ndash3980 2009
[142] M E Tremblay R L Lowery and A K Majewska ldquoMicroglialinteractions with synapses are modulated by visual experiencerdquoPLoS Biology vol 8 no 11 Article ID e1000527 2010
[143] M E Tremblay M L Zettel J R Ison P D Allen and A KMajewska ldquoEffects of aging and sensory loss on glial cells inmouse visual and auditory corticesrdquo GLIA vol 60 no 4 pp541ndash558 2012
[144] D P Schafer E K Lehrman A G Kautzman et al ldquoMicrogliasculpt postnatal neural circuits in an activity and complement-dependent mannerrdquo Neuron vol 74 no 4 pp 691ndash705 2012
[145] H Nakanishi ldquoMicroglial functions and proteasesrdquo MolecularNeurobiology vol 27 no 2 pp 163ndash176 2003
[146] M E Tremblay and A K Majewska ldquoA role for microglia insynaptic plasticityrdquoCommunicative and Integrative Biology vol4 no 2 pp 220ndash222 2011
[147] R C Paolicelli G Bolasco F Pagani et al ldquoSynaptic pruning bymicroglia is necessary for normal brain developmentrdquo Sciencevol 333 no 6048 pp 1456ndash1458 2011
[148] GKempermannHGKuhn and FHGage ldquoMore hippocam-pal neurons in adult mice living in an enriched environmentrdquoNature vol 386 no 6624 pp 493ndash495 1997
[149] M Nilsson E Perfilieva U Johansson O Orwar and P SEriksson ldquoEnriched environment increases neurogenesis in theadult rat dentate gyrus and improves spatial memoryrdquo Journalof Neurobiology vol 39 no 4 pp 569ndash578 1999
[150] H van Praag G Kempermann and F H Gage ldquoRunningincreases cell proliferation and neurogenesis in the adult mousedentate gyrusrdquo Nature Neuroscience vol 2 no 3 pp 266ndash2701999
[151] D Young P A Lawlor P Leone M Dragunow and MJ During ldquoEnvironmental enrichment inhibits spontaneousapoptosis prevents seizures and is neuroprotectiverdquo NatureMedicine vol 5 no 4 pp 448ndash453 1999
[152] L L Williamson A Chao and S D Bilbo ldquoEnvironmentalenrichment alters glial antigen expression and neuroimmunefunction in the adult rat hippocampusrdquo Brain Behavior andImmunity vol 26 no 3 pp 500ndash510 2012
[153] L Maggi M Scianni I Branchi I DrsquoAndrea C Lauro and CLimatola ldquoCX(3)CR1 deficiency alters hippocampal-dependentplasticity phenomena blunting the effects of enriched environ-mentrdquo Frontiers in Cellular Neuroscience vol 5 article 22 2011
[154] I Goshen A Avital T Kreisel T Licht M Segal and RYirmiya ldquoEnvironmental enrichment restores memory func-tioning in mice with impaired IL-1 signaling via reinstatementof long-term potentiation and spine size enlargementrdquo Journalof Neuroscience vol 29 no 11 pp 3395ndash3403 2009
[155] Y Ziv N Ron O Butovsky et al ldquoImmune cells contribute tothe maintenance of neurogenesis and spatial learning abilitiesin adulthoodrdquo Nature Neuroscience vol 9 no 2 pp 268ndash2752006
[156] J Kipnis H Cohen M Cardon Y Ziv and M Schwartz ldquoTcell deficiency leads to cognitive dysfunction implications fortherapeutic vaccination for schizophrenia and other psychiatricconditionsrdquo Proceedings of the National Academy of Sciences ofthe United States of America vol 101 no 21 pp 8180ndash8185 2004
[157] S A Wolf B Steiner A Akpinarli et al ldquoCD4-positive Tlymphocytes provide a neuroimmunological link in the control
Neural Plasticity 15
of adult hippocampal neurogenesisrdquo Journal of Immunologyvol 182 no 7 pp 3979ndash3984 2009
[158] G J Huang A L Smith D H D Gray et al ldquoA genetic andfunctional relationship between T cells and cellular prolifera-tion in the adult hippocampusrdquo PLOS Biology vol 8 no 12Article ID e1000561 2010
[159] R M Ransohoff and B Engelhardt ldquoThe anatomical andcellular basis of immune surveillance in the central nervoussystemrdquoNature Reviews Immunology vol 12 no 9 pp 623ndash6352012
[160] M Olah G Ping A H De Haas et al ldquoEnhanced hippocampalneurogenesis in the absence of microglia T cell interactionand microglia activation in the murine running wheel modelrdquoGLIA vol 57 no 10 pp 1046ndash1061 2009
[161] E Gebara S Sultan J Kocher-Braissant and N Toni ldquoAdulthippocampal neurogenesis inversely correlates with microgliain conditions of voluntary running and agingrdquo Frontiers inNeuroscience vol 7 article 145 2013
[162] R Aharoni B Kayhan R Eilam M Sela and R ArnonldquoGlatiramer acetate-specific T cells in the brain express T helper23 cytokines and brain-derived neurotrophic factor in siturdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 100 no 2 pp 14157ndash14162 2003
[163] C Rossi A Angelucci L Costantin et al ldquoBrain-derivedneurotrophic factor (BDNF) is required for the enhancementof hippocampal neurogenesis following environmental enrich-mentrdquo European Journal of Neuroscience vol 24 no 7 pp 1850ndash1856 2006
2 Neural Plasticity
were revealed to be exceptional sensors of their environmentresponding on a time scale of minutes to even subtle vari-ations of their milieu by undergoing concerted changes inmorphology and gene expression [4 5] During pathologicalinsults ldquoactivatedrdquo microglia were particularly shown tothicken and retract their processes extend filopodia prolif-erate and migrate release factors and compounds influenc-ing neuronal survival (such as proinflammatory cytokinestrophic factors reactive oxygen species (ROS) etc) andphagocytose pathogens degenerating cells and debris thusproviding better understanding of their roles in orchestratingthe inflammatory response [6] These abilities as immunecells are also recruited during normal physiological condi-tions where ldquosurveillantrdquo microglia further participate inthe remodeling of neuronal circuits by their phagocyticelimination of synapses and their regulation of glutamater-gic receptors maturation and synaptic transmission amongother previously unexpected roles [7ndash9] in addition totheir crucial involvement in the phagocytic elimination ofnewborn cells in the context of adult neurogenesis [10]
Our review will discuss the emerging roles of microgliain adult hippocampal neurogenesis and their regulation byinflammation during chronic stress aging and neurode-generative diseases with a particular emphasis on theirunderlying molecular mechanisms and their functional con-sequences for learning and memory (Figure 1)
2 A Brief Overview ofAdult Hippocampal Neurogenesis
Adult hippocampal neurogenesis is continuously maintainedby the proliferation of neural stem cells located in thesubgranular zone (SGZ) [11ndash13] These neuroprogenitorshave been named ldquoradial glia-like cellsrdquo (rNSCs) or type 1cells since they morphologically and functionally resemblethe embryonic radial glia They have also been defined asldquoquiescent neuroprogenitorsrdquo because only a small percentageof the population is actively dividing during normal phys-iological conditions The lineage of these cells is frequentlytraced by using analogs of the nucleotide thymidine suchas bromodeoxyuridine (BrdU) which gets incorporated intothe DNA of dividing cells during the S phase and can bedetected by immunofluorescence Alternatively their lineagecan be traced by labeling with fluorescent reporters which aredelivered to dividing cells by retroviral vectors or expressedby specific cell type promoters via inducible transgenic mice(for a review of the methods commonly used to study adultneurogenesis see [14]) The daughter cells of rNSCs alsocalled type 2 cells or amplifying neuroprogenitors (ANPs)rapidly expand their pool by proliferating before becomingpostmitotic neuroblasts Within a month these neuroblastsdifferentiate and integrate as mature neurons into the hip-pocampal circuitry [15] They however display unique elec-trophysiological characteristics during several months beingmore excitable than mature neurons [16] and constitute aspecial cell population that is particularly inclined to undergosynaptic remodeling and activity-dependent plasticity [17]
These unique properties of the newborn neurons andthe neurogenic cascade in general suggested that adulthippocampal neurogenesis could play an important rolein hippocampal-dependent functions that require exten-sive neuroplasticity such as learning and memory Indeedactivity-dependent plasticity and learning are long knownfor modulating adult neurogenesis in a complex yet specificmanner with adult hippocampal neurogenesis being influ-enced by learning tasks which depend on the hippocam-pus [44 45] For instance hippocampal-dependent learningparadigms were found to regulate the survival of newbornneurons in a positive manner that depends on the timingbetween their birth and the phases of learning [46 47] Young(15ndash2 months old) newborn neurons were also shown tobe preferentially activated during memory recall in a watermaze task compared to mature neurons as determined bycolabeling of BrdU with immediate early genes such as c-Fos and Arc in which expression correlates with neuronalfiring [48] Nonetheless it has only been in the last fewyears that loss-of-function and gain-of-function approacheswith inducible transgenic mice were able to confirm thatadult hippocampal neurogenesis is necessary for synaptictransmission and plasticity including the induction of long-term potentiation (LTP) and long-term depression [49] aswell as trace learning in conditioned protocols [50] memoryretention in spatial learning tasks [51 52] and encoding ofoverlapping input patterns that is pattern separation [53]
Adult hippocampal neurogenesis and its functionalimplications for learning and memory are however influ-enced negatively by a variety of conditions that are commonlyassociatedwithmicroglial activation and inflammation in thebrain such as chronic stress aging and neurodegenerativediseases as we will review herein Indeed inflammationcaused by irradiation produces a sustained inhibition ofneurogenesis notably by decreasing the proliferation andneuronal differentiation of the progenitors and thereforeexposure to therapeutic doses of cranial irradiation has beenwidely used for modulating neurogenesis experimentallybefore the development of more specific approaches [54]
3 Regulation of Adult HippocampalNeurogenesis by Inflammation
Inflammation is a natural bodily response to damage orinfection that is generally mediated by proinflammatorycytokines such as interleukin 1 beta (IL-1120573) interleukin 6 (IL-6) and tumour necrosis factor alpha (TNF120572) in additionto lipidic mediators such as prostaglandins and leukotrienesOftentimes it is associated with an increased production ofROS as well as nitric oxide (NO) Together these proin-flammatory mediators lead to an increase in local bloodflow adhesion and extravasation of circulating monocytesneutrophils and lymphocytes [55] In the brainmicroglia arethe main orchestrator of the neuroinflammatory responsebut other resident cell types including astrocytes endothelialcells mast cells perivascular and meningeal macrophagesand even neurons can produce proinflammatory mediatorsthough perhaps not to the same extent as microglia [56]
Figure 1 The effects of surveillant and inflammatory microglia on the adult hippocampal neurogenic cascade During physiologicalconditions surveillant microglia effectively phagocytose the excess of apoptotic newborn cells and may release antineurogenic factorssuch as TGF120573 This anti-inflammatory state is maintained by neuronal (tethered or released) fractalkine Enriched environment drivesmicroglia towards a phenotype supportive of neurogenesis via the production of IGF-1 In contrast inflammatory challenge triggered byLPS irradiation aging or AD induces the production of proinflammatory cytokines such as IL-1120573 TNF120572 and IL-6 by microglia as well asresident astrocytes and infiltrating monocytes neutrophils and lymphocytes These cytokines have profound detrimental effects on adultneurogenesis by reducing the proliferation survival integration and differentiation of the newborn neurons and decreasing their recallduring learning and memory paradigms
In addition peripheral immune cells invading the CNSduring inflammation can further produce proinflammatorymediators but the respective contribution ofmicroglia versusother cell types in the inflammatory response of the brain ispoorly understood
The harmful effects of inflammation are also widelydetermined by the actual levels of proinflammatory media-tors released rather than the occurrence or absence of aninflammatory response in itself For instance TNF120572 regulatessynaptic plasticity by potentiating the cell surface expressionof AMPA glutamatergic receptors thus resulting in a homeo-static scaling following prolonged blockage of neuronal activ-ity during visual system development [57] However TNF120572also produces differential effects at higher concentrationsranging from an inhibition of long-term potentiation to anenhancement of glutamate-mediated excitotoxicity in vitro[58] Inflammation induced by chronic ventricular infusionof bacterial lipopolysaccharides (LPS a main componentof the outer membrane of Gram-negative bacteria) that isthe most widely used method for inducing an inflammatorychallenge also increases ex vivo the hippocampal levels ofTNF120572 and IL-1120573 thereby impairing novel place recognitionspatial learning and memory formation but all these cog-nitive deficits can be restored by pharmacological treatment
with a TNF120572 protein synthesis inhibitor a novel analog ofthalidomide 361015840-dithiothalidomide [59]
The impact of inflammation on adult hippocampal neu-rogenesis was originally discovered by Olle Lindvall andTheo Palmerrsquos groups in 2003 showing that systemic orintrahippocampal administration of LPS reduces the for-mation of newborn neurons in the adult hippocampus aneffect that is prevented by indomethacin a nonsteroidal anti-inflammatory drug (NSAID) which inhibits the synthesis ofproinflammatory prostaglandins [60 61] Similarly inflam-mation can determine the increase in neurogenesis that isdriven by seizures a context in which neurogenesis can beprevented by LPS and increased by the anti-inflammatoryantibiotic minocycline [60] In these studies hippocampalproliferation remained unaffected by LPS orminocycline andthus it is likely that inflammation targeted the survival ofnewborn cells [60 61] as LPS is known to increase SGZapoptosis [62] Inflammation also has further downstreameffects on the neurogenic cascade For instance LPS increasesthe number of thin dendritic spines and the expressionof the excitatory synapses marker ldquopostsynaptic densityprotein of 95kDardquo (PSD95) in newborn neurons LPS inaddition increases the expression ofGABAA receptors at earlystages of synapse formation leading to suggesting a possible
4 Neural Plasticity
imbalance of excitatory and inhibitory neurotransmissionin these young neurons [63] Finally LPS also prevents theintegration of newborn neurons into behaviourally relevantnetworks including most notably their activation duringspatial exploration as determined by the percentage of BrdUcells colabeled with the immediate early gene Arc [64]
Importantly none of these manipulations is specific tomicroglia and may directly or indirectly affect other braincells involved in the inflammatory response of the brain Forinstance both LPS andminocycline affect astrocytic functionin vitro and in vivo [65ndash69] Furthermore LPS is knownto drive infiltration of monocytes and neutrophils into thebrain parenchyma [70] Monocytes and neutrophils producemajor proinflammatorymediators and could therefore act onthe neurogenic cascade as well The implication of microgliain LPS-induced decrease in neurogenesis is nonethelesssupported in vivo by the negative correlation between thenumber of newborn neurons (BrdU+ NeuN+ cells) andthe number of ldquoactivatedrdquo microglia (ie expressing ED1)[60] ED1 also called CD68 or macrosialin is a lysosomalprotein which is overexpressed during inflammatory chal-lenge While the location of ED1 previously suggested itsinvolvement in phagocytosis its loss of function did not resultin phagocytosis deficits and thus its function still remainsunknown (reviewed in [10]) The number of ED1-positivemicroglia also negatively correlates with neurogenesis duringinflammation provoked by cranial irradiation [61] Whilecorrelation does not involve causation nor can pinpoint tothe underlying mechanism these experiments were the firstto reveal a potential role for ldquoactivatedrdquo microglia in theregulation of adult hippocampal neurogenesis More directevidence of microglial mediation in LPS deleterious effectswas obtained from in vitro experiments as it was shown thatconditionedmedia fromLPS-challengedmicroglia containedIL-6 which in turn caused apoptosis of neuroblasts [61]Nonetheless astrocytes can also release IL-6 when stimulatedwith TNF120572 or IL-1120573 [71] and chronic astrocytic releaseof IL-6 in transgenic mice reduced proliferation survivaland differentiation of newborn cells thus resulting in anet decrease in neurogenesis [72] In summary while thedetrimental impact of inflammation on neurogenesis is wellestablished more work is needed to define the specific rolesplayed by the various inflammatory cells populating thebrain
4 Inflammation Associated withChronic Stress
Across health and disease the most prevalent condi-tion that is associated with neuroinflammation is ldquochronicstressrdquo which commonly refers to the repeated or sus-tained inability to cope with stressful environmental socialand psychological constraints Chronic stress is character-ized by an imbalanced secretion of glucocorticoids by thehypothalamic-pituitary-adrenal (HPA) axis (most notablycortisol in humans and corticosterone in rodents) whichleads to an altered brain remodelingmassive loss of synapsesand compromised cognitive function [73] In particular an
impairment of spatial learning working memory noveltyseeking and decision making has been associated withchronic stress [74] Glucocorticoids are well known fortheir anti-inflammatory properties as they interfere withNF-120581B-mediated cytokine transcription ultimately delayingwound healing [75] They are also potent anti-inflammatorymediators in vivo [76] and in purified microglia cultures[77] Recently repeated administration of high doses ofglucocorticoids by intraperitoneal injection to mimic theirrelease by chronic stress was also shown to induce a lossof dendritic spines in the motor cortex while impairinglearning of a motor task A transcription-dependent pathwayacting downstream of the glucocorticoid receptor GR wasproposed [78 79] but the particular cell types involved werenot identified
Microglia are considered to be a direct target of the gluco-corticoids as they were shown to express GR during normalphysiological conditions in vivo [77] In fact transgenic micelacking GR in microglia and macrophages show an increasedproduction of proinflammatory mediators (including TNF120572and IL-1120573) and greater neuronal damage in response to anintraparenchymal injection of LPS compared to wild-typemice [80] In contrast glucocorticoids are considered to beproinflammatory in the chronically stressed brain [81] whereamong other changes they can promote inflammation oxida-tive stress neurodegeneration andmicroglial activation [82]For example repeated restraint stress induces microglialproliferation and morphological changes including a hyper-ramification of their processes in the adult hippocampusfollowing restraint stress [83] but a nearly complete lossof processes in the context of social defeat [84] Prenatalrestraint stress also causes an increase in the basal levels ofTNF120572 and IL-1120573 while increasing the proportion ofmicrogliashowing a reactive morphology in the adult hippocampus[85] Similarly social defeat leads to an enhanced responseto the inflammatory challenge induced by intraperitonealinjection of LPS including an increased production of TNF120572and IL-1120573 and expression of inducible NO synthase (iNOS)by microglia accompanied by an increased infiltration ofcirculating monocytes [84 86] Therefore microglia are astrong candidate for mediating some of the effects of stresson adult neurogenesis as will be discussed below in synergywith other types of inflammatory cells
Chronic stress is well known for its negative effects onhippocampal neurogenesis (reviewed in [87 88]) althoughnot all stress paradigms are equally effective [89] Severalstress paradigms can decrease neuroprogenitors proliferationin the tree shrew [90] and inmice [91 92] although this effectseems to be compensated by an increased survival of newbornneurons [92] and whether stress results in a net increaseor decrease in neurogenesis remains controversial (reviewedin [87 88]) The effects of stress on adult neurogenesisseem to be mediated at least partially by glucocorticoidsbecause mice lacking a single copy of the GR gene showbehavioural symptoms of depression including learned help-lessness neuroendocrine alterations of the HPA axis andimpaired neurogenesis [93] In parallel chronic stress isassociated with an increased inflammatory response whichmay inhibit neurogenesis as well For instance serum levels
Neural Plasticity 5
of IL-1120573 and IL-6 are significantly increased in depressedpatients [94] In mice restraint stress leads to a widespreadactivation of NF-120581B in the hippocampus including at thelevel of neuroprogenitors [95] and increased protein levels ofIL-1120573 [96] In addition to the direct role of glucocorticoidsIL-1120573 also seems to mediate some of the effects of mildchronic stress because in vivomanipulations that block IL-1120573(either pharmacologically or in null transgenic mice) preventthe anhedonic stress response and the antineurogenic effectof stress [91 96]Moreover the corticoids and IL-1120573 pathwaysmay regulate each other in a bidirectional manner becausethe administration of a GR antagonist can blunt the LPS-induced production of hippocampal IL-1120573 in stressed mice[97] whereas mice knockout for the IL-1120573 receptor (IL-1R1)fail to display the characteristic elevation of corticosteroneinduced by mild chronic stress [96] Another stress-relatedcytokine IL-6 induces depressive phenotypes and preventsthe antidepressant actions of fluoxetinewhen administered tomice in vivo [98] So far the effects of stress on neurogenesisvia corticosteroids and inflammation have been assumed tobe cell autonomous as neuroprogenitors express both GR[99] and IL-1R1 [95] The potential participation of microgliais yet to be determined but there are some reports of adirect effect of stress on microglial activation For instancemicroglia acutely isolated frommice subjected to acute stress(by inescapable tail shock) showed a primed response to LPSchallenge by producing higher levels of IL-1120573mRNA ex vivo[100] and the specific loss of expression of GR in microglialeads to a blunted inflammatory response in vitro and to adecreased neuronal damage in vivo in response to LPS [80]In stress paradigms these enhanced responses of microgliato inflammatory challenges are similar to their age-relatedldquoprimingrdquo which has been associated with and is possiblydue to an increased basal production of proinflammatorymediators However whether microglia express increasedlevels of IL-1120573 and other proinflammatory cytokines inresponse to stressful events is presently unclear [101] It is thuspossible that some of the antineurogenic effects of stress areexerted bymeans of microglial-dependent inflammation butthis hypothesis remains to be experimentally tested
5 Inflammation Associated with Aging andNeurodegenerative Diseases
Inflammation is also commonly associated with normalaging and neurodegenerative diseases and therefore couldrepresent a putative underlying mechanism that explainstheir decrease in hippocampal neurogenesis Nonethelessinflammation is also associated with neurological diseasessuch as epilepsy or stroke where neurogenesis is thought tobe increased although the data from rodents and humans issomewhat conflictive [102] Neurogenesis is well known todecline throughout adulthood and normal aging in rodentsand humans [103 104] but the decay ismore pronounced andoccurs later in life in mice than in humans [105] The aging-associated decrease in neurogenesis has been shown to occurmainly as a consequence of exhaustion of the rNSC popula-tion which after being recruited and activated undergo three
rounds of mitosis in average and then terminally differentiateinto astrocytes [12 106] In addition a reduced mitoticcapacity of the neuroprogenitors could further contribute todecreasing neurogenesis [106] and moreover an age-relatedincrease in the levels of proinflammatory cytokines couldalso hinder neurogenesis in the aging brain Serum levelsof IL-1120573 IL-6 and TNF120572 are elevated in elderly patients[107 108] Aged microglia express higher levels of theseproinflammatory cytokines and show a greater response toLPS inflammatory challenge that is a ldquoprimedrdquo responsethan their younger counterparts [109] The origin of thislow-grade age-related inflammation (ldquoinflamm-agingrdquo [110])remains unknown and may be related to both aging anddamage to the surrounding neurons as well as aging of theimmune system per se
At the cellular level stress to the endoplasmic reticulum(ER) caused by various perturbations such as nutrient deple-tion disturbances in calcium or redox status or increasedlevels of misfolded proteins can induce a cell-autonomousinflammatory response to neurons Stress to the ER a mul-tifunctional organelle which is involved in protein foldinglipid biosynthesis and calcium storage triggers a homeostaticresponse mechanism named the unfolding protein response(UPR) aiming to clear the unfolded proteins in order torestore normal ER homeostasis [111] However if the ERstress cannot be resolved theUPR also initiates inflammatoryand apoptotic pathways via activation of the transcriptionfactor NF-120581B which controls the expression of most proin-flammatory cytokines [112] In the brain ER stress is ofteninitiated by the formation of abnormal protein aggregatesin several neurodegenerative diseases such as Alzheimerrsquosdisease (AD) Parkinsonrsquos disease (PD) amyotrophic lateralsclerosis (ALS) Huntingtonrsquos disease (HD) and prion-relateddisorders [113] This neurodegeneration-associated ER stressis assumed to occur mostly in neurons but there aresome examples of microglial protein misfolding as well Forinstance both microglia and neurons overexpress CHOP(CEBP homologous protein) a transcription factor whichis activated during ER stress in human patients and mousemodels of ALS [114] Inflammation has been speculated tobe a main negative contributor to the pathology of ALS[115] but a direct microglial involvement in mediating theinflammatory response to abnormal protein aggregation inALS and other neurodegenerative conditions remains to betested Finally ER stress has been linked to a variety of inflam-matory conditions [116 117] including chronic stress diet-induced obesity and drug abuse as well as atherosclerosisand arthritis [118ndash120] During normal aging a progressivedecline in expression and activity of key ER molecularchaperones and folding enzymes could also compromise theadaptive response of the UPR thereby contributing to theage-associated decline in cellular functions [118] Thereforeaging is strongly associated with a chronic ER stress whichleads to increased activation of NF-120581B [112] however thecontribution of the different brain cell types to ldquoinflamm-agingrdquo is still poorly understood The detrimental effects onneurogenesis of increased proinflammatory cytokines in theaging brain are not necessarily related to microglia but alsoto stressed neurons Furthermore ER stress may also cause a
6 Neural Plasticity
cell-autonomous response in neural stem cells [121] althoughits impact on neurogenesis remains to be experimentallydetermined
In addition aging is accompanied by an increased levelof mitochondrial oxidative stress which in turn activatesthe ldquoInflammasomerdquo [122] a group of multimeric proteinscomprising the interleukin 1 converting enzyme (ICE cas-pase 1) which serves to release the active form of thecytokine [123] IL-1120573 may act directly on rNSCs (visualisedby labeling with the Sox2 marker) as they express IL-1R1 in the adult hippocampus [91] Treatment with IL-1120573decreases hippocampal proliferation in young mice [91] andpharmacological inhibition of ICE partially restores the num-ber of newborn neurons in aged mice without significantlyaffecting their differentiation rate [124] Transgenic IL-1120573overexpression results in chronic inflammation and deple-tion of doublecortin-labeled neuroblasts thus mimickingthe aging-associated depletion of neurogenesis [125] Theactual mechanism of action of IL-1120573 on neurogenesis inaged mice including decreased proliferation of rNSCsANPsand survival of newborn neurons remains undeterminedMicroglia are a main source of IL-1120573 in the aging brain butthe hypothesis that microglia-derived IL-1120573 is responsiblefor depleting neurogenesis in the aging brain remains to bedirectly tested
The regulation of neurogenesis by IL-1120573 in the agingbrain has been further linked to the activity of anothercytokine the chemokine fractalkine or CX3CL1 Fractalkinehas soluble and membrane-tethered forms and is exclu-sively expressed by neurons while the fractalkine receptor(CX3CR1) is expressed in the brain by microglia alone [126]Thismodule forms a unique neuron-microglia signalling unitthat controls the extent of microglial inflammation in severalneurodegenerative conditions including PD ALS [127] orAD [128] In fact CX3CR1 blocking antibodies increasethe production of hippocampal IL-1120573 when administeredto young adult rats [129] Importantly chronic treatmentwith fractalkine increases hippocampal proliferation and thenumber of neuroblasts in aged (22 months old) but notyoung (3 months old) or middle-aged rats (12 months old)whereas an antagonists of CX3CR1 has the opposite effectsin young but not in middle-aged nor old rats [129] Sincefractalkine expression is decreased during aging [129] areduced neuron-microglia signalling might be releasing thebrake on microglial contribution to inflammatory responsesalthough increased levels of fractalkine were instead reportedin aged rat hippocampus by other studies [68] Additionalinsights into the role of fractalkine signalling come fromknock-in mice in which the endogenous CX3CR1 locus isreplaced by the fluorescent reporter GFP [126] The initialstudies suggested that CX3CR1GFPGFP (ie CX3CR1minusminus)mice have no significant differences in brain development andfunctions [130] but more systematic investigations recentlyrevealed a long list of hippocampal-dependent changes inyoung (3 months old) CX3CR1GFPGFP and CX3CR1GFP+mice compared to wild-type mice These changes notablyincluded decreased neuroprogenitors proliferation and neu-roblasts number impaired LTP performance in contextual
fear conditioning and water maze spatial learning and mem-ory and importantly increased IL-1120573 protein levels [131]Thesignalling pathway of fractalkine-IL-1120573 is functionally rele-vant because IL-1R1 antagonists rescued LTP and cognitivefunction in CX3CR1GFPGFP mice [131] In sum even thoughneuronal fractalkine seems to be sufficient for restrainingthe inflammatory activity of microglia in young rats itsdownregulation during aging could activate the microglialinflammatory response and thereby subsequently reduce theproliferation of remaining neuroprogenitors
In AD inflammatory cytokines such as IL-1120573 are over-expressed in the microglia associated with the amyloid beta(A120573) plaques of postmortem samples [132] and in transgenicmice modeling the disease [133] The loss of synapses (fromhippocampus to frontal cortex) is one of the main patho-logical substrates in this disease but adult neurogenesis isalso severely reduced in most mouse models of AD possiblydue to a decreased proliferation of neuroprogenitors and adecreased survival of newborn cells even though the putativechanges in the neurogenic cascade in postmortem samplesremain controversial (reviewed in [102]) This lack of agree-ment is possibly explained by the fact that the vast majorityof AD cases have a late onset over 65 years of age when littleneurogenesis remains In contrast in most transgenic ADmouse models the A120573 accumulation cognitive deficits andchanges in neurogenesis are already detectable in young ani-mals (2-3 months old) The study of AD is further hinderedby the difficulty in comparing the time course and pathologyacross different mouse models For instance early treatmentwith minocycline can improve cognition and reduce A120573burden in mice expressing the human amyloid precursorprotein (APP) [134] In contrast in mice expressing APP anda mutated form of presenilin 1 (PS1) which is part of the 120574secretase pathway that cleaves A120573 inflammation is reducedwithout any detectable changes in A120573 plaques deposition[135] Concomitantly with a decrease in tissue inflamma-tory cytokines and number of microglial cells minocyclinerestores neurogenesis and hippocampus-dependent memorydeficits in these APPPS1 mice [135] indirectly suggestingthat cognitive decay in AD may be at least in part relatedto a detrimental effect of inflammation on hippocampalneurogenesis Direct evidence that neurogenesis is associatedwith the cognitive performance in AD is still lacking Furtherresearch is also necessary to determine the neurogenic targetsof AD-related inflammation One central open questionfor future therapies aiming at increasing neurogenesis andcognition in AD is whether neuroprogenitors are spared orwhether their age-induced loss becomes accelerated Ratherthan increasing the proliferation and neurogenic output ofthe few rNSCs remaining in an old AD brain it may be morerelevant to develop strategies that prevent the age-related lossof neuroprogenitors in presymptomatic patients
In summary inflammation associated with a wide varietyof experimental models of disease produces strong detri-mental effects on hippocampal neurogenesis These effectson human neurogenesis are however not so well describedand in vitro IL-1120573 increases the proliferation of hip-pocampal embryonic neuroprogenitors but decreases their
Neural Plasticity 7
differentiation into neurons [136] Novel methods to assesshippocampal neurogenesis in the living human brain frommetabolomics of neuroprogenitors to hippocampal bloodbrain volume (reviewed in [102]) will help to determine thecontribution of inflammation to adult neurogenesis in thehealthy and diseased human brain during aging
6 Normal Physiological Conditions
In the healthy mature brain microglia are an essential com-ponent of the neurogenic SGZ niche where they physicallyintermingle with neuroprogenitors neuroblasts and new-born neurons [62] Here surveillant microglia effectively andrapidly phagocytose the excess of newborn cells undergoingapoptosis [62] Importantly microglial phagocytosis in theadult SGZ is not disturbed by inflammation associated withaging or by LPS challenge as the phagocytic index (iethe proportion of apoptotic cells completely engulfed bymicroglia) is maintained over 90 in these conditions [62]Nonetheless the consequences of microglial phagocytosis onadult hippocampal neurogenesis remain elusive Treatment ofmice with annexin V which binds to the phosphatidylserine(PS) receptor and prevents the recognition of PS on thesurface of apoptotic cells presumably blocking phagocytosisincreases the number of apoptotic cells in the SGZ [40] Con-comitantly annexin V reduces neurogenesis by decreasingthe survival of neuroblasts without affecting neuroprogeni-tors proliferation [40] Similar results were obtained in trans-genic mice knock-out for ELMO1 a cytoplasm protein whichpromotes the internalization of apoptotic cells althoughthe effects on neurogenesis were ascribed to a decreasedphagocytic activity of neuroblasts [40]The actual phagocytictarget of the neuroblasts remains undetermined but thenewborn apoptotic cells in the adult SGZ are exclusivelyphagocytosed by microglia at least in physiological condi-tions [62] Nevertheless none of the above manipulationshas specifically tested the role of microglial phagocytosisin hippocampal-dependent learning and memory and thusthe functional impact of microglial phagocytosis in adultneurogenic niches during normal physiological conditionsremains to be elucidated
Microglial phagocytosis of apoptotic cells is activelyanti-inflammatory at least in vitro and thus it has beenhypothesized that anti-inflammatory cytokines produced byphagocytic microglia may further regulate neurogenesis [10]For instance transforming growth factor beta (TGF120573) whichis produced by phagocytic microglia in vitro [137] inhibitsthe proliferation of SGZ neuroprogenitors [138] Microgliaare further able to produce proneurogenic factors in vitro[139] When primed with cytokines associated with T helpercells such as interleukin 4 (IL-4) or low doses of interferongamma (IFN120574) culturedmicroglia support neurogenesis andoligodendrogenesis through decreased production of TNF120572and increased production of insulin-like growth factor 1(IGF-1) [139] an inducer of neuroprogenitor proliferation[26] A list of potential factors produced by microgliaand known to act on neuroprogenitor proliferation can
be found in Table 1 In addition recent observations sug-gest that neuroprogenitor cells may not only regulate theirown environment but also influence microglial functionsFor instance vascular endothelial growth factor (VEGF)produced by cultured neuroprecursor cells directly affectsmicroglial proliferation migration and phagocytosis [20]More potential factors produced by neuroprogenitors shownto be influencing microglial activity and function can befound in Table 2 However it has to be taken into accountthat most of these observations were obtained in culture andthat further research is needed in order to elucidate whetherthose factors are also secreted and have the same regulatoryresponses in vivo
In addition microglial capacity to remodel and eliminatesynaptic structures during normal physiological conditionshas suggested that microglia could also control the synap-tic integration of the newborn neurons generated duringadult hippocampal neurogenesis [140] Three main mech-anisms were proposed (1) the phagocytic elimination ofnonapoptotic axon terminals and dendritic spines (2) theproteolytic remodeling of the perisynaptic environmentand (3) the concomitant structural remodeling of dendriticspines [7 140] Indeed microglial contacts with synapticelements are frequently observed in the cortex during normalphysiological conditions sometimes accompanied by theirengulfment and phagocytic elimination [141ndash143] as in thedeveloping retinogeniculate system [144] Microglial cells aredistinctively surrounded by pockets of extracellular spacecontrarily to all the other cellular elements [142] suggestingthat microglia could remodel the volume and geometryof the extracellular space and thus the concentration ofvarious ions neurotransmitters and signalling moleculesin the synaptic environment Whether microglia create thepockets of extracellular space themselves or not remainsunknown but these pockets could result from microglialrelease of extracellular proteases such as metalloproteinasesand cathepsins [145] which are well known for influencingthe formation structural remodeling and elimination ofdendritic spines in situ and also experience-dependent plas-ticity in vivo [7 146] More recently microglial phagocytosisof synaptic components was also observed in the developinghippocampus in the unique time window of synaptogenesisa process which is notably regulated by fractalkine-CX3CR1signalling [147] Therefore the attractive hypothesis thatmicroglial sculpts the circuitry of newborn cells in the adulthippocampus deserves further attention
Lastly microglia were also involved in increasing adulthippocampal neurogenesis in the enriched environment(EE) experimental paradigm EE is a paradigm mimick-ing some features of the normal living circumstances ofwild animals as it gives them access to social interactionstoys running wheels and edible treats EE has long beenknown to enhance neurogenesis by acting on newborncells survival resulting ultimately in an enlargement ofthe dentate gyrus [148] Functionally these changes areaccompanied by enhanced spatial learning and memoryformation with the water maze paradigm [149] Similarincreases in neurogenesis are obtained by subjecting miceto voluntary running paradigms although in this case the
8 Neural Plasticity
Table 1 Summary of factors secreted by microglia and the potential effect they have on neuroprogenitors in vitro
Microglia secreted factors Reference Modulation of neural progenitor cells ReferenceBDNF [18] Differentiation [19]EGF [20] Survival expansion proliferation differentiation [21]FGF120573 [22] Survival and expansion [23]GDNF [24] Survival migration and differentiation [25]IGF-1 [21] Proliferation [26]IL-1120573 [27] Reduction in migration [27]IL-6 [28] Inhibition of neurogenesis [29]IL-7 [20] Differentiation [30]IL-11 [20] Differentiation [30]NT-4 [24] Differentiation [31]PDGF [32] Expansion and differentiation [33]TGF120573 [34] Inhibition of proliferation [19]
Table 2 Summary of factors secreted by neuroprogenitors and the potential effect they have on microglia in vitro
NPC secreted factors Reference Modulation of microglia ReferenceBDNF [18] Proliferation and induction of phagocytic activity [35]Haptoglobin [24] Neuroprotection [36]IL-1120573 [37] Intracellular Ca+2 elevation and proliferation [22]IL-6 [37] Increase in proliferation [38]M-CSF [20] Mitogen [39]NGF [40] Decrease in LPS-induced NO [41]TGF120573 [37] Inhibition of TNF120572 secretion [42]TNF120572 [37] Upregulation of IL-10 secretion [43]VEGF [20] Induction of chemotaxis and proliferation [20]
effect is mediated by increased neuroprogenitor proliferation[150] During inflammatory conditions EE is antiapoptoticand neuroprotective [151] and it limits the hippocampalresponse to LPS challenge by decreasing the expression ofseveral cytokines and chemokines including IL1-120573 andTNF120572[152] In fact EE is believed to counteract the inflammatoryenvironment and rescue the decreased number of neuroblastsin CX3CR1GFPGFP mice compared to wild-type mice [153]The effects of EE are independent of the IL-1120573 signallingpathway as it increases neurogenesis in mice that are nullfor IL-1R1 [154] EE also induces microglial proliferation andexpression of the proneurogenic IGF-1 [155] but the fullphenotype of microglia in EE compared to standard housingand its impact on the neurogenic cascade remains to bedetermined
The mechanisms behind the anti-inflammatory actionsof EE are unknown but they were suggested to involvemicroglial interactions with T lymphocytes through anincreased expression of themajor histocompatibility complexof class II (MHC-II) during EE [155] MHC-II is responsiblefor presenting the phagocytosed and degraded antigens tothe antibodies expressed on the surface of a subtype ofT lymphocytes (T helper or CD4+ cells) thus initiatingtheir activation and production of antigen-specific antibod-ies Severe combined immunodeficient (SCID) mice lackingeither T and B lymphocytes or nude mice lacking only Tcells have impaired proliferation and neurogenesis in normal
and EE housing compared to wild-type mice [155] as wellas impaired performance in the water maze [156] Similarlyantibody-based depletion of T helper lymphocytes impairsbasal and exercise-induced proliferation and neurogenesis[157] Furthermore a genetic study in heterogeneous stockmice which descend from eight inbred progenitor strainshas found a significant positive correlation between geneticloci associated to hippocampal proliferation and to theproportion of CD4+ cells among blood CD3+ lymphocytes[158] Additional experiments are needed to fully determinethe possible interactions between microglia and T cellsin neurogenesis because at least in normal physiologicalconditions (1) T cell surveillance of the brain parenchymais minimal (2) microglia are poor antigen presenting cellsand (3) antigen presentation by means of MHC-II family ofmolecules is thought to occur outside the brain that is in themeninges and choroid plexus [159] In fact during voluntaryexercise there are no significant changes in T cell surveillanceof the hippocampus nor a direct interaction between T cellsand microglia nor any changes in the gene expression profileof microglia including that of IGF-1 IL-1120573 and TNF120572 [160]The number of microglia is also inversely correlated withthe number of hippocampal proliferating cells rNSCs andneuroblasts in aged (8 months) mice subjected to voluntaryrunning as well as in vitro cocultures of microglia andneuroprogenitors which has been interpreted as resultingfrom an overall inhibitory effect of microglia on adult
Neural Plasticity 9
neurogenesis [161] Even though EE is clearly a more com-plex environmental factor than voluntary running furtherresearch is necessary to disregard nonspecific or indirecteffects of genetic or antibody-based T cells depletion onmicroglia and other brain cell populations including rNSCsFor instance adoptive transfer of T helper cells treated withglatiramer acetate a synthetic analog of myelin basic protein(MBP) approved for the treatment of multiple sclerosis pro-duces a bystander effect on resident astrocytes and microgliaby increasing their expression of anti-inflammatory cytokinessuch as TGF120573 [162] Alternatively it has been suggested thatT cells may mediate an indirect effect on adult hippocampalneurogenesis by increasing the production of brain-derivedneurotrophic factor (BDNF) [157] which is involved in theproneurogenic actions of EE [163] Whether BDNF cancounteract the detrimental effects of T cell depletion on neu-rogenesis remains unknownOverall the roles ofmicroglia inEE and running-induced neurogenesis are unclear and haveto be addressed with more precise experimental designs Insummary surveillant microglia are part of the physical nichesurrounding the neural stem cells and newborn neurons ofthe mature hippocampus where they continuously phagocy-tose the excess of newborn cellsMicroglia were also linked tothe proneurogenic and anti-inflammatory effects of voluntaryrunning and EE but direct evidence is missing The overallcontribution of microglia to neurogenesis and learning andmemory in normal physiological conditions remains largelyunexplored at this early stage in the field
7 Conclusion
In light of these observations microglia are now emergingas important effector cells during normal brain developmentand functions including adult hippocampal neurogenesisMicroglia can exert a positive or negative influence onthe proliferation survival or differentiation of newborncells depending on the inflammatory context For instancemicroglia can compromise the neurogenic cascade duringchronic stress aging and neurodegenerative diseases bytheir release of proinflammatory cytokines such as IL-1120573IL-6 and TNF120572 A reduced fractalkine signalling betweenneurons and microglia could also be involved during normalaging However microglia are not necessarily the only celltype implicated because astrocytes endothelial cells mastcells perivascular and meningeal macrophages and to alesser extent neurons and invading peripheral immune cellscould further contribute by releasing proinflammatorymedi-ators
Additionally microglia were shown to phagocytose theexcess of newborn neurons undergoing apoptosis in thehippocampal neurogenic niche during normal physiologicalconditions while a similar role in the synaptic integrationof newborn cells was also proposed in light of their capacityto phagocytose synaptic elements Lastly microglial interac-tions with T cells leading to the release of anti-inflammatorycytokines neurotrophic factors and other proneurogenicmediators (notably during EE and voluntary running) couldcounteract the detrimental effects of inflammation on adult
hippocampal neurogenesis and their functional implicationsfor learning and memory
However further research is necessary to assess the rela-tive contribution of microglia versus other types of residentand infiltrating inflammatory cells and to determine thenature of the effector cytokines and other inflammatorymediators involved as well as their cellular andmolecular tar-gets in the neurogenic cascade Such research will undoubt-edly help to develop novel strategies aiming at protecting theneurogenic potential and ultimately its essential contributionto learning and memory
The authors declare that there is no conflict of interestsregarding the publication of this paper
Acknowledgments
This work was supported by grants from the Spanish Min-istry of Economy and Competitiveness to Amanda Sierra(BFU2012-32089) and Juan M Encinas (SAF2012-40085)from Basque Government (Saiotek S-PC 12UN014) and Iker-basque start-up funds to JuanM Encinas andAmanda Sierraand fromTheBanting Research Foundation the Scottish RiteCharitable Foundation of Canada and start-up funds fromUniversite Laval andCentre de recherche duCHUdeQuebecto Marie-Eve Tremblay
References
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[2] F Ginhoux S Lim G Hoeffel D Low and T Huber ldquoOriginand differentiation of microgliardquo Frontiers in Cellular Neuro-science vol 7 article 45 2013
[3] E Gomez Perdiguero C Schulz and F Geissmann ldquoDevelop-ment and homeostasis of ldquoresidentrdquomyeloid cells the case of themicrogliardquo GLIA vol 61 no 1 pp 112ndash120 2013
[4] H Kettenmann F Kirchhoff and A Verkhratsky ldquoMicroglianew roles for the synaptic stripperrdquo Neuron vol 77 no 1 pp10ndash18 2013
[5] A Aguzzi B A Barres and M L Bennett ldquoMicroglia scape-goat saboteur or something elserdquo Science vol 339 no 6116 pp156ndash161 2013
[6] K Helmut U K Hanisch M Noda and A VerkhratskyldquoPhysiology of microgliardquo Physiological Reviews vol 91 no 2pp 461ndash553 2011
[7] M E Tremblay B Stevens A Sierra H Wake A Bessis andA Nimmerjahn ldquoThe role of microglia in the healthy brainrdquoJournal of Neuroscience vol 31 no 45 pp 16064ndash16069 2011
[8] A Miyamoto H Wake A J Moorhouse and J NabekuraldquoMicroglia and synapse interactions fine tuaning neural circuitsand candidate moleculesrdquo Frontiers in Cellular Neurosciencevol 7 article 70 2013
[9] C Bechade Y Cantaut-Belarif and A Bessis ldquoMicroglialcontrol of neuronal activityrdquo Frontiers in Cellular Neurosciencevol 7 article 32 2013
[10] A Sierra O Abiega A Shahraz and H Neumann ldquoJanus-faced microglia beneficial and detrimental consequences ofmicroglial phagocytosisrdquo Frontiers in Cellular Neuroscience vol7 article 6 2013
[11] G Kempermann S Jessberger B Steiner and G KronenbergldquoMilestones of neuronal development in the adult hippocam-pusrdquo Trends in Neurosciences vol 27 no 8 pp 447ndash452 2004
[12] J M Encinas T V Michurina N Peunova et al ldquoDivision-coupled astrocytic differentiation and age-related depletion ofneural stem cells in the adult hippocampusrdquo Cell Stem Cell vol8 no 5 pp 566ndash579 2011
[13] M A Bonaguidi M A Wheeler J S Shapiro et al ldquoIn vivoclonal analysis reveals self-renewing and multipotent adultneural stem cell characteristicsrdquo Cell vol 145 no 7 pp 1142ndash1155 2011
[14] J J Breunig J I Arellano J D Macklis and P RakicldquoEverything that glitters isnrsquot gold a critical review of postnatalneural precursor analysesrdquo Cell Stem Cell vol 1 no 6 pp 612ndash627 2007
[15] L S Overstreet-Wadiche and G L Westbrook ldquoFunctionalmaturation of adult-generated granule cellsrdquoHippocampus vol16 no 3 pp 208ndash215 2006
[16] S Ge C H Yang K S Hsu G L Ming andH Song ldquoA criticalperiod for enhanced synaptic plasticity in newly generatedneurons of the adult brainrdquo Neuron vol 54 no 4 pp 559ndash5662007
[17] E Bruel-Jungerman C Rampon and S Laroche ldquoAdult hip-pocampal neurogenesis synaptic plasticity and memory factsand hypothesesrdquo Reviews in the Neurosciences vol 18 no 2 pp93ndash114 2007
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[19] M Krampert S R Chirasani F P Wachs et al ldquoSmad7regulates the adult neural stemprogenitor cell pool in a trans-forming growth factor 120573- and bone morphogenetic protein-independent mannerrdquo Molecular and Cellular Biology vol 30no 14 pp 3685ndash3694 2010
[20] K I Mosher R H Andres T Fukuhara et al ldquoNeural pro-genitor cells regulate microglia functions and activityrdquo NatureNeuroscience vol 15 no 11 pp 1485ndash1487 2012
[21] V Tropepe M Sibilia B G Ciruna J Rossant E F Wagnerand D van der Kooy ldquoDistinct neural stem cells proliferatein response to EGF and FGF in the developing mouse telen-cephalonrdquo Developmental Biology vol 208 no 1 pp 166ndash1881999
[22] S U Kim and J De Vellis ldquoMicroglia in health and diseaserdquoJournal of Neuroscience Research vol 81 no 3 pp 302ndash3132005
[23] B A Reynolds and R L Rietze ldquoNeural stem cells andneurospheresmdashre-evaluating the relationshiprdquoNatureMethodsvol 2 no 5 pp 333ndash336 2005
[24] K Satake Y Matsuyama M Kamiya et al ldquoUp-regulation ofglial cell line-derived neurotrophic factor (GDNF) followingtraumatic spinal cord injuryrdquo NeuroReport vol 11 no 17 pp3877ndash3881 2000
[25] Y M Yoo C J Lee and Y J Kim ldquoExogenous GDNF increasesthe migration of the neural stem cells with no protectionagainst kainic acid-induced excitotoxic cell death in ratsrdquo BrainResearch vol 1486 pp 27ndash38 2012
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Neural Plasticity 11
[27] K Striedinger and E Scemes ldquoInterleukin-1120573 affects calciumsignaling and in vitro cell migration of astrocyte progenitorsrdquoJournal of Neuroimmunology vol 196 no 1-2 pp 116ndash123 2008
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[29] G Kempermann and H Neumann ldquoMicroglia the enemywithinrdquo Science vol 302 no 5651 pp 1689ndash1690 2003
[30] M F Mehler R Rozental M Dougherty D C Spray and JA Kessler ldquoCytokine regulation of neuronal differentiation ofhippocampal progenitor cellsrdquo Nature vol 362 no 6415 pp62ndash65 1993
[31] U Gurok C Steinhoff B Lipkowitz H H Ropers C Scharffand U A Nuber ldquoGene expression changes in the course ofneural progenitor cell differentiationrdquo Journal of Neurosciencevol 24 no 26 pp 5982ndash6002 2004
[32] J B Demoulin M Enarsson J Larsson A Essaghir C HHeldin and K Forsberg-Nilsson ldquoThe gene expression profileof PDGF-treated neural stem cells corresponds to partiallydifferentiated neurons and gliardquo Growth Factors vol 24 no 3pp 184ndash196 2006
[33] F C Mansergh M A Wride and D E Rancourt ldquoNeuronsfrom stem cells implications for understanding nervous systemdevelopment and repairrdquo Biochemistry and Cell Biology vol 78no 5 pp 613ndash628 2000
[34] F C Alcantara Gomes V De Oliveira Sousa and L RomaoldquoEmerging roles for TGF-1205731 in nervous system developmentrdquoInternational Journal of Developmental Neuroscience vol 23 no5 pp 413ndash424 2005
[35] S Elkabes E M DiCicco-Bloom and I B Black ldquoBrainmicrogliamacrophages express neurotrophins that selectivelyregulate microglial proliferation and functionrdquo Journal of Neu-roscience vol 16 no 8 pp 2508ndash2521 1996
[36] U K Hanisch and H Kettenmann ldquoMicroglia active sensorand versatile effector cells in the normal and pathologic brainrdquoNature Neuroscience vol 10 no 11 pp 1387ndash1394 2007
[37] H J Klassen T F Ng Y Kurimoto et al ldquoMultipotent retinalprogenitors express developmental markers differentiate intoretinal neurons and preserve light-mediated behaviorrdquo Inves-tigative Ophthalmology and Visual Science vol 45 no 11 pp4167ndash4173 2004
[38] W J Streit S D Hurley T S McGraw and S L Semple-Rowland ldquoComparative evaluation of cytokine profiles andreactive gliosis supports a critical role for interleukin-6 inneuron-glia signaling during regenerationrdquo Journal of Neuro-science Research vol 61 no 1 pp 10ndash20 2000
[39] A Suzumura M Sawada H Yamamoto and T MarunouchildquoEffects of colony stimulating factors on isolated microglia invitrordquo Journal of Neuroimmunology vol 30 no 2-3 pp 111ndash1201990
[40] Z Lu M R Elliott Y Chen et al ldquoPhagocytic activity ofneuronal progenitors regulates adult neurogenesisrdquoNature CellBiology vol 13 no 9 pp 1076ndash1084 2011
[41] K Nakajima Y Kikuchi E Ikoma et al ldquoNeurotrophinsregulate the function of cultured microgliardquo GLIA vol 24 no3 pp 272ndash289 1998
[42] P A Lodge and S Sriram ldquoRegulation of microglial activationby TGF-120573 IL-10 and CSF-1rdquo Journal of Leukocyte Biology vol60 no 4 pp 502ndash508 1996
[43] W S Sheng S Hu F H Kravitz P K Peterson and C C ChaoldquoTumor necrosis factor alpha upregulates humanmicroglial cell
production of interleukin-10 in vitrordquo Clinical and DiagnosticLaboratory Immunology vol 2 no 5 pp 604ndash608 1995
[44] G LMing andH Song ldquoAdult neurogenesis in themammalianbrain significant answers and significant questionsrdquo Neuronvol 70 no 4 pp 687ndash702 2011
[45] E Bruel-Jungerman S Davis C Rampon and S LarocheldquoLong-term potentiation enhances neurogenesis in the adultdentate gyrusrdquo Journal of Neuroscience vol 26 no 22 pp 5888ndash5893 2006
[46] E Drapeau M F Montaron S Aguerre and D N AbrousldquoLearning-induced survival of new neurons depends on thecognitive status of aged ratsrdquo Journal of Neuroscience vol 27no 22 pp 6037ndash6044 2007
[47] A Mouret G Gheusi M M Gabellec F De Chaumont J COlivo-Marin and P M Lledo ldquoLearning and survival of newlygenerated neurons when timemattersrdquo Journal of Neurosciencevol 28 no 45 pp 11511ndash11516 2008
[48] N Kee C M Teixeira A H Wang and P W FranklandldquoPreferential incorporation of adult-generated granule cellsinto spatial memory networks in the dentate gyrusrdquo NatureNeuroscience vol 10 no 3 pp 355ndash362 2007
[49] F Massa M Koelh T Wiesner et al ldquoConditional reduction ofadult neurogenesis impairs bidirectional hippocampal synapticplasticityrdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 108 no 16 pp 6644ndash6649 2011
[50] T J Shors G Miesegaes A Beylin M Zhao T Rydel and EGould ldquoNeurogenesis in the adult is involved in the formationof tracememoriesrdquoNature vol 410 no 6826 pp 372ndash376 2001
[51] W Deng M D Saxe I S Gallina and F H Gage ldquoAdult-born hippocampal dentate granule cells undergoingmaturationmodulate learning and memory in the brainrdquo Journal of Neuro-science vol 29 no 43 pp 13532ndash13542 2009
[52] M Arruda-Carvalho M Sakaguchi K G Akers S A Josselynand P W Frankland ldquoPosttraining ablation of adult-generatedneurons degrades previously acquired memoriesrdquo Journal ofNeuroscience vol 31 no 42 pp 15113ndash15127 2011
[53] A Sahay K N Scobie A S Hill et al ldquoIncreasing adulthippocampal neurogenesis is sufficient to improve patternseparationrdquo Nature vol 472 no 7344 pp 466ndash470 2011
[54] G LMing andH Song ldquoAdult neurogenesis in themammaliancentral nervous systemrdquoAnnual Review of Neuroscience vol 28pp 223ndash250 2005
[55] K Newton and V M Dixit ldquoSignaling in innate immunity andinflammationrdquo Cold Spring Harbor Perspectives in Biology vol4 no 3 2012
[56] H K Jeong K Ji K Min and E H Joe ldquoBrain inflammationand microglia facts and misconceptionsrdquo Experimental Neuro-biology vol 22 no 2 pp 59ndash67 2013
[57] D Stellwagen and R CMalenka ldquoSynaptic scalingmediated byglial TNF-120572rdquo Nature vol 440 no 7087 pp 1054ndash1059 2006
[58] M Pickering D Cumiskey and J J OrsquoConnor ldquoActions of TNF-120572 on glutamatergic synaptic transmission in the central nervoussystemrdquo Experimental Physiology vol 90 no 5 pp 663ndash6702005
[59] K Belarbi T Jopson D Tweedie et al ldquoTNF-120572 protein synthe-sis inhibitor restores neuronal function and reverses cognitivedeficits induced by chronic neuroinflammationrdquo Journal ofNeuroinflammation vol 9 article 23 2012
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12 Neural Plasticity
[61] M L Monje H Toda and T D Palmer ldquoInflammatoryblockade restores adult hippocampal neurogenesisrdquo Sciencevol 302 no 5651 pp 1760ndash1765 2003
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[63] D Chugh P Nilsson S A Afjei A Bakochi and C T EkdahlldquoBrain inflammation induces post-synaptic changes duringearly synapse formation in adult-born hippocampal neuronsrdquoExperimental Neurobiology vol 250 pp 176ndash188 2013
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[65] S Johann E Kampmann B Denecke et al ldquoExpression ofenzymes involved in the prostanoid metabolism by corticalastrocytes after LPS-induced inflammationrdquo Journal of Molec-ular Neuroscience vol 34 no 2 pp 177ndash185 2008
[66] P V B Reddy K V Rama Rao and M D NorenbergldquoInhibitors of the mitochondrial permeability transition reduceammonia-induced cell swelling in cultured astrocytesrdquo Journalof Neuroscience Research vol 87 no 12 pp 2677ndash2685 2009
[67] H Nie H Zhang and H R Weng ldquoMinocycline preventsimpaired glial glutamate uptake in the spinal sensory synapsesof neuropathic ratsrdquo Neuroscience vol 170 no 3 pp 901ndash9122010
[68] F Cerbai D Lana D Nosi et al ldquoThe neuron-astrocyte-microglia triad in normal brain ageing and in a model ofneuroinflammation in the rat hippocampusrdquo PLoS ONE vol 7no 9 Article ID e45250 2012
[69] W J Jin S W Feng Z Feng S M Lu T Qi and Y N QianldquoMinocycline improves postoperative cognitive impairment inaged mice by inhibiting astrocytic activationrdquo NeuroReport2013
[70] K A Ji M S Yang H K Jeong et al ldquoResident microgliadie and infiltrated neutrophils and monocytes become majorinflammatory cells in lipopolysaccharide-injected brainrdquoGLIAvol 55 no 15 pp 1577ndash1588 2007
[71] N J van Wagoner J W Oh P Repovic and E N BenvenisteldquoInterleukin-6 (IL-6) production by astrocytes autocrine reg-ulation by IL-6 and the soluble IL-6 receptorrdquo Journal ofNeuroscience vol 19 no 13 pp 5236ndash5244 1999
[72] L Vallieres I L Campbell F H Gage and P E SawchenkoldquoReduced hippocampal neurogenesis in adult transgenic micewith chronic astrocytic production of interleukin-6rdquo Journal ofNeuroscience vol 22 no 2 pp 486ndash492 2002
[73] B S McEwen ldquoPhysiology and neurobiology of stress andadaptation central role of the brainrdquo Physiological Reviews vol87 no 3 pp 873ndash904 2007
[74] V LuineMVillegas CMartinez and B SMcEwen ldquoRepeatedstress causes reversible impairments of spatial memory perfor-mancerdquo Brain Research vol 639 no 1 pp 167ndash170 1994
[75] S Rivest ldquoMolecular insights on the cerebral innate immunesystemrdquo Brain Behavior and Immunity vol 17 no 1 pp 13ndash192003
[76] S Nadeau and S Rivest ldquoEndotoxemia prevents the cerebralinflammatory wave induced by intraparenchymal lipopolysac-charide injection role of glucocorticoids and CD14rdquo Journal ofImmunology vol 169 no 6 pp 3370ndash3381 2002
[77] A Sierra A Gottfried-Blackmore T A Milner B S McEwenand K Bulloch ldquoSteroid hormone receptor expression andfunction in microgliardquo GLIA vol 56 no 6 pp 659ndash674 2008
[78] C Liston andW B Gan ldquoGlucocorticoids are critical regulatorsof dendritic spine development and plasticity in vivordquo Proceed-ings of the National Academy of Sciences of the United States ofAmerica vol 108 no 38 pp 16074ndash16079 2011
[79] C Liston J M Cichon F Jeanneteau Z Jia M V Chaoand W B Gan ldquoCircadian glucocorticoid oscillations pro-mote learning-dependent synapse formation andmaintenancerdquoNature Neuroscience vol 16 no 6 pp 698ndash705 2013
[80] M A Carrillo-de Sauvage L Maatouk I Arnoux et al ldquoPotentand multiple regulatory actions of microglial glucocorticoidreceptors during CNS inflammationrdquo Cell Death amp Differenti-ation vol 20 no 11 pp 1546ndash1557 2013
[81] S F Sorrells J R Caso C DMunhoz and RM Sapolsky ldquoThestressed CNS when glucocorticoids aggravate inflammationrdquoNeuron vol 64 no 1 pp 33ndash39 2009
[82] M A Bellavance and S Rivest ldquoThe neuroendocrine controlof the innate immune system in health and brain diseasesrdquoImmunological Reviews vol 248 no 1 pp 36ndash55 2012
[83] R J Tynan S Naicker M Hinwood et al ldquoChronic stress altersthe density and morphology of microglia in a subset of stress-responsive brain regionsrdquo Brain Behavior and Immunity vol24 no 7 pp 1058ndash1068 2010
[84] E S Wohleb N D Powell J P Godbout and J F SheridanldquoStress-induced recruitment of bone marrow-derived mono-cytes to the brain promotes anxiety-like behaviorrdquo The Journalof Neuroscience vol 33 no 34 pp 13820ndash13833 2013
[85] Y Diz-Chaves M Astiz M J Bellini and L M Garcia-SeguraldquoPrenatal stress increases the expression of proinflammatorycytokines and exacerbates the inflammatory response to LPS inthe hippocampal formation of adultmalemicerdquoBrain Behaviorand Immunity vol 28 pp 196ndash206 2013
[86] E S Wohleb A M Fenn A M Pacenta N D Powell J FSheridan and J P Godbout ldquoPeripheral innate immune chal-lenge exaggerated microglia activation increased the numberof inflammatory CNSmacrophages and prolonged social with-drawal in socially defeated micerdquo Psychoneuroendocrinologyvol 37 no 9 pp 1491ndash1505 2012
[87] C Mirescu and E Gould ldquoStress and adult neurogenesisrdquoHippocampus vol 16 no 3 pp 233ndash238 2006
[88] J LWarner-Schmidt andR SDuman ldquoHippocampal neuroge-nesis opposing effects of stress and antidepressant treatmentrdquoHippocampus vol 16 no 3 pp 239ndash249 2006
[89] N D Hanson M J Owens K A Boss-Williams J M Weissand C B Nemeroff ldquoSeveral stressors fail to reduce adulthippocampal neurogenesisrdquo Psychoneuroendocrinology vol 36no 10 pp 1520ndash1529 2011
[90] E Gould B S McEwen P Tanapat L A M Galea and EFuchs ldquoNeurogenesis in the dentate gyrus of the adult treeshrew is regulated by psychosocial stress and NMDA receptoractivationrdquo Journal of Neuroscience vol 17 no 7 pp 2492ndash24981997
[91] JW Koo andR S Duman ldquoIL-1120573 is an essentialmediator of theantineurogenic and anhedonic effects of stressrdquo Proceedings ofthe National Academy of Sciences of the United States of Americavol 105 no 2 pp 751ndash756 2008
[92] D C Lagace M H Donovan N A Decarolis et al ldquoAdulthippocampal neurogenesis is functionally important for stress-induced social avoidancerdquo Proceedings of the National Academy
Neural Plasticity 13
of Sciences of the United States of America vol 107 no 9 pp4436ndash4441 2010
[93] G Kronenberg I Kirste D Inta et al ldquoReduced hippocampalneurogenesis in the GR+- genetic mousemodel of depressionrdquoEuropean Archives of Psychiatry and Clinical Neuroscience vol259 no 8 pp 499ndash504 2009
[94] M B Howren D M Lamkin and J Suls ldquoAssociations ofdepression with c-reactive protein IL-1 and IL-6 a meta-analysisrdquo Psychosomatic Medicine vol 71 no 2 pp 171ndash1862009
[95] J W Koo S J Russo D Ferguson E J Nestler and R SDuman ldquoNuclear factor-120581B is a critical mediator of stress-impaired neurogenesis and depressive behaviorrdquo Proceedings ofthe National Academy of Sciences of the United States of Americavol 107 no 6 pp 2669ndash2674 2010
[96] I Goshen T Kreisel O Ben-Menachem-Zidon et al ldquoBraininterleukin-1 mediates chronic stress-induced depression inmice via adrenocortical activation and hippocampal neuroge-nesis suppressionrdquo Molecular Psychiatry vol 13 no 7 pp 717ndash728 2008
[97] C D Munhoz L B Lepsch E M Kawamoto et al ldquoChronicunpredictable stress exacerbates lipopolysaccharide-inducedactivation of nuclear factor-120581B in the frontal cortex andhippocampus via glucocorticoid secretionrdquo Journal of Neuro-science vol 26 no 14 pp 3813ndash3820 2006
[98] S J Sukoff Rizzo S J Neal Z A Hughes et al ldquoEvidence forsustained elevation of IL-6 in the CNS as a key contributorof depressive-like phenotypesrdquo Translational Psychiatry vol 2article e199 2012
[99] A Garcia B Steiner G Kronenberg A Bick-Sander and GKempermann ldquoAge-dependent expression of glucocorticoid-andmineralocorticoid receptors on neural precursor cell popu-lations in the adult murine hippocampusrdquoAging Cell vol 3 no6 pp 363ndash371 2004
[100] M G Frank B M Thompson L R Watkins and S F MaierldquoGlucocorticoids mediate stress-induced priming of microglialpro-inflammatory responsesrdquo Brain Behavior and Immunityvol 26 no 2 pp 337ndash345 2012
[101] S Sugama M Fujita M Hashimoto and B Conti ldquoStressinduced morphological microglial activation in the rodentbrain involvement of interleukin-18rdquoNeuroscience vol 146 no3 pp 1388ndash1399 2007
[102] A Sierra J M Encinas and M Maletic-Savatic ldquoAdult humanneurogenesis from microscopy to magnetic resonance imag-ingrdquo Frontiers in Neuroscience vol 5 article 47 2011
[103] H G Kuhn H Dickinson-Anson and F H Gage ldquoNeurogen-esis in the dentate gyrus of the adult rat age-related decrease ofneuronal progenitor proliferationrdquo Journal of Neuroscience vol16 no 6 pp 2027ndash2033 1996
[104] L N Manganas X Zhang Y Li et al ldquoMagnetic resonancespectroscopy identifies neural progenitor cells in the live humanbrainrdquo Science vol 318 no 5852 pp 980ndash985 2007
[105] K L Spalding O Bergmann K Alkass et al ldquoDynamics ofhippocampal neurogenesis in adult humansrdquo Cell vol 153 no6 pp 1219ndash1227 2013
[106] J M Encinas and A Sierra ldquoNeural stem cell deforestationas the main force driving the age-related decline in adulthippocampal neurogenesisrdquo Behavioural Brain Research vol227 no 2 pp 433ndash439 2012
[107] K S Krabbe M Pedersen andH Bruunsgaard ldquoInflammatorymediators in the elderlyrdquo Experimental Gerontology vol 39 no5 pp 687ndash699 2004
[108] B S Diniz A L Teixeira L Talib W F Gattaz andO V Forlenza ldquoInterleukin-1120573 serum levels is increased inantidepressant-free elderly depressed patientsrdquo American Jour-nal of Geriatric Psychiatry vol 18 no 2 pp 172ndash176 2010
[109] A Sierra A C Gottfried-Blackmore B S Mcewen and KBulloch ldquoMicroglia derived from aging mice exhibit an alteredinflammatory profilerdquo GLIA vol 55 no 4 pp 412ndash424 2007
[110] C FranceschiM Bonafe S Valensin et al ldquoInflamm-aging Anevolutionary perspective on immunosenescencerdquo Annals of theNew York Academy of Sciences vol 908 pp 244ndash254 2000
[111] R Sano and J C Reed ldquoER stress-induced cell death mecha-nismsrdquoBiochimica et BiophysicaActa vol 1833 no 12 pp 3460ndash3470 2013
[112] S Z Hasnain R Lourie I Das A C H Chen and MA McGuckin ldquoThe interplay between endoplasmic reticulumstress and inflammationrdquo Immunology and Cell Biology vol 90no 3 pp 260ndash270 2012
[113] S Matus L H Glimcher and C Hetz ldquoProtein folding stressin neurodegenerative diseases a glimpse into the ERrdquo CurrentOpinion in Cell Biology vol 23 no 2 pp 239ndash252 2011
[114] Y Ito M Yamada H Tanaka et al ldquoInvolvement of CHOP anER-stress apoptotic mediator in both human sporadic ALS andALS model micerdquo Neurobiology of Disease vol 36 no 3 pp470ndash476 2009
[115] D Papadimitriou V Le Verche A Jacquier B Ikiz S Przed-borski and D B Re ldquoInflammation in ALS and SMA sortingout the good from the evilrdquo Neurobiology of Disease vol 37 no3 pp 493ndash502 2010
[116] A R Johnson J J Milner and LMakowski ldquoThe inflammationhighway metabolism accelerates inflammatory traffic in obe-sityrdquo Immunological Reviews vol 249 no 1 pp 218ndash238 2012
[117] S Buch H Yao M Guo et al ldquoCocaine and HIV-1 interplayin CNS cellular and molecular mechanismsrdquo Current HIVResearch vol 10 no 5 pp 425ndash428 2012
[118] M K Brown and N Naidoo ldquoThe endoplasmic reticulumstress response in aging and age-related diseasesrdquo Frontiers inPhysiology vol 3 article 263 2012
[119] G Castro C Areias MF L Weissmann et al ldquoDiet-inducedobesity induces endoplasmic reticulum stress and insulin resis-tance in the amygdala of ratsrdquo FEBS Open Bio vol 3 pp 443ndash449 2013
[120] A A Pavlovsky D Boehning D Li Y Zhang X Fan andT A Green ldquoPsychological stress cocaine and natural rewardeach induce endoplasmic reticulum stress genes in rat brainrdquoNeuroscience vol 246 pp 160ndash169 2013
[121] G GargiuloM CesaroniM Serresi et al ldquoIn vivo RNAi screenfor BMI1 targets identifies TGF-betaBMP-ER stress pathwaysas key regulators of neural- and malignant glioma-stem cellhomeostasisrdquo Cancer Cell vol 23 no 5 pp 660ndash676 2013
[122] A Salminen K Kaarniranta and A Kauppinen ldquoInflammag-ing disturbed interplay between autophagy and inflamma-somesrdquo Aging vol 4 no 3 pp 166ndash175 2012
[123] E Latz T S Xiao andA Stutz ldquoActivation and regulation of theinflammasomesrdquoNature Reviews Immunology vol 13 no 6 pp397ndash411 2013
[124] C Gemma A D Bachstetter M J Cole M Fister C Hudsonand P C Bickford ldquoBlockade of caspase-1 increases neurogene-sis in the aged hippocampusrdquo European Journal of Neurosciencevol 26 no 10 pp 2795ndash2803 2007
[125] M D Wu A M Hein M J Moravan S S Shaftel J AOlschowka and M K OrsquoBanion ldquoAdult murine hippocampal
14 Neural Plasticity
neurogenesis is inhibited by sustained IL-1120573 and not rescued byvoluntary runningrdquo Brain Behavior and Immunity vol 26 no2 pp 292ndash300 2012
[126] Y Wolf S Yona K W Kim and S Jung ldquoMicroglia seen fromthe CX3CR1 anglerdquo Frontiers in Cellular Neuroscience vol 7article 26 2013
[127] A E Cardona E P Pioro M E Sasse et al ldquoControl ofmicroglial neurotoxicity by the fractalkine receptorrdquo NatureNeuroscience vol 9 no 7 pp 917ndash924 2006
[128] K Bhaskar M Konerth O N Kokiko-Cochran A Cardona RM Ransohoff and B T Lamb ldquoRegulation of tau pathology bythe microglial fractalkine receptorrdquo Neuron vol 68 no 1 pp19ndash31 2010
[129] A D Bachstetter J M Morganti J Jernberg et al ldquoFractalkineand CX3CR1 regulate hippocampal neurogenesis in adult andaged ratsrdquo Neurobiology of Aging vol 32 no 11 pp 2030ndash20442011
[130] S Jung J Aliberti P Graemmel et al ldquoAnalysis of fractalkinereceptor CX3CR1 function by targeted deletion and greenfluorescent protein reporter gene insertionrdquo Molecular andCellular Biology vol 20 no 11 pp 4106ndash4114 2000
[131] J T Rogers J M Morganti A D Bachstetter et al ldquoCX3CR1deficiency leads to impairment of hippocampal cognitive func-tion and synaptic plasticityrdquo Journal of Neuroscience vol 31 no45 pp 16241ndash16250 2011
[132] W S T Griffin L C Stanley C Ling et al ldquoBrain interleukin1 and S-100 immunoreactivity are elevated in Down syndromeand Alzheimer diseaserdquo Proceedings of the National Academy ofSciences of the United States of America vol 86 no 19 pp 7611ndash7615 1989
[133] W C Benzing J RWujek E KWard et al ldquoEvidence for glial-mediated inflammation in aged APP(SW) transgenic micerdquoNeurobiology of Aging vol 20 no 6 pp 581ndash589 1999
[134] T J Seabrook L Jiang M Maier and C A Lemere ldquoMinocy-cline affects microglia activation A120573 deposition and behaviorin APP-tg micerdquo GLIA vol 53 no 7 pp 776ndash782 2006
[135] B Biscaro O Lindvall G Tesco C T Ekdahl and RM NitschldquoInhibition of microglial activation protects hippocampal neu-rogenesis and improves cognitive deficits in a transgenic mousemodel for Alzheimerrsquos diseaserdquoNeurodegenerative Diseases vol9 no 4 pp 187ndash198 2012
[136] P A Zunszain C Anacker A Cattaneo et al ldquoInterleukin-1120573a new regulator of the kynurenine pathway affecting humanhippocampal neurogenesisrdquo Neuropsychopharmacology vol 37no 4 pp 939ndash949 2012
[137] R De Simone M Antonietta Ajmone-Cat P Tirassa and LMinghetti ldquoApoptotic PC12 cells exposing phosphatidylserinepromote the production of anti-inflammatory and neuropro-tective molecules bymicroglial cellsrdquo Journal of Neuropathologyand Experimental Neurology vol 62 no 2 pp 208ndash216 2003
[138] M S Buckwalter M Yamane B S Coleman et al ldquoChroni-cally increased transforming growth factor-1205731 strongly inhibitshippocampal neurogenesis in aged micerdquo American Journal ofPathology vol 169 no 1 pp 154ndash164 2006
[139] O Butovsky Y Ziv A Schwartz et al ldquoMicroglia activatedby IL-4 or IFN-120574 differentially induce neurogenesis and oligo-dendrogenesis from adult stemprogenitor cellsrdquoMolecular andCellular Neuroscience vol 31 no 1 pp 149ndash160 2006
[140] C T Ekdahl ldquoMicroglial activationmdashtuning and pruning adultneurogenesisrdquo Frontiers in Pharmacology vol 3 article 41 2012
[141] HWakeA JMoorhouse S Jinno S Kohsaka and JNabekuraldquoResting microglia directly monitor the functional state ofsynapses in vivo and determine the fate of ischemic terminalsrdquoJournal of Neuroscience vol 29 no 13 pp 3974ndash3980 2009
[142] M E Tremblay R L Lowery and A K Majewska ldquoMicroglialinteractions with synapses are modulated by visual experiencerdquoPLoS Biology vol 8 no 11 Article ID e1000527 2010
[143] M E Tremblay M L Zettel J R Ison P D Allen and A KMajewska ldquoEffects of aging and sensory loss on glial cells inmouse visual and auditory corticesrdquo GLIA vol 60 no 4 pp541ndash558 2012
[144] D P Schafer E K Lehrman A G Kautzman et al ldquoMicrogliasculpt postnatal neural circuits in an activity and complement-dependent mannerrdquo Neuron vol 74 no 4 pp 691ndash705 2012
[145] H Nakanishi ldquoMicroglial functions and proteasesrdquo MolecularNeurobiology vol 27 no 2 pp 163ndash176 2003
[146] M E Tremblay and A K Majewska ldquoA role for microglia insynaptic plasticityrdquoCommunicative and Integrative Biology vol4 no 2 pp 220ndash222 2011
[147] R C Paolicelli G Bolasco F Pagani et al ldquoSynaptic pruning bymicroglia is necessary for normal brain developmentrdquo Sciencevol 333 no 6048 pp 1456ndash1458 2011
[148] GKempermannHGKuhn and FHGage ldquoMore hippocam-pal neurons in adult mice living in an enriched environmentrdquoNature vol 386 no 6624 pp 493ndash495 1997
[149] M Nilsson E Perfilieva U Johansson O Orwar and P SEriksson ldquoEnriched environment increases neurogenesis in theadult rat dentate gyrus and improves spatial memoryrdquo Journalof Neurobiology vol 39 no 4 pp 569ndash578 1999
[150] H van Praag G Kempermann and F H Gage ldquoRunningincreases cell proliferation and neurogenesis in the adult mousedentate gyrusrdquo Nature Neuroscience vol 2 no 3 pp 266ndash2701999
[151] D Young P A Lawlor P Leone M Dragunow and MJ During ldquoEnvironmental enrichment inhibits spontaneousapoptosis prevents seizures and is neuroprotectiverdquo NatureMedicine vol 5 no 4 pp 448ndash453 1999
[152] L L Williamson A Chao and S D Bilbo ldquoEnvironmentalenrichment alters glial antigen expression and neuroimmunefunction in the adult rat hippocampusrdquo Brain Behavior andImmunity vol 26 no 3 pp 500ndash510 2012
[153] L Maggi M Scianni I Branchi I DrsquoAndrea C Lauro and CLimatola ldquoCX(3)CR1 deficiency alters hippocampal-dependentplasticity phenomena blunting the effects of enriched environ-mentrdquo Frontiers in Cellular Neuroscience vol 5 article 22 2011
[154] I Goshen A Avital T Kreisel T Licht M Segal and RYirmiya ldquoEnvironmental enrichment restores memory func-tioning in mice with impaired IL-1 signaling via reinstatementof long-term potentiation and spine size enlargementrdquo Journalof Neuroscience vol 29 no 11 pp 3395ndash3403 2009
[155] Y Ziv N Ron O Butovsky et al ldquoImmune cells contribute tothe maintenance of neurogenesis and spatial learning abilitiesin adulthoodrdquo Nature Neuroscience vol 9 no 2 pp 268ndash2752006
[156] J Kipnis H Cohen M Cardon Y Ziv and M Schwartz ldquoTcell deficiency leads to cognitive dysfunction implications fortherapeutic vaccination for schizophrenia and other psychiatricconditionsrdquo Proceedings of the National Academy of Sciences ofthe United States of America vol 101 no 21 pp 8180ndash8185 2004
[157] S A Wolf B Steiner A Akpinarli et al ldquoCD4-positive Tlymphocytes provide a neuroimmunological link in the control
Neural Plasticity 15
of adult hippocampal neurogenesisrdquo Journal of Immunologyvol 182 no 7 pp 3979ndash3984 2009
[158] G J Huang A L Smith D H D Gray et al ldquoA genetic andfunctional relationship between T cells and cellular prolifera-tion in the adult hippocampusrdquo PLOS Biology vol 8 no 12Article ID e1000561 2010
[159] R M Ransohoff and B Engelhardt ldquoThe anatomical andcellular basis of immune surveillance in the central nervoussystemrdquoNature Reviews Immunology vol 12 no 9 pp 623ndash6352012
[160] M Olah G Ping A H De Haas et al ldquoEnhanced hippocampalneurogenesis in the absence of microglia T cell interactionand microglia activation in the murine running wheel modelrdquoGLIA vol 57 no 10 pp 1046ndash1061 2009
[161] E Gebara S Sultan J Kocher-Braissant and N Toni ldquoAdulthippocampal neurogenesis inversely correlates with microgliain conditions of voluntary running and agingrdquo Frontiers inNeuroscience vol 7 article 145 2013
[162] R Aharoni B Kayhan R Eilam M Sela and R ArnonldquoGlatiramer acetate-specific T cells in the brain express T helper23 cytokines and brain-derived neurotrophic factor in siturdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 100 no 2 pp 14157ndash14162 2003
[163] C Rossi A Angelucci L Costantin et al ldquoBrain-derivedneurotrophic factor (BDNF) is required for the enhancementof hippocampal neurogenesis following environmental enrich-mentrdquo European Journal of Neuroscience vol 24 no 7 pp 1850ndash1856 2006
Figure 1 The effects of surveillant and inflammatory microglia on the adult hippocampal neurogenic cascade During physiologicalconditions surveillant microglia effectively phagocytose the excess of apoptotic newborn cells and may release antineurogenic factorssuch as TGF120573 This anti-inflammatory state is maintained by neuronal (tethered or released) fractalkine Enriched environment drivesmicroglia towards a phenotype supportive of neurogenesis via the production of IGF-1 In contrast inflammatory challenge triggered byLPS irradiation aging or AD induces the production of proinflammatory cytokines such as IL-1120573 TNF120572 and IL-6 by microglia as well asresident astrocytes and infiltrating monocytes neutrophils and lymphocytes These cytokines have profound detrimental effects on adultneurogenesis by reducing the proliferation survival integration and differentiation of the newborn neurons and decreasing their recallduring learning and memory paradigms
In addition peripheral immune cells invading the CNSduring inflammation can further produce proinflammatorymediators but the respective contribution ofmicroglia versusother cell types in the inflammatory response of the brain ispoorly understood
The harmful effects of inflammation are also widelydetermined by the actual levels of proinflammatory media-tors released rather than the occurrence or absence of aninflammatory response in itself For instance TNF120572 regulatessynaptic plasticity by potentiating the cell surface expressionof AMPA glutamatergic receptors thus resulting in a homeo-static scaling following prolonged blockage of neuronal activ-ity during visual system development [57] However TNF120572also produces differential effects at higher concentrationsranging from an inhibition of long-term potentiation to anenhancement of glutamate-mediated excitotoxicity in vitro[58] Inflammation induced by chronic ventricular infusionof bacterial lipopolysaccharides (LPS a main componentof the outer membrane of Gram-negative bacteria) that isthe most widely used method for inducing an inflammatorychallenge also increases ex vivo the hippocampal levels ofTNF120572 and IL-1120573 thereby impairing novel place recognitionspatial learning and memory formation but all these cog-nitive deficits can be restored by pharmacological treatment
with a TNF120572 protein synthesis inhibitor a novel analog ofthalidomide 361015840-dithiothalidomide [59]
The impact of inflammation on adult hippocampal neu-rogenesis was originally discovered by Olle Lindvall andTheo Palmerrsquos groups in 2003 showing that systemic orintrahippocampal administration of LPS reduces the for-mation of newborn neurons in the adult hippocampus aneffect that is prevented by indomethacin a nonsteroidal anti-inflammatory drug (NSAID) which inhibits the synthesis ofproinflammatory prostaglandins [60 61] Similarly inflam-mation can determine the increase in neurogenesis that isdriven by seizures a context in which neurogenesis can beprevented by LPS and increased by the anti-inflammatoryantibiotic minocycline [60] In these studies hippocampalproliferation remained unaffected by LPS orminocycline andthus it is likely that inflammation targeted the survival ofnewborn cells [60 61] as LPS is known to increase SGZapoptosis [62] Inflammation also has further downstreameffects on the neurogenic cascade For instance LPS increasesthe number of thin dendritic spines and the expressionof the excitatory synapses marker ldquopostsynaptic densityprotein of 95kDardquo (PSD95) in newborn neurons LPS inaddition increases the expression ofGABAA receptors at earlystages of synapse formation leading to suggesting a possible
4 Neural Plasticity
imbalance of excitatory and inhibitory neurotransmissionin these young neurons [63] Finally LPS also prevents theintegration of newborn neurons into behaviourally relevantnetworks including most notably their activation duringspatial exploration as determined by the percentage of BrdUcells colabeled with the immediate early gene Arc [64]
Importantly none of these manipulations is specific tomicroglia and may directly or indirectly affect other braincells involved in the inflammatory response of the brain Forinstance both LPS andminocycline affect astrocytic functionin vitro and in vivo [65ndash69] Furthermore LPS is knownto drive infiltration of monocytes and neutrophils into thebrain parenchyma [70] Monocytes and neutrophils producemajor proinflammatorymediators and could therefore act onthe neurogenic cascade as well The implication of microgliain LPS-induced decrease in neurogenesis is nonethelesssupported in vivo by the negative correlation between thenumber of newborn neurons (BrdU+ NeuN+ cells) andthe number of ldquoactivatedrdquo microglia (ie expressing ED1)[60] ED1 also called CD68 or macrosialin is a lysosomalprotein which is overexpressed during inflammatory chal-lenge While the location of ED1 previously suggested itsinvolvement in phagocytosis its loss of function did not resultin phagocytosis deficits and thus its function still remainsunknown (reviewed in [10]) The number of ED1-positivemicroglia also negatively correlates with neurogenesis duringinflammation provoked by cranial irradiation [61] Whilecorrelation does not involve causation nor can pinpoint tothe underlying mechanism these experiments were the firstto reveal a potential role for ldquoactivatedrdquo microglia in theregulation of adult hippocampal neurogenesis More directevidence of microglial mediation in LPS deleterious effectswas obtained from in vitro experiments as it was shown thatconditionedmedia fromLPS-challengedmicroglia containedIL-6 which in turn caused apoptosis of neuroblasts [61]Nonetheless astrocytes can also release IL-6 when stimulatedwith TNF120572 or IL-1120573 [71] and chronic astrocytic releaseof IL-6 in transgenic mice reduced proliferation survivaland differentiation of newborn cells thus resulting in anet decrease in neurogenesis [72] In summary while thedetrimental impact of inflammation on neurogenesis is wellestablished more work is needed to define the specific rolesplayed by the various inflammatory cells populating thebrain
4 Inflammation Associated withChronic Stress
Across health and disease the most prevalent condi-tion that is associated with neuroinflammation is ldquochronicstressrdquo which commonly refers to the repeated or sus-tained inability to cope with stressful environmental socialand psychological constraints Chronic stress is character-ized by an imbalanced secretion of glucocorticoids by thehypothalamic-pituitary-adrenal (HPA) axis (most notablycortisol in humans and corticosterone in rodents) whichleads to an altered brain remodelingmassive loss of synapsesand compromised cognitive function [73] In particular an
impairment of spatial learning working memory noveltyseeking and decision making has been associated withchronic stress [74] Glucocorticoids are well known fortheir anti-inflammatory properties as they interfere withNF-120581B-mediated cytokine transcription ultimately delayingwound healing [75] They are also potent anti-inflammatorymediators in vivo [76] and in purified microglia cultures[77] Recently repeated administration of high doses ofglucocorticoids by intraperitoneal injection to mimic theirrelease by chronic stress was also shown to induce a lossof dendritic spines in the motor cortex while impairinglearning of a motor task A transcription-dependent pathwayacting downstream of the glucocorticoid receptor GR wasproposed [78 79] but the particular cell types involved werenot identified
Microglia are considered to be a direct target of the gluco-corticoids as they were shown to express GR during normalphysiological conditions in vivo [77] In fact transgenic micelacking GR in microglia and macrophages show an increasedproduction of proinflammatory mediators (including TNF120572and IL-1120573) and greater neuronal damage in response to anintraparenchymal injection of LPS compared to wild-typemice [80] In contrast glucocorticoids are considered to beproinflammatory in the chronically stressed brain [81] whereamong other changes they can promote inflammation oxida-tive stress neurodegeneration andmicroglial activation [82]For example repeated restraint stress induces microglialproliferation and morphological changes including a hyper-ramification of their processes in the adult hippocampusfollowing restraint stress [83] but a nearly complete lossof processes in the context of social defeat [84] Prenatalrestraint stress also causes an increase in the basal levels ofTNF120572 and IL-1120573 while increasing the proportion ofmicrogliashowing a reactive morphology in the adult hippocampus[85] Similarly social defeat leads to an enhanced responseto the inflammatory challenge induced by intraperitonealinjection of LPS including an increased production of TNF120572and IL-1120573 and expression of inducible NO synthase (iNOS)by microglia accompanied by an increased infiltration ofcirculating monocytes [84 86] Therefore microglia are astrong candidate for mediating some of the effects of stresson adult neurogenesis as will be discussed below in synergywith other types of inflammatory cells
Chronic stress is well known for its negative effects onhippocampal neurogenesis (reviewed in [87 88]) althoughnot all stress paradigms are equally effective [89] Severalstress paradigms can decrease neuroprogenitors proliferationin the tree shrew [90] and inmice [91 92] although this effectseems to be compensated by an increased survival of newbornneurons [92] and whether stress results in a net increaseor decrease in neurogenesis remains controversial (reviewedin [87 88]) The effects of stress on adult neurogenesisseem to be mediated at least partially by glucocorticoidsbecause mice lacking a single copy of the GR gene showbehavioural symptoms of depression including learned help-lessness neuroendocrine alterations of the HPA axis andimpaired neurogenesis [93] In parallel chronic stress isassociated with an increased inflammatory response whichmay inhibit neurogenesis as well For instance serum levels
Neural Plasticity 5
of IL-1120573 and IL-6 are significantly increased in depressedpatients [94] In mice restraint stress leads to a widespreadactivation of NF-120581B in the hippocampus including at thelevel of neuroprogenitors [95] and increased protein levels ofIL-1120573 [96] In addition to the direct role of glucocorticoidsIL-1120573 also seems to mediate some of the effects of mildchronic stress because in vivomanipulations that block IL-1120573(either pharmacologically or in null transgenic mice) preventthe anhedonic stress response and the antineurogenic effectof stress [91 96]Moreover the corticoids and IL-1120573 pathwaysmay regulate each other in a bidirectional manner becausethe administration of a GR antagonist can blunt the LPS-induced production of hippocampal IL-1120573 in stressed mice[97] whereas mice knockout for the IL-1120573 receptor (IL-1R1)fail to display the characteristic elevation of corticosteroneinduced by mild chronic stress [96] Another stress-relatedcytokine IL-6 induces depressive phenotypes and preventsthe antidepressant actions of fluoxetinewhen administered tomice in vivo [98] So far the effects of stress on neurogenesisvia corticosteroids and inflammation have been assumed tobe cell autonomous as neuroprogenitors express both GR[99] and IL-1R1 [95] The potential participation of microgliais yet to be determined but there are some reports of adirect effect of stress on microglial activation For instancemicroglia acutely isolated frommice subjected to acute stress(by inescapable tail shock) showed a primed response to LPSchallenge by producing higher levels of IL-1120573mRNA ex vivo[100] and the specific loss of expression of GR in microglialeads to a blunted inflammatory response in vitro and to adecreased neuronal damage in vivo in response to LPS [80]In stress paradigms these enhanced responses of microgliato inflammatory challenges are similar to their age-relatedldquoprimingrdquo which has been associated with and is possiblydue to an increased basal production of proinflammatorymediators However whether microglia express increasedlevels of IL-1120573 and other proinflammatory cytokines inresponse to stressful events is presently unclear [101] It is thuspossible that some of the antineurogenic effects of stress areexerted bymeans of microglial-dependent inflammation butthis hypothesis remains to be experimentally tested
5 Inflammation Associated with Aging andNeurodegenerative Diseases
Inflammation is also commonly associated with normalaging and neurodegenerative diseases and therefore couldrepresent a putative underlying mechanism that explainstheir decrease in hippocampal neurogenesis Nonethelessinflammation is also associated with neurological diseasessuch as epilepsy or stroke where neurogenesis is thought tobe increased although the data from rodents and humans issomewhat conflictive [102] Neurogenesis is well known todecline throughout adulthood and normal aging in rodentsand humans [103 104] but the decay ismore pronounced andoccurs later in life in mice than in humans [105] The aging-associated decrease in neurogenesis has been shown to occurmainly as a consequence of exhaustion of the rNSC popula-tion which after being recruited and activated undergo three
rounds of mitosis in average and then terminally differentiateinto astrocytes [12 106] In addition a reduced mitoticcapacity of the neuroprogenitors could further contribute todecreasing neurogenesis [106] and moreover an age-relatedincrease in the levels of proinflammatory cytokines couldalso hinder neurogenesis in the aging brain Serum levelsof IL-1120573 IL-6 and TNF120572 are elevated in elderly patients[107 108] Aged microglia express higher levels of theseproinflammatory cytokines and show a greater response toLPS inflammatory challenge that is a ldquoprimedrdquo responsethan their younger counterparts [109] The origin of thislow-grade age-related inflammation (ldquoinflamm-agingrdquo [110])remains unknown and may be related to both aging anddamage to the surrounding neurons as well as aging of theimmune system per se
At the cellular level stress to the endoplasmic reticulum(ER) caused by various perturbations such as nutrient deple-tion disturbances in calcium or redox status or increasedlevels of misfolded proteins can induce a cell-autonomousinflammatory response to neurons Stress to the ER a mul-tifunctional organelle which is involved in protein foldinglipid biosynthesis and calcium storage triggers a homeostaticresponse mechanism named the unfolding protein response(UPR) aiming to clear the unfolded proteins in order torestore normal ER homeostasis [111] However if the ERstress cannot be resolved theUPR also initiates inflammatoryand apoptotic pathways via activation of the transcriptionfactor NF-120581B which controls the expression of most proin-flammatory cytokines [112] In the brain ER stress is ofteninitiated by the formation of abnormal protein aggregatesin several neurodegenerative diseases such as Alzheimerrsquosdisease (AD) Parkinsonrsquos disease (PD) amyotrophic lateralsclerosis (ALS) Huntingtonrsquos disease (HD) and prion-relateddisorders [113] This neurodegeneration-associated ER stressis assumed to occur mostly in neurons but there aresome examples of microglial protein misfolding as well Forinstance both microglia and neurons overexpress CHOP(CEBP homologous protein) a transcription factor whichis activated during ER stress in human patients and mousemodels of ALS [114] Inflammation has been speculated tobe a main negative contributor to the pathology of ALS[115] but a direct microglial involvement in mediating theinflammatory response to abnormal protein aggregation inALS and other neurodegenerative conditions remains to betested Finally ER stress has been linked to a variety of inflam-matory conditions [116 117] including chronic stress diet-induced obesity and drug abuse as well as atherosclerosisand arthritis [118ndash120] During normal aging a progressivedecline in expression and activity of key ER molecularchaperones and folding enzymes could also compromise theadaptive response of the UPR thereby contributing to theage-associated decline in cellular functions [118] Thereforeaging is strongly associated with a chronic ER stress whichleads to increased activation of NF-120581B [112] however thecontribution of the different brain cell types to ldquoinflamm-agingrdquo is still poorly understood The detrimental effects onneurogenesis of increased proinflammatory cytokines in theaging brain are not necessarily related to microglia but alsoto stressed neurons Furthermore ER stress may also cause a
6 Neural Plasticity
cell-autonomous response in neural stem cells [121] althoughits impact on neurogenesis remains to be experimentallydetermined
In addition aging is accompanied by an increased levelof mitochondrial oxidative stress which in turn activatesthe ldquoInflammasomerdquo [122] a group of multimeric proteinscomprising the interleukin 1 converting enzyme (ICE cas-pase 1) which serves to release the active form of thecytokine [123] IL-1120573 may act directly on rNSCs (visualisedby labeling with the Sox2 marker) as they express IL-1R1 in the adult hippocampus [91] Treatment with IL-1120573decreases hippocampal proliferation in young mice [91] andpharmacological inhibition of ICE partially restores the num-ber of newborn neurons in aged mice without significantlyaffecting their differentiation rate [124] Transgenic IL-1120573overexpression results in chronic inflammation and deple-tion of doublecortin-labeled neuroblasts thus mimickingthe aging-associated depletion of neurogenesis [125] Theactual mechanism of action of IL-1120573 on neurogenesis inaged mice including decreased proliferation of rNSCsANPsand survival of newborn neurons remains undeterminedMicroglia are a main source of IL-1120573 in the aging brain butthe hypothesis that microglia-derived IL-1120573 is responsiblefor depleting neurogenesis in the aging brain remains to bedirectly tested
The regulation of neurogenesis by IL-1120573 in the agingbrain has been further linked to the activity of anothercytokine the chemokine fractalkine or CX3CL1 Fractalkinehas soluble and membrane-tethered forms and is exclu-sively expressed by neurons while the fractalkine receptor(CX3CR1) is expressed in the brain by microglia alone [126]Thismodule forms a unique neuron-microglia signalling unitthat controls the extent of microglial inflammation in severalneurodegenerative conditions including PD ALS [127] orAD [128] In fact CX3CR1 blocking antibodies increasethe production of hippocampal IL-1120573 when administeredto young adult rats [129] Importantly chronic treatmentwith fractalkine increases hippocampal proliferation and thenumber of neuroblasts in aged (22 months old) but notyoung (3 months old) or middle-aged rats (12 months old)whereas an antagonists of CX3CR1 has the opposite effectsin young but not in middle-aged nor old rats [129] Sincefractalkine expression is decreased during aging [129] areduced neuron-microglia signalling might be releasing thebrake on microglial contribution to inflammatory responsesalthough increased levels of fractalkine were instead reportedin aged rat hippocampus by other studies [68] Additionalinsights into the role of fractalkine signalling come fromknock-in mice in which the endogenous CX3CR1 locus isreplaced by the fluorescent reporter GFP [126] The initialstudies suggested that CX3CR1GFPGFP (ie CX3CR1minusminus)mice have no significant differences in brain development andfunctions [130] but more systematic investigations recentlyrevealed a long list of hippocampal-dependent changes inyoung (3 months old) CX3CR1GFPGFP and CX3CR1GFP+mice compared to wild-type mice These changes notablyincluded decreased neuroprogenitors proliferation and neu-roblasts number impaired LTP performance in contextual
fear conditioning and water maze spatial learning and mem-ory and importantly increased IL-1120573 protein levels [131]Thesignalling pathway of fractalkine-IL-1120573 is functionally rele-vant because IL-1R1 antagonists rescued LTP and cognitivefunction in CX3CR1GFPGFP mice [131] In sum even thoughneuronal fractalkine seems to be sufficient for restrainingthe inflammatory activity of microglia in young rats itsdownregulation during aging could activate the microglialinflammatory response and thereby subsequently reduce theproliferation of remaining neuroprogenitors
In AD inflammatory cytokines such as IL-1120573 are over-expressed in the microglia associated with the amyloid beta(A120573) plaques of postmortem samples [132] and in transgenicmice modeling the disease [133] The loss of synapses (fromhippocampus to frontal cortex) is one of the main patho-logical substrates in this disease but adult neurogenesis isalso severely reduced in most mouse models of AD possiblydue to a decreased proliferation of neuroprogenitors and adecreased survival of newborn cells even though the putativechanges in the neurogenic cascade in postmortem samplesremain controversial (reviewed in [102]) This lack of agree-ment is possibly explained by the fact that the vast majorityof AD cases have a late onset over 65 years of age when littleneurogenesis remains In contrast in most transgenic ADmouse models the A120573 accumulation cognitive deficits andchanges in neurogenesis are already detectable in young ani-mals (2-3 months old) The study of AD is further hinderedby the difficulty in comparing the time course and pathologyacross different mouse models For instance early treatmentwith minocycline can improve cognition and reduce A120573burden in mice expressing the human amyloid precursorprotein (APP) [134] In contrast in mice expressing APP anda mutated form of presenilin 1 (PS1) which is part of the 120574secretase pathway that cleaves A120573 inflammation is reducedwithout any detectable changes in A120573 plaques deposition[135] Concomitantly with a decrease in tissue inflamma-tory cytokines and number of microglial cells minocyclinerestores neurogenesis and hippocampus-dependent memorydeficits in these APPPS1 mice [135] indirectly suggestingthat cognitive decay in AD may be at least in part relatedto a detrimental effect of inflammation on hippocampalneurogenesis Direct evidence that neurogenesis is associatedwith the cognitive performance in AD is still lacking Furtherresearch is also necessary to determine the neurogenic targetsof AD-related inflammation One central open questionfor future therapies aiming at increasing neurogenesis andcognition in AD is whether neuroprogenitors are spared orwhether their age-induced loss becomes accelerated Ratherthan increasing the proliferation and neurogenic output ofthe few rNSCs remaining in an old AD brain it may be morerelevant to develop strategies that prevent the age-related lossof neuroprogenitors in presymptomatic patients
In summary inflammation associated with a wide varietyof experimental models of disease produces strong detri-mental effects on hippocampal neurogenesis These effectson human neurogenesis are however not so well describedand in vitro IL-1120573 increases the proliferation of hip-pocampal embryonic neuroprogenitors but decreases their
Neural Plasticity 7
differentiation into neurons [136] Novel methods to assesshippocampal neurogenesis in the living human brain frommetabolomics of neuroprogenitors to hippocampal bloodbrain volume (reviewed in [102]) will help to determine thecontribution of inflammation to adult neurogenesis in thehealthy and diseased human brain during aging
6 Normal Physiological Conditions
In the healthy mature brain microglia are an essential com-ponent of the neurogenic SGZ niche where they physicallyintermingle with neuroprogenitors neuroblasts and new-born neurons [62] Here surveillant microglia effectively andrapidly phagocytose the excess of newborn cells undergoingapoptosis [62] Importantly microglial phagocytosis in theadult SGZ is not disturbed by inflammation associated withaging or by LPS challenge as the phagocytic index (iethe proportion of apoptotic cells completely engulfed bymicroglia) is maintained over 90 in these conditions [62]Nonetheless the consequences of microglial phagocytosis onadult hippocampal neurogenesis remain elusive Treatment ofmice with annexin V which binds to the phosphatidylserine(PS) receptor and prevents the recognition of PS on thesurface of apoptotic cells presumably blocking phagocytosisincreases the number of apoptotic cells in the SGZ [40] Con-comitantly annexin V reduces neurogenesis by decreasingthe survival of neuroblasts without affecting neuroprogeni-tors proliferation [40] Similar results were obtained in trans-genic mice knock-out for ELMO1 a cytoplasm protein whichpromotes the internalization of apoptotic cells althoughthe effects on neurogenesis were ascribed to a decreasedphagocytic activity of neuroblasts [40]The actual phagocytictarget of the neuroblasts remains undetermined but thenewborn apoptotic cells in the adult SGZ are exclusivelyphagocytosed by microglia at least in physiological condi-tions [62] Nevertheless none of the above manipulationshas specifically tested the role of microglial phagocytosisin hippocampal-dependent learning and memory and thusthe functional impact of microglial phagocytosis in adultneurogenic niches during normal physiological conditionsremains to be elucidated
Microglial phagocytosis of apoptotic cells is activelyanti-inflammatory at least in vitro and thus it has beenhypothesized that anti-inflammatory cytokines produced byphagocytic microglia may further regulate neurogenesis [10]For instance transforming growth factor beta (TGF120573) whichis produced by phagocytic microglia in vitro [137] inhibitsthe proliferation of SGZ neuroprogenitors [138] Microgliaare further able to produce proneurogenic factors in vitro[139] When primed with cytokines associated with T helpercells such as interleukin 4 (IL-4) or low doses of interferongamma (IFN120574) culturedmicroglia support neurogenesis andoligodendrogenesis through decreased production of TNF120572and increased production of insulin-like growth factor 1(IGF-1) [139] an inducer of neuroprogenitor proliferation[26] A list of potential factors produced by microgliaand known to act on neuroprogenitor proliferation can
be found in Table 1 In addition recent observations sug-gest that neuroprogenitor cells may not only regulate theirown environment but also influence microglial functionsFor instance vascular endothelial growth factor (VEGF)produced by cultured neuroprecursor cells directly affectsmicroglial proliferation migration and phagocytosis [20]More potential factors produced by neuroprogenitors shownto be influencing microglial activity and function can befound in Table 2 However it has to be taken into accountthat most of these observations were obtained in culture andthat further research is needed in order to elucidate whetherthose factors are also secreted and have the same regulatoryresponses in vivo
In addition microglial capacity to remodel and eliminatesynaptic structures during normal physiological conditionshas suggested that microglia could also control the synap-tic integration of the newborn neurons generated duringadult hippocampal neurogenesis [140] Three main mech-anisms were proposed (1) the phagocytic elimination ofnonapoptotic axon terminals and dendritic spines (2) theproteolytic remodeling of the perisynaptic environmentand (3) the concomitant structural remodeling of dendriticspines [7 140] Indeed microglial contacts with synapticelements are frequently observed in the cortex during normalphysiological conditions sometimes accompanied by theirengulfment and phagocytic elimination [141ndash143] as in thedeveloping retinogeniculate system [144] Microglial cells aredistinctively surrounded by pockets of extracellular spacecontrarily to all the other cellular elements [142] suggestingthat microglia could remodel the volume and geometryof the extracellular space and thus the concentration ofvarious ions neurotransmitters and signalling moleculesin the synaptic environment Whether microglia create thepockets of extracellular space themselves or not remainsunknown but these pockets could result from microglialrelease of extracellular proteases such as metalloproteinasesand cathepsins [145] which are well known for influencingthe formation structural remodeling and elimination ofdendritic spines in situ and also experience-dependent plas-ticity in vivo [7 146] More recently microglial phagocytosisof synaptic components was also observed in the developinghippocampus in the unique time window of synaptogenesisa process which is notably regulated by fractalkine-CX3CR1signalling [147] Therefore the attractive hypothesis thatmicroglial sculpts the circuitry of newborn cells in the adulthippocampus deserves further attention
Lastly microglia were also involved in increasing adulthippocampal neurogenesis in the enriched environment(EE) experimental paradigm EE is a paradigm mimick-ing some features of the normal living circumstances ofwild animals as it gives them access to social interactionstoys running wheels and edible treats EE has long beenknown to enhance neurogenesis by acting on newborncells survival resulting ultimately in an enlargement ofthe dentate gyrus [148] Functionally these changes areaccompanied by enhanced spatial learning and memoryformation with the water maze paradigm [149] Similarincreases in neurogenesis are obtained by subjecting miceto voluntary running paradigms although in this case the
8 Neural Plasticity
Table 1 Summary of factors secreted by microglia and the potential effect they have on neuroprogenitors in vitro
Microglia secreted factors Reference Modulation of neural progenitor cells ReferenceBDNF [18] Differentiation [19]EGF [20] Survival expansion proliferation differentiation [21]FGF120573 [22] Survival and expansion [23]GDNF [24] Survival migration and differentiation [25]IGF-1 [21] Proliferation [26]IL-1120573 [27] Reduction in migration [27]IL-6 [28] Inhibition of neurogenesis [29]IL-7 [20] Differentiation [30]IL-11 [20] Differentiation [30]NT-4 [24] Differentiation [31]PDGF [32] Expansion and differentiation [33]TGF120573 [34] Inhibition of proliferation [19]
Table 2 Summary of factors secreted by neuroprogenitors and the potential effect they have on microglia in vitro
NPC secreted factors Reference Modulation of microglia ReferenceBDNF [18] Proliferation and induction of phagocytic activity [35]Haptoglobin [24] Neuroprotection [36]IL-1120573 [37] Intracellular Ca+2 elevation and proliferation [22]IL-6 [37] Increase in proliferation [38]M-CSF [20] Mitogen [39]NGF [40] Decrease in LPS-induced NO [41]TGF120573 [37] Inhibition of TNF120572 secretion [42]TNF120572 [37] Upregulation of IL-10 secretion [43]VEGF [20] Induction of chemotaxis and proliferation [20]
effect is mediated by increased neuroprogenitor proliferation[150] During inflammatory conditions EE is antiapoptoticand neuroprotective [151] and it limits the hippocampalresponse to LPS challenge by decreasing the expression ofseveral cytokines and chemokines including IL1-120573 andTNF120572[152] In fact EE is believed to counteract the inflammatoryenvironment and rescue the decreased number of neuroblastsin CX3CR1GFPGFP mice compared to wild-type mice [153]The effects of EE are independent of the IL-1120573 signallingpathway as it increases neurogenesis in mice that are nullfor IL-1R1 [154] EE also induces microglial proliferation andexpression of the proneurogenic IGF-1 [155] but the fullphenotype of microglia in EE compared to standard housingand its impact on the neurogenic cascade remains to bedetermined
The mechanisms behind the anti-inflammatory actionsof EE are unknown but they were suggested to involvemicroglial interactions with T lymphocytes through anincreased expression of themajor histocompatibility complexof class II (MHC-II) during EE [155] MHC-II is responsiblefor presenting the phagocytosed and degraded antigens tothe antibodies expressed on the surface of a subtype ofT lymphocytes (T helper or CD4+ cells) thus initiatingtheir activation and production of antigen-specific antibod-ies Severe combined immunodeficient (SCID) mice lackingeither T and B lymphocytes or nude mice lacking only Tcells have impaired proliferation and neurogenesis in normal
and EE housing compared to wild-type mice [155] as wellas impaired performance in the water maze [156] Similarlyantibody-based depletion of T helper lymphocytes impairsbasal and exercise-induced proliferation and neurogenesis[157] Furthermore a genetic study in heterogeneous stockmice which descend from eight inbred progenitor strainshas found a significant positive correlation between geneticloci associated to hippocampal proliferation and to theproportion of CD4+ cells among blood CD3+ lymphocytes[158] Additional experiments are needed to fully determinethe possible interactions between microglia and T cellsin neurogenesis because at least in normal physiologicalconditions (1) T cell surveillance of the brain parenchymais minimal (2) microglia are poor antigen presenting cellsand (3) antigen presentation by means of MHC-II family ofmolecules is thought to occur outside the brain that is in themeninges and choroid plexus [159] In fact during voluntaryexercise there are no significant changes in T cell surveillanceof the hippocampus nor a direct interaction between T cellsand microglia nor any changes in the gene expression profileof microglia including that of IGF-1 IL-1120573 and TNF120572 [160]The number of microglia is also inversely correlated withthe number of hippocampal proliferating cells rNSCs andneuroblasts in aged (8 months) mice subjected to voluntaryrunning as well as in vitro cocultures of microglia andneuroprogenitors which has been interpreted as resultingfrom an overall inhibitory effect of microglia on adult
Neural Plasticity 9
neurogenesis [161] Even though EE is clearly a more com-plex environmental factor than voluntary running furtherresearch is necessary to disregard nonspecific or indirecteffects of genetic or antibody-based T cells depletion onmicroglia and other brain cell populations including rNSCsFor instance adoptive transfer of T helper cells treated withglatiramer acetate a synthetic analog of myelin basic protein(MBP) approved for the treatment of multiple sclerosis pro-duces a bystander effect on resident astrocytes and microgliaby increasing their expression of anti-inflammatory cytokinessuch as TGF120573 [162] Alternatively it has been suggested thatT cells may mediate an indirect effect on adult hippocampalneurogenesis by increasing the production of brain-derivedneurotrophic factor (BDNF) [157] which is involved in theproneurogenic actions of EE [163] Whether BDNF cancounteract the detrimental effects of T cell depletion on neu-rogenesis remains unknownOverall the roles ofmicroglia inEE and running-induced neurogenesis are unclear and haveto be addressed with more precise experimental designs Insummary surveillant microglia are part of the physical nichesurrounding the neural stem cells and newborn neurons ofthe mature hippocampus where they continuously phagocy-tose the excess of newborn cellsMicroglia were also linked tothe proneurogenic and anti-inflammatory effects of voluntaryrunning and EE but direct evidence is missing The overallcontribution of microglia to neurogenesis and learning andmemory in normal physiological conditions remains largelyunexplored at this early stage in the field
7 Conclusion
In light of these observations microglia are now emergingas important effector cells during normal brain developmentand functions including adult hippocampal neurogenesisMicroglia can exert a positive or negative influence onthe proliferation survival or differentiation of newborncells depending on the inflammatory context For instancemicroglia can compromise the neurogenic cascade duringchronic stress aging and neurodegenerative diseases bytheir release of proinflammatory cytokines such as IL-1120573IL-6 and TNF120572 A reduced fractalkine signalling betweenneurons and microglia could also be involved during normalaging However microglia are not necessarily the only celltype implicated because astrocytes endothelial cells mastcells perivascular and meningeal macrophages and to alesser extent neurons and invading peripheral immune cellscould further contribute by releasing proinflammatorymedi-ators
Additionally microglia were shown to phagocytose theexcess of newborn neurons undergoing apoptosis in thehippocampal neurogenic niche during normal physiologicalconditions while a similar role in the synaptic integrationof newborn cells was also proposed in light of their capacityto phagocytose synaptic elements Lastly microglial interac-tions with T cells leading to the release of anti-inflammatorycytokines neurotrophic factors and other proneurogenicmediators (notably during EE and voluntary running) couldcounteract the detrimental effects of inflammation on adult
hippocampal neurogenesis and their functional implicationsfor learning and memory
However further research is necessary to assess the rela-tive contribution of microglia versus other types of residentand infiltrating inflammatory cells and to determine thenature of the effector cytokines and other inflammatorymediators involved as well as their cellular andmolecular tar-gets in the neurogenic cascade Such research will undoubt-edly help to develop novel strategies aiming at protecting theneurogenic potential and ultimately its essential contributionto learning and memory
The authors declare that there is no conflict of interestsregarding the publication of this paper
Acknowledgments
This work was supported by grants from the Spanish Min-istry of Economy and Competitiveness to Amanda Sierra(BFU2012-32089) and Juan M Encinas (SAF2012-40085)from Basque Government (Saiotek S-PC 12UN014) and Iker-basque start-up funds to JuanM Encinas andAmanda Sierraand fromTheBanting Research Foundation the Scottish RiteCharitable Foundation of Canada and start-up funds fromUniversite Laval andCentre de recherche duCHUdeQuebecto Marie-Eve Tremblay
References
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[2] F Ginhoux S Lim G Hoeffel D Low and T Huber ldquoOriginand differentiation of microgliardquo Frontiers in Cellular Neuro-science vol 7 article 45 2013
[3] E Gomez Perdiguero C Schulz and F Geissmann ldquoDevelop-ment and homeostasis of ldquoresidentrdquomyeloid cells the case of themicrogliardquo GLIA vol 61 no 1 pp 112ndash120 2013
[4] H Kettenmann F Kirchhoff and A Verkhratsky ldquoMicroglianew roles for the synaptic stripperrdquo Neuron vol 77 no 1 pp10ndash18 2013
[5] A Aguzzi B A Barres and M L Bennett ldquoMicroglia scape-goat saboteur or something elserdquo Science vol 339 no 6116 pp156ndash161 2013
[6] K Helmut U K Hanisch M Noda and A VerkhratskyldquoPhysiology of microgliardquo Physiological Reviews vol 91 no 2pp 461ndash553 2011
[7] M E Tremblay B Stevens A Sierra H Wake A Bessis andA Nimmerjahn ldquoThe role of microglia in the healthy brainrdquoJournal of Neuroscience vol 31 no 45 pp 16064ndash16069 2011
[8] A Miyamoto H Wake A J Moorhouse and J NabekuraldquoMicroglia and synapse interactions fine tuaning neural circuitsand candidate moleculesrdquo Frontiers in Cellular Neurosciencevol 7 article 70 2013
[9] C Bechade Y Cantaut-Belarif and A Bessis ldquoMicroglialcontrol of neuronal activityrdquo Frontiers in Cellular Neurosciencevol 7 article 32 2013
[10] A Sierra O Abiega A Shahraz and H Neumann ldquoJanus-faced microglia beneficial and detrimental consequences ofmicroglial phagocytosisrdquo Frontiers in Cellular Neuroscience vol7 article 6 2013
[11] G Kempermann S Jessberger B Steiner and G KronenbergldquoMilestones of neuronal development in the adult hippocam-pusrdquo Trends in Neurosciences vol 27 no 8 pp 447ndash452 2004
[12] J M Encinas T V Michurina N Peunova et al ldquoDivision-coupled astrocytic differentiation and age-related depletion ofneural stem cells in the adult hippocampusrdquo Cell Stem Cell vol8 no 5 pp 566ndash579 2011
[13] M A Bonaguidi M A Wheeler J S Shapiro et al ldquoIn vivoclonal analysis reveals self-renewing and multipotent adultneural stem cell characteristicsrdquo Cell vol 145 no 7 pp 1142ndash1155 2011
[14] J J Breunig J I Arellano J D Macklis and P RakicldquoEverything that glitters isnrsquot gold a critical review of postnatalneural precursor analysesrdquo Cell Stem Cell vol 1 no 6 pp 612ndash627 2007
[15] L S Overstreet-Wadiche and G L Westbrook ldquoFunctionalmaturation of adult-generated granule cellsrdquoHippocampus vol16 no 3 pp 208ndash215 2006
[16] S Ge C H Yang K S Hsu G L Ming andH Song ldquoA criticalperiod for enhanced synaptic plasticity in newly generatedneurons of the adult brainrdquo Neuron vol 54 no 4 pp 559ndash5662007
[17] E Bruel-Jungerman C Rampon and S Laroche ldquoAdult hip-pocampal neurogenesis synaptic plasticity and memory factsand hypothesesrdquo Reviews in the Neurosciences vol 18 no 2 pp93ndash114 2007
[18] K Nakajima S Honda Y Tohyama Y Imai S Kohsaka andT Kurihara ldquoNeurotrophin secretion from cultured microgliardquoJournal of Neuroscience Research vol 65 no 4 pp 322ndash3312001
[19] M Krampert S R Chirasani F P Wachs et al ldquoSmad7regulates the adult neural stemprogenitor cell pool in a trans-forming growth factor 120573- and bone morphogenetic protein-independent mannerrdquo Molecular and Cellular Biology vol 30no 14 pp 3685ndash3694 2010
[20] K I Mosher R H Andres T Fukuhara et al ldquoNeural pro-genitor cells regulate microglia functions and activityrdquo NatureNeuroscience vol 15 no 11 pp 1485ndash1487 2012
[21] V Tropepe M Sibilia B G Ciruna J Rossant E F Wagnerand D van der Kooy ldquoDistinct neural stem cells proliferatein response to EGF and FGF in the developing mouse telen-cephalonrdquo Developmental Biology vol 208 no 1 pp 166ndash1881999
[22] S U Kim and J De Vellis ldquoMicroglia in health and diseaserdquoJournal of Neuroscience Research vol 81 no 3 pp 302ndash3132005
[23] B A Reynolds and R L Rietze ldquoNeural stem cells andneurospheresmdashre-evaluating the relationshiprdquoNatureMethodsvol 2 no 5 pp 333ndash336 2005
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[26] J L Trejo E Carro and I Torres-Aleman ldquoCirculating insulin-like growth factor I mediates exercise-induced increases in thenumber of new neurons in the adult hippocampusrdquo Journal ofNeuroscience vol 21 no 5 pp 1628ndash1634 2001
Neural Plasticity 11
[27] K Striedinger and E Scemes ldquoInterleukin-1120573 affects calciumsignaling and in vitro cell migration of astrocyte progenitorsrdquoJournal of Neuroimmunology vol 196 no 1-2 pp 116ndash123 2008
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[29] G Kempermann and H Neumann ldquoMicroglia the enemywithinrdquo Science vol 302 no 5651 pp 1689ndash1690 2003
[30] M F Mehler R Rozental M Dougherty D C Spray and JA Kessler ldquoCytokine regulation of neuronal differentiation ofhippocampal progenitor cellsrdquo Nature vol 362 no 6415 pp62ndash65 1993
[31] U Gurok C Steinhoff B Lipkowitz H H Ropers C Scharffand U A Nuber ldquoGene expression changes in the course ofneural progenitor cell differentiationrdquo Journal of Neurosciencevol 24 no 26 pp 5982ndash6002 2004
[32] J B Demoulin M Enarsson J Larsson A Essaghir C HHeldin and K Forsberg-Nilsson ldquoThe gene expression profileof PDGF-treated neural stem cells corresponds to partiallydifferentiated neurons and gliardquo Growth Factors vol 24 no 3pp 184ndash196 2006
[33] F C Mansergh M A Wride and D E Rancourt ldquoNeuronsfrom stem cells implications for understanding nervous systemdevelopment and repairrdquo Biochemistry and Cell Biology vol 78no 5 pp 613ndash628 2000
[34] F C Alcantara Gomes V De Oliveira Sousa and L RomaoldquoEmerging roles for TGF-1205731 in nervous system developmentrdquoInternational Journal of Developmental Neuroscience vol 23 no5 pp 413ndash424 2005
[35] S Elkabes E M DiCicco-Bloom and I B Black ldquoBrainmicrogliamacrophages express neurotrophins that selectivelyregulate microglial proliferation and functionrdquo Journal of Neu-roscience vol 16 no 8 pp 2508ndash2521 1996
[36] U K Hanisch and H Kettenmann ldquoMicroglia active sensorand versatile effector cells in the normal and pathologic brainrdquoNature Neuroscience vol 10 no 11 pp 1387ndash1394 2007
[37] H J Klassen T F Ng Y Kurimoto et al ldquoMultipotent retinalprogenitors express developmental markers differentiate intoretinal neurons and preserve light-mediated behaviorrdquo Inves-tigative Ophthalmology and Visual Science vol 45 no 11 pp4167ndash4173 2004
[38] W J Streit S D Hurley T S McGraw and S L Semple-Rowland ldquoComparative evaluation of cytokine profiles andreactive gliosis supports a critical role for interleukin-6 inneuron-glia signaling during regenerationrdquo Journal of Neuro-science Research vol 61 no 1 pp 10ndash20 2000
[39] A Suzumura M Sawada H Yamamoto and T MarunouchildquoEffects of colony stimulating factors on isolated microglia invitrordquo Journal of Neuroimmunology vol 30 no 2-3 pp 111ndash1201990
[40] Z Lu M R Elliott Y Chen et al ldquoPhagocytic activity ofneuronal progenitors regulates adult neurogenesisrdquoNature CellBiology vol 13 no 9 pp 1076ndash1084 2011
[41] K Nakajima Y Kikuchi E Ikoma et al ldquoNeurotrophinsregulate the function of cultured microgliardquo GLIA vol 24 no3 pp 272ndash289 1998
[42] P A Lodge and S Sriram ldquoRegulation of microglial activationby TGF-120573 IL-10 and CSF-1rdquo Journal of Leukocyte Biology vol60 no 4 pp 502ndash508 1996
[43] W S Sheng S Hu F H Kravitz P K Peterson and C C ChaoldquoTumor necrosis factor alpha upregulates humanmicroglial cell
production of interleukin-10 in vitrordquo Clinical and DiagnosticLaboratory Immunology vol 2 no 5 pp 604ndash608 1995
[44] G LMing andH Song ldquoAdult neurogenesis in themammalianbrain significant answers and significant questionsrdquo Neuronvol 70 no 4 pp 687ndash702 2011
[45] E Bruel-Jungerman S Davis C Rampon and S LarocheldquoLong-term potentiation enhances neurogenesis in the adultdentate gyrusrdquo Journal of Neuroscience vol 26 no 22 pp 5888ndash5893 2006
[46] E Drapeau M F Montaron S Aguerre and D N AbrousldquoLearning-induced survival of new neurons depends on thecognitive status of aged ratsrdquo Journal of Neuroscience vol 27no 22 pp 6037ndash6044 2007
[47] A Mouret G Gheusi M M Gabellec F De Chaumont J COlivo-Marin and P M Lledo ldquoLearning and survival of newlygenerated neurons when timemattersrdquo Journal of Neurosciencevol 28 no 45 pp 11511ndash11516 2008
[48] N Kee C M Teixeira A H Wang and P W FranklandldquoPreferential incorporation of adult-generated granule cellsinto spatial memory networks in the dentate gyrusrdquo NatureNeuroscience vol 10 no 3 pp 355ndash362 2007
[49] F Massa M Koelh T Wiesner et al ldquoConditional reduction ofadult neurogenesis impairs bidirectional hippocampal synapticplasticityrdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 108 no 16 pp 6644ndash6649 2011
[50] T J Shors G Miesegaes A Beylin M Zhao T Rydel and EGould ldquoNeurogenesis in the adult is involved in the formationof tracememoriesrdquoNature vol 410 no 6826 pp 372ndash376 2001
[51] W Deng M D Saxe I S Gallina and F H Gage ldquoAdult-born hippocampal dentate granule cells undergoingmaturationmodulate learning and memory in the brainrdquo Journal of Neuro-science vol 29 no 43 pp 13532ndash13542 2009
[52] M Arruda-Carvalho M Sakaguchi K G Akers S A Josselynand P W Frankland ldquoPosttraining ablation of adult-generatedneurons degrades previously acquired memoriesrdquo Journal ofNeuroscience vol 31 no 42 pp 15113ndash15127 2011
[53] A Sahay K N Scobie A S Hill et al ldquoIncreasing adulthippocampal neurogenesis is sufficient to improve patternseparationrdquo Nature vol 472 no 7344 pp 466ndash470 2011
[54] G LMing andH Song ldquoAdult neurogenesis in themammaliancentral nervous systemrdquoAnnual Review of Neuroscience vol 28pp 223ndash250 2005
[55] K Newton and V M Dixit ldquoSignaling in innate immunity andinflammationrdquo Cold Spring Harbor Perspectives in Biology vol4 no 3 2012
[56] H K Jeong K Ji K Min and E H Joe ldquoBrain inflammationand microglia facts and misconceptionsrdquo Experimental Neuro-biology vol 22 no 2 pp 59ndash67 2013
[57] D Stellwagen and R CMalenka ldquoSynaptic scalingmediated byglial TNF-120572rdquo Nature vol 440 no 7087 pp 1054ndash1059 2006
[58] M Pickering D Cumiskey and J J OrsquoConnor ldquoActions of TNF-120572 on glutamatergic synaptic transmission in the central nervoussystemrdquo Experimental Physiology vol 90 no 5 pp 663ndash6702005
[59] K Belarbi T Jopson D Tweedie et al ldquoTNF-120572 protein synthe-sis inhibitor restores neuronal function and reverses cognitivedeficits induced by chronic neuroinflammationrdquo Journal ofNeuroinflammation vol 9 article 23 2012
[60] C T Ekdahl J H Claasen S Bonde Z Kokaia andO LindvallldquoInflammation is detrimental for neurogenesis in adult brainrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 100 no 23 pp 13632ndash13637 2003
12 Neural Plasticity
[61] M L Monje H Toda and T D Palmer ldquoInflammatoryblockade restores adult hippocampal neurogenesisrdquo Sciencevol 302 no 5651 pp 1760ndash1765 2003
[62] A Sierra J M Encinas J J P Deudero et al ldquoMicroglia shapeadult hippocampal neurogenesis through apoptosis-coupledphagocytosisrdquo Cell Stem Cell vol 7 no 4 pp 483ndash495 2010
[63] D Chugh P Nilsson S A Afjei A Bakochi and C T EkdahlldquoBrain inflammation induces post-synaptic changes duringearly synapse formation in adult-born hippocampal neuronsrdquoExperimental Neurobiology vol 250 pp 176ndash188 2013
[64] K Belarbi C Arellano R Ferguson T Jopson and S RosildquoChronic neuroinflammation impacts the recruitment of adult-born neurons into behaviorally relevant hippocampal net-worksrdquo Brain Behavior and Immunity vol 26 no 1 pp 18ndash232012
[65] S Johann E Kampmann B Denecke et al ldquoExpression ofenzymes involved in the prostanoid metabolism by corticalastrocytes after LPS-induced inflammationrdquo Journal of Molec-ular Neuroscience vol 34 no 2 pp 177ndash185 2008
[66] P V B Reddy K V Rama Rao and M D NorenbergldquoInhibitors of the mitochondrial permeability transition reduceammonia-induced cell swelling in cultured astrocytesrdquo Journalof Neuroscience Research vol 87 no 12 pp 2677ndash2685 2009
[67] H Nie H Zhang and H R Weng ldquoMinocycline preventsimpaired glial glutamate uptake in the spinal sensory synapsesof neuropathic ratsrdquo Neuroscience vol 170 no 3 pp 901ndash9122010
[68] F Cerbai D Lana D Nosi et al ldquoThe neuron-astrocyte-microglia triad in normal brain ageing and in a model ofneuroinflammation in the rat hippocampusrdquo PLoS ONE vol 7no 9 Article ID e45250 2012
[69] W J Jin S W Feng Z Feng S M Lu T Qi and Y N QianldquoMinocycline improves postoperative cognitive impairment inaged mice by inhibiting astrocytic activationrdquo NeuroReport2013
[70] K A Ji M S Yang H K Jeong et al ldquoResident microgliadie and infiltrated neutrophils and monocytes become majorinflammatory cells in lipopolysaccharide-injected brainrdquoGLIAvol 55 no 15 pp 1577ndash1588 2007
[71] N J van Wagoner J W Oh P Repovic and E N BenvenisteldquoInterleukin-6 (IL-6) production by astrocytes autocrine reg-ulation by IL-6 and the soluble IL-6 receptorrdquo Journal ofNeuroscience vol 19 no 13 pp 5236ndash5244 1999
[72] L Vallieres I L Campbell F H Gage and P E SawchenkoldquoReduced hippocampal neurogenesis in adult transgenic micewith chronic astrocytic production of interleukin-6rdquo Journal ofNeuroscience vol 22 no 2 pp 486ndash492 2002
[73] B S McEwen ldquoPhysiology and neurobiology of stress andadaptation central role of the brainrdquo Physiological Reviews vol87 no 3 pp 873ndash904 2007
[74] V LuineMVillegas CMartinez and B SMcEwen ldquoRepeatedstress causes reversible impairments of spatial memory perfor-mancerdquo Brain Research vol 639 no 1 pp 167ndash170 1994
[75] S Rivest ldquoMolecular insights on the cerebral innate immunesystemrdquo Brain Behavior and Immunity vol 17 no 1 pp 13ndash192003
[76] S Nadeau and S Rivest ldquoEndotoxemia prevents the cerebralinflammatory wave induced by intraparenchymal lipopolysac-charide injection role of glucocorticoids and CD14rdquo Journal ofImmunology vol 169 no 6 pp 3370ndash3381 2002
[77] A Sierra A Gottfried-Blackmore T A Milner B S McEwenand K Bulloch ldquoSteroid hormone receptor expression andfunction in microgliardquo GLIA vol 56 no 6 pp 659ndash674 2008
[78] C Liston andW B Gan ldquoGlucocorticoids are critical regulatorsof dendritic spine development and plasticity in vivordquo Proceed-ings of the National Academy of Sciences of the United States ofAmerica vol 108 no 38 pp 16074ndash16079 2011
[79] C Liston J M Cichon F Jeanneteau Z Jia M V Chaoand W B Gan ldquoCircadian glucocorticoid oscillations pro-mote learning-dependent synapse formation andmaintenancerdquoNature Neuroscience vol 16 no 6 pp 698ndash705 2013
[80] M A Carrillo-de Sauvage L Maatouk I Arnoux et al ldquoPotentand multiple regulatory actions of microglial glucocorticoidreceptors during CNS inflammationrdquo Cell Death amp Differenti-ation vol 20 no 11 pp 1546ndash1557 2013
[81] S F Sorrells J R Caso C DMunhoz and RM Sapolsky ldquoThestressed CNS when glucocorticoids aggravate inflammationrdquoNeuron vol 64 no 1 pp 33ndash39 2009
[82] M A Bellavance and S Rivest ldquoThe neuroendocrine controlof the innate immune system in health and brain diseasesrdquoImmunological Reviews vol 248 no 1 pp 36ndash55 2012
[83] R J Tynan S Naicker M Hinwood et al ldquoChronic stress altersthe density and morphology of microglia in a subset of stress-responsive brain regionsrdquo Brain Behavior and Immunity vol24 no 7 pp 1058ndash1068 2010
[84] E S Wohleb N D Powell J P Godbout and J F SheridanldquoStress-induced recruitment of bone marrow-derived mono-cytes to the brain promotes anxiety-like behaviorrdquo The Journalof Neuroscience vol 33 no 34 pp 13820ndash13833 2013
[85] Y Diz-Chaves M Astiz M J Bellini and L M Garcia-SeguraldquoPrenatal stress increases the expression of proinflammatorycytokines and exacerbates the inflammatory response to LPS inthe hippocampal formation of adultmalemicerdquoBrain Behaviorand Immunity vol 28 pp 196ndash206 2013
[86] E S Wohleb A M Fenn A M Pacenta N D Powell J FSheridan and J P Godbout ldquoPeripheral innate immune chal-lenge exaggerated microglia activation increased the numberof inflammatory CNSmacrophages and prolonged social with-drawal in socially defeated micerdquo Psychoneuroendocrinologyvol 37 no 9 pp 1491ndash1505 2012
[87] C Mirescu and E Gould ldquoStress and adult neurogenesisrdquoHippocampus vol 16 no 3 pp 233ndash238 2006
[88] J LWarner-Schmidt andR SDuman ldquoHippocampal neuroge-nesis opposing effects of stress and antidepressant treatmentrdquoHippocampus vol 16 no 3 pp 239ndash249 2006
[89] N D Hanson M J Owens K A Boss-Williams J M Weissand C B Nemeroff ldquoSeveral stressors fail to reduce adulthippocampal neurogenesisrdquo Psychoneuroendocrinology vol 36no 10 pp 1520ndash1529 2011
[90] E Gould B S McEwen P Tanapat L A M Galea and EFuchs ldquoNeurogenesis in the dentate gyrus of the adult treeshrew is regulated by psychosocial stress and NMDA receptoractivationrdquo Journal of Neuroscience vol 17 no 7 pp 2492ndash24981997
[91] JW Koo andR S Duman ldquoIL-1120573 is an essentialmediator of theantineurogenic and anhedonic effects of stressrdquo Proceedings ofthe National Academy of Sciences of the United States of Americavol 105 no 2 pp 751ndash756 2008
[92] D C Lagace M H Donovan N A Decarolis et al ldquoAdulthippocampal neurogenesis is functionally important for stress-induced social avoidancerdquo Proceedings of the National Academy
Neural Plasticity 13
of Sciences of the United States of America vol 107 no 9 pp4436ndash4441 2010
[93] G Kronenberg I Kirste D Inta et al ldquoReduced hippocampalneurogenesis in the GR+- genetic mousemodel of depressionrdquoEuropean Archives of Psychiatry and Clinical Neuroscience vol259 no 8 pp 499ndash504 2009
[94] M B Howren D M Lamkin and J Suls ldquoAssociations ofdepression with c-reactive protein IL-1 and IL-6 a meta-analysisrdquo Psychosomatic Medicine vol 71 no 2 pp 171ndash1862009
[95] J W Koo S J Russo D Ferguson E J Nestler and R SDuman ldquoNuclear factor-120581B is a critical mediator of stress-impaired neurogenesis and depressive behaviorrdquo Proceedings ofthe National Academy of Sciences of the United States of Americavol 107 no 6 pp 2669ndash2674 2010
[96] I Goshen T Kreisel O Ben-Menachem-Zidon et al ldquoBraininterleukin-1 mediates chronic stress-induced depression inmice via adrenocortical activation and hippocampal neuroge-nesis suppressionrdquo Molecular Psychiatry vol 13 no 7 pp 717ndash728 2008
[97] C D Munhoz L B Lepsch E M Kawamoto et al ldquoChronicunpredictable stress exacerbates lipopolysaccharide-inducedactivation of nuclear factor-120581B in the frontal cortex andhippocampus via glucocorticoid secretionrdquo Journal of Neuro-science vol 26 no 14 pp 3813ndash3820 2006
[98] S J Sukoff Rizzo S J Neal Z A Hughes et al ldquoEvidence forsustained elevation of IL-6 in the CNS as a key contributorof depressive-like phenotypesrdquo Translational Psychiatry vol 2article e199 2012
[99] A Garcia B Steiner G Kronenberg A Bick-Sander and GKempermann ldquoAge-dependent expression of glucocorticoid-andmineralocorticoid receptors on neural precursor cell popu-lations in the adult murine hippocampusrdquoAging Cell vol 3 no6 pp 363ndash371 2004
[100] M G Frank B M Thompson L R Watkins and S F MaierldquoGlucocorticoids mediate stress-induced priming of microglialpro-inflammatory responsesrdquo Brain Behavior and Immunityvol 26 no 2 pp 337ndash345 2012
[101] S Sugama M Fujita M Hashimoto and B Conti ldquoStressinduced morphological microglial activation in the rodentbrain involvement of interleukin-18rdquoNeuroscience vol 146 no3 pp 1388ndash1399 2007
[102] A Sierra J M Encinas and M Maletic-Savatic ldquoAdult humanneurogenesis from microscopy to magnetic resonance imag-ingrdquo Frontiers in Neuroscience vol 5 article 47 2011
[103] H G Kuhn H Dickinson-Anson and F H Gage ldquoNeurogen-esis in the dentate gyrus of the adult rat age-related decrease ofneuronal progenitor proliferationrdquo Journal of Neuroscience vol16 no 6 pp 2027ndash2033 1996
[104] L N Manganas X Zhang Y Li et al ldquoMagnetic resonancespectroscopy identifies neural progenitor cells in the live humanbrainrdquo Science vol 318 no 5852 pp 980ndash985 2007
[105] K L Spalding O Bergmann K Alkass et al ldquoDynamics ofhippocampal neurogenesis in adult humansrdquo Cell vol 153 no6 pp 1219ndash1227 2013
[106] J M Encinas and A Sierra ldquoNeural stem cell deforestationas the main force driving the age-related decline in adulthippocampal neurogenesisrdquo Behavioural Brain Research vol227 no 2 pp 433ndash439 2012
[107] K S Krabbe M Pedersen andH Bruunsgaard ldquoInflammatorymediators in the elderlyrdquo Experimental Gerontology vol 39 no5 pp 687ndash699 2004
[108] B S Diniz A L Teixeira L Talib W F Gattaz andO V Forlenza ldquoInterleukin-1120573 serum levels is increased inantidepressant-free elderly depressed patientsrdquo American Jour-nal of Geriatric Psychiatry vol 18 no 2 pp 172ndash176 2010
[109] A Sierra A C Gottfried-Blackmore B S Mcewen and KBulloch ldquoMicroglia derived from aging mice exhibit an alteredinflammatory profilerdquo GLIA vol 55 no 4 pp 412ndash424 2007
[110] C FranceschiM Bonafe S Valensin et al ldquoInflamm-aging Anevolutionary perspective on immunosenescencerdquo Annals of theNew York Academy of Sciences vol 908 pp 244ndash254 2000
[111] R Sano and J C Reed ldquoER stress-induced cell death mecha-nismsrdquoBiochimica et BiophysicaActa vol 1833 no 12 pp 3460ndash3470 2013
[112] S Z Hasnain R Lourie I Das A C H Chen and MA McGuckin ldquoThe interplay between endoplasmic reticulumstress and inflammationrdquo Immunology and Cell Biology vol 90no 3 pp 260ndash270 2012
[113] S Matus L H Glimcher and C Hetz ldquoProtein folding stressin neurodegenerative diseases a glimpse into the ERrdquo CurrentOpinion in Cell Biology vol 23 no 2 pp 239ndash252 2011
[114] Y Ito M Yamada H Tanaka et al ldquoInvolvement of CHOP anER-stress apoptotic mediator in both human sporadic ALS andALS model micerdquo Neurobiology of Disease vol 36 no 3 pp470ndash476 2009
[115] D Papadimitriou V Le Verche A Jacquier B Ikiz S Przed-borski and D B Re ldquoInflammation in ALS and SMA sortingout the good from the evilrdquo Neurobiology of Disease vol 37 no3 pp 493ndash502 2010
[116] A R Johnson J J Milner and LMakowski ldquoThe inflammationhighway metabolism accelerates inflammatory traffic in obe-sityrdquo Immunological Reviews vol 249 no 1 pp 218ndash238 2012
[117] S Buch H Yao M Guo et al ldquoCocaine and HIV-1 interplayin CNS cellular and molecular mechanismsrdquo Current HIVResearch vol 10 no 5 pp 425ndash428 2012
[118] M K Brown and N Naidoo ldquoThe endoplasmic reticulumstress response in aging and age-related diseasesrdquo Frontiers inPhysiology vol 3 article 263 2012
[119] G Castro C Areias MF L Weissmann et al ldquoDiet-inducedobesity induces endoplasmic reticulum stress and insulin resis-tance in the amygdala of ratsrdquo FEBS Open Bio vol 3 pp 443ndash449 2013
[120] A A Pavlovsky D Boehning D Li Y Zhang X Fan andT A Green ldquoPsychological stress cocaine and natural rewardeach induce endoplasmic reticulum stress genes in rat brainrdquoNeuroscience vol 246 pp 160ndash169 2013
[121] G GargiuloM CesaroniM Serresi et al ldquoIn vivo RNAi screenfor BMI1 targets identifies TGF-betaBMP-ER stress pathwaysas key regulators of neural- and malignant glioma-stem cellhomeostasisrdquo Cancer Cell vol 23 no 5 pp 660ndash676 2013
[122] A Salminen K Kaarniranta and A Kauppinen ldquoInflammag-ing disturbed interplay between autophagy and inflamma-somesrdquo Aging vol 4 no 3 pp 166ndash175 2012
[123] E Latz T S Xiao andA Stutz ldquoActivation and regulation of theinflammasomesrdquoNature Reviews Immunology vol 13 no 6 pp397ndash411 2013
[124] C Gemma A D Bachstetter M J Cole M Fister C Hudsonand P C Bickford ldquoBlockade of caspase-1 increases neurogene-sis in the aged hippocampusrdquo European Journal of Neurosciencevol 26 no 10 pp 2795ndash2803 2007
[125] M D Wu A M Hein M J Moravan S S Shaftel J AOlschowka and M K OrsquoBanion ldquoAdult murine hippocampal
14 Neural Plasticity
neurogenesis is inhibited by sustained IL-1120573 and not rescued byvoluntary runningrdquo Brain Behavior and Immunity vol 26 no2 pp 292ndash300 2012
[126] Y Wolf S Yona K W Kim and S Jung ldquoMicroglia seen fromthe CX3CR1 anglerdquo Frontiers in Cellular Neuroscience vol 7article 26 2013
[127] A E Cardona E P Pioro M E Sasse et al ldquoControl ofmicroglial neurotoxicity by the fractalkine receptorrdquo NatureNeuroscience vol 9 no 7 pp 917ndash924 2006
[128] K Bhaskar M Konerth O N Kokiko-Cochran A Cardona RM Ransohoff and B T Lamb ldquoRegulation of tau pathology bythe microglial fractalkine receptorrdquo Neuron vol 68 no 1 pp19ndash31 2010
[129] A D Bachstetter J M Morganti J Jernberg et al ldquoFractalkineand CX3CR1 regulate hippocampal neurogenesis in adult andaged ratsrdquo Neurobiology of Aging vol 32 no 11 pp 2030ndash20442011
[130] S Jung J Aliberti P Graemmel et al ldquoAnalysis of fractalkinereceptor CX3CR1 function by targeted deletion and greenfluorescent protein reporter gene insertionrdquo Molecular andCellular Biology vol 20 no 11 pp 4106ndash4114 2000
[131] J T Rogers J M Morganti A D Bachstetter et al ldquoCX3CR1deficiency leads to impairment of hippocampal cognitive func-tion and synaptic plasticityrdquo Journal of Neuroscience vol 31 no45 pp 16241ndash16250 2011
[132] W S T Griffin L C Stanley C Ling et al ldquoBrain interleukin1 and S-100 immunoreactivity are elevated in Down syndromeand Alzheimer diseaserdquo Proceedings of the National Academy ofSciences of the United States of America vol 86 no 19 pp 7611ndash7615 1989
[133] W C Benzing J RWujek E KWard et al ldquoEvidence for glial-mediated inflammation in aged APP(SW) transgenic micerdquoNeurobiology of Aging vol 20 no 6 pp 581ndash589 1999
[134] T J Seabrook L Jiang M Maier and C A Lemere ldquoMinocy-cline affects microglia activation A120573 deposition and behaviorin APP-tg micerdquo GLIA vol 53 no 7 pp 776ndash782 2006
[135] B Biscaro O Lindvall G Tesco C T Ekdahl and RM NitschldquoInhibition of microglial activation protects hippocampal neu-rogenesis and improves cognitive deficits in a transgenic mousemodel for Alzheimerrsquos diseaserdquoNeurodegenerative Diseases vol9 no 4 pp 187ndash198 2012
[136] P A Zunszain C Anacker A Cattaneo et al ldquoInterleukin-1120573a new regulator of the kynurenine pathway affecting humanhippocampal neurogenesisrdquo Neuropsychopharmacology vol 37no 4 pp 939ndash949 2012
[137] R De Simone M Antonietta Ajmone-Cat P Tirassa and LMinghetti ldquoApoptotic PC12 cells exposing phosphatidylserinepromote the production of anti-inflammatory and neuropro-tective molecules bymicroglial cellsrdquo Journal of Neuropathologyand Experimental Neurology vol 62 no 2 pp 208ndash216 2003
[138] M S Buckwalter M Yamane B S Coleman et al ldquoChroni-cally increased transforming growth factor-1205731 strongly inhibitshippocampal neurogenesis in aged micerdquo American Journal ofPathology vol 169 no 1 pp 154ndash164 2006
[139] O Butovsky Y Ziv A Schwartz et al ldquoMicroglia activatedby IL-4 or IFN-120574 differentially induce neurogenesis and oligo-dendrogenesis from adult stemprogenitor cellsrdquoMolecular andCellular Neuroscience vol 31 no 1 pp 149ndash160 2006
[140] C T Ekdahl ldquoMicroglial activationmdashtuning and pruning adultneurogenesisrdquo Frontiers in Pharmacology vol 3 article 41 2012
[141] HWakeA JMoorhouse S Jinno S Kohsaka and JNabekuraldquoResting microglia directly monitor the functional state ofsynapses in vivo and determine the fate of ischemic terminalsrdquoJournal of Neuroscience vol 29 no 13 pp 3974ndash3980 2009
[142] M E Tremblay R L Lowery and A K Majewska ldquoMicroglialinteractions with synapses are modulated by visual experiencerdquoPLoS Biology vol 8 no 11 Article ID e1000527 2010
[143] M E Tremblay M L Zettel J R Ison P D Allen and A KMajewska ldquoEffects of aging and sensory loss on glial cells inmouse visual and auditory corticesrdquo GLIA vol 60 no 4 pp541ndash558 2012
[144] D P Schafer E K Lehrman A G Kautzman et al ldquoMicrogliasculpt postnatal neural circuits in an activity and complement-dependent mannerrdquo Neuron vol 74 no 4 pp 691ndash705 2012
[145] H Nakanishi ldquoMicroglial functions and proteasesrdquo MolecularNeurobiology vol 27 no 2 pp 163ndash176 2003
[146] M E Tremblay and A K Majewska ldquoA role for microglia insynaptic plasticityrdquoCommunicative and Integrative Biology vol4 no 2 pp 220ndash222 2011
[147] R C Paolicelli G Bolasco F Pagani et al ldquoSynaptic pruning bymicroglia is necessary for normal brain developmentrdquo Sciencevol 333 no 6048 pp 1456ndash1458 2011
[148] GKempermannHGKuhn and FHGage ldquoMore hippocam-pal neurons in adult mice living in an enriched environmentrdquoNature vol 386 no 6624 pp 493ndash495 1997
[149] M Nilsson E Perfilieva U Johansson O Orwar and P SEriksson ldquoEnriched environment increases neurogenesis in theadult rat dentate gyrus and improves spatial memoryrdquo Journalof Neurobiology vol 39 no 4 pp 569ndash578 1999
[150] H van Praag G Kempermann and F H Gage ldquoRunningincreases cell proliferation and neurogenesis in the adult mousedentate gyrusrdquo Nature Neuroscience vol 2 no 3 pp 266ndash2701999
[151] D Young P A Lawlor P Leone M Dragunow and MJ During ldquoEnvironmental enrichment inhibits spontaneousapoptosis prevents seizures and is neuroprotectiverdquo NatureMedicine vol 5 no 4 pp 448ndash453 1999
[152] L L Williamson A Chao and S D Bilbo ldquoEnvironmentalenrichment alters glial antigen expression and neuroimmunefunction in the adult rat hippocampusrdquo Brain Behavior andImmunity vol 26 no 3 pp 500ndash510 2012
[153] L Maggi M Scianni I Branchi I DrsquoAndrea C Lauro and CLimatola ldquoCX(3)CR1 deficiency alters hippocampal-dependentplasticity phenomena blunting the effects of enriched environ-mentrdquo Frontiers in Cellular Neuroscience vol 5 article 22 2011
[154] I Goshen A Avital T Kreisel T Licht M Segal and RYirmiya ldquoEnvironmental enrichment restores memory func-tioning in mice with impaired IL-1 signaling via reinstatementof long-term potentiation and spine size enlargementrdquo Journalof Neuroscience vol 29 no 11 pp 3395ndash3403 2009
[155] Y Ziv N Ron O Butovsky et al ldquoImmune cells contribute tothe maintenance of neurogenesis and spatial learning abilitiesin adulthoodrdquo Nature Neuroscience vol 9 no 2 pp 268ndash2752006
[156] J Kipnis H Cohen M Cardon Y Ziv and M Schwartz ldquoTcell deficiency leads to cognitive dysfunction implications fortherapeutic vaccination for schizophrenia and other psychiatricconditionsrdquo Proceedings of the National Academy of Sciences ofthe United States of America vol 101 no 21 pp 8180ndash8185 2004
[157] S A Wolf B Steiner A Akpinarli et al ldquoCD4-positive Tlymphocytes provide a neuroimmunological link in the control
Neural Plasticity 15
of adult hippocampal neurogenesisrdquo Journal of Immunologyvol 182 no 7 pp 3979ndash3984 2009
[158] G J Huang A L Smith D H D Gray et al ldquoA genetic andfunctional relationship between T cells and cellular prolifera-tion in the adult hippocampusrdquo PLOS Biology vol 8 no 12Article ID e1000561 2010
[159] R M Ransohoff and B Engelhardt ldquoThe anatomical andcellular basis of immune surveillance in the central nervoussystemrdquoNature Reviews Immunology vol 12 no 9 pp 623ndash6352012
[160] M Olah G Ping A H De Haas et al ldquoEnhanced hippocampalneurogenesis in the absence of microglia T cell interactionand microglia activation in the murine running wheel modelrdquoGLIA vol 57 no 10 pp 1046ndash1061 2009
[161] E Gebara S Sultan J Kocher-Braissant and N Toni ldquoAdulthippocampal neurogenesis inversely correlates with microgliain conditions of voluntary running and agingrdquo Frontiers inNeuroscience vol 7 article 145 2013
[162] R Aharoni B Kayhan R Eilam M Sela and R ArnonldquoGlatiramer acetate-specific T cells in the brain express T helper23 cytokines and brain-derived neurotrophic factor in siturdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 100 no 2 pp 14157ndash14162 2003
[163] C Rossi A Angelucci L Costantin et al ldquoBrain-derivedneurotrophic factor (BDNF) is required for the enhancementof hippocampal neurogenesis following environmental enrich-mentrdquo European Journal of Neuroscience vol 24 no 7 pp 1850ndash1856 2006
4 Neural Plasticity
imbalance of excitatory and inhibitory neurotransmissionin these young neurons [63] Finally LPS also prevents theintegration of newborn neurons into behaviourally relevantnetworks including most notably their activation duringspatial exploration as determined by the percentage of BrdUcells colabeled with the immediate early gene Arc [64]
Importantly none of these manipulations is specific tomicroglia and may directly or indirectly affect other braincells involved in the inflammatory response of the brain Forinstance both LPS andminocycline affect astrocytic functionin vitro and in vivo [65ndash69] Furthermore LPS is knownto drive infiltration of monocytes and neutrophils into thebrain parenchyma [70] Monocytes and neutrophils producemajor proinflammatorymediators and could therefore act onthe neurogenic cascade as well The implication of microgliain LPS-induced decrease in neurogenesis is nonethelesssupported in vivo by the negative correlation between thenumber of newborn neurons (BrdU+ NeuN+ cells) andthe number of ldquoactivatedrdquo microglia (ie expressing ED1)[60] ED1 also called CD68 or macrosialin is a lysosomalprotein which is overexpressed during inflammatory chal-lenge While the location of ED1 previously suggested itsinvolvement in phagocytosis its loss of function did not resultin phagocytosis deficits and thus its function still remainsunknown (reviewed in [10]) The number of ED1-positivemicroglia also negatively correlates with neurogenesis duringinflammation provoked by cranial irradiation [61] Whilecorrelation does not involve causation nor can pinpoint tothe underlying mechanism these experiments were the firstto reveal a potential role for ldquoactivatedrdquo microglia in theregulation of adult hippocampal neurogenesis More directevidence of microglial mediation in LPS deleterious effectswas obtained from in vitro experiments as it was shown thatconditionedmedia fromLPS-challengedmicroglia containedIL-6 which in turn caused apoptosis of neuroblasts [61]Nonetheless astrocytes can also release IL-6 when stimulatedwith TNF120572 or IL-1120573 [71] and chronic astrocytic releaseof IL-6 in transgenic mice reduced proliferation survivaland differentiation of newborn cells thus resulting in anet decrease in neurogenesis [72] In summary while thedetrimental impact of inflammation on neurogenesis is wellestablished more work is needed to define the specific rolesplayed by the various inflammatory cells populating thebrain
4 Inflammation Associated withChronic Stress
Across health and disease the most prevalent condi-tion that is associated with neuroinflammation is ldquochronicstressrdquo which commonly refers to the repeated or sus-tained inability to cope with stressful environmental socialand psychological constraints Chronic stress is character-ized by an imbalanced secretion of glucocorticoids by thehypothalamic-pituitary-adrenal (HPA) axis (most notablycortisol in humans and corticosterone in rodents) whichleads to an altered brain remodelingmassive loss of synapsesand compromised cognitive function [73] In particular an
impairment of spatial learning working memory noveltyseeking and decision making has been associated withchronic stress [74] Glucocorticoids are well known fortheir anti-inflammatory properties as they interfere withNF-120581B-mediated cytokine transcription ultimately delayingwound healing [75] They are also potent anti-inflammatorymediators in vivo [76] and in purified microglia cultures[77] Recently repeated administration of high doses ofglucocorticoids by intraperitoneal injection to mimic theirrelease by chronic stress was also shown to induce a lossof dendritic spines in the motor cortex while impairinglearning of a motor task A transcription-dependent pathwayacting downstream of the glucocorticoid receptor GR wasproposed [78 79] but the particular cell types involved werenot identified
Microglia are considered to be a direct target of the gluco-corticoids as they were shown to express GR during normalphysiological conditions in vivo [77] In fact transgenic micelacking GR in microglia and macrophages show an increasedproduction of proinflammatory mediators (including TNF120572and IL-1120573) and greater neuronal damage in response to anintraparenchymal injection of LPS compared to wild-typemice [80] In contrast glucocorticoids are considered to beproinflammatory in the chronically stressed brain [81] whereamong other changes they can promote inflammation oxida-tive stress neurodegeneration andmicroglial activation [82]For example repeated restraint stress induces microglialproliferation and morphological changes including a hyper-ramification of their processes in the adult hippocampusfollowing restraint stress [83] but a nearly complete lossof processes in the context of social defeat [84] Prenatalrestraint stress also causes an increase in the basal levels ofTNF120572 and IL-1120573 while increasing the proportion ofmicrogliashowing a reactive morphology in the adult hippocampus[85] Similarly social defeat leads to an enhanced responseto the inflammatory challenge induced by intraperitonealinjection of LPS including an increased production of TNF120572and IL-1120573 and expression of inducible NO synthase (iNOS)by microglia accompanied by an increased infiltration ofcirculating monocytes [84 86] Therefore microglia are astrong candidate for mediating some of the effects of stresson adult neurogenesis as will be discussed below in synergywith other types of inflammatory cells
Chronic stress is well known for its negative effects onhippocampal neurogenesis (reviewed in [87 88]) althoughnot all stress paradigms are equally effective [89] Severalstress paradigms can decrease neuroprogenitors proliferationin the tree shrew [90] and inmice [91 92] although this effectseems to be compensated by an increased survival of newbornneurons [92] and whether stress results in a net increaseor decrease in neurogenesis remains controversial (reviewedin [87 88]) The effects of stress on adult neurogenesisseem to be mediated at least partially by glucocorticoidsbecause mice lacking a single copy of the GR gene showbehavioural symptoms of depression including learned help-lessness neuroendocrine alterations of the HPA axis andimpaired neurogenesis [93] In parallel chronic stress isassociated with an increased inflammatory response whichmay inhibit neurogenesis as well For instance serum levels
Neural Plasticity 5
of IL-1120573 and IL-6 are significantly increased in depressedpatients [94] In mice restraint stress leads to a widespreadactivation of NF-120581B in the hippocampus including at thelevel of neuroprogenitors [95] and increased protein levels ofIL-1120573 [96] In addition to the direct role of glucocorticoidsIL-1120573 also seems to mediate some of the effects of mildchronic stress because in vivomanipulations that block IL-1120573(either pharmacologically or in null transgenic mice) preventthe anhedonic stress response and the antineurogenic effectof stress [91 96]Moreover the corticoids and IL-1120573 pathwaysmay regulate each other in a bidirectional manner becausethe administration of a GR antagonist can blunt the LPS-induced production of hippocampal IL-1120573 in stressed mice[97] whereas mice knockout for the IL-1120573 receptor (IL-1R1)fail to display the characteristic elevation of corticosteroneinduced by mild chronic stress [96] Another stress-relatedcytokine IL-6 induces depressive phenotypes and preventsthe antidepressant actions of fluoxetinewhen administered tomice in vivo [98] So far the effects of stress on neurogenesisvia corticosteroids and inflammation have been assumed tobe cell autonomous as neuroprogenitors express both GR[99] and IL-1R1 [95] The potential participation of microgliais yet to be determined but there are some reports of adirect effect of stress on microglial activation For instancemicroglia acutely isolated frommice subjected to acute stress(by inescapable tail shock) showed a primed response to LPSchallenge by producing higher levels of IL-1120573mRNA ex vivo[100] and the specific loss of expression of GR in microglialeads to a blunted inflammatory response in vitro and to adecreased neuronal damage in vivo in response to LPS [80]In stress paradigms these enhanced responses of microgliato inflammatory challenges are similar to their age-relatedldquoprimingrdquo which has been associated with and is possiblydue to an increased basal production of proinflammatorymediators However whether microglia express increasedlevels of IL-1120573 and other proinflammatory cytokines inresponse to stressful events is presently unclear [101] It is thuspossible that some of the antineurogenic effects of stress areexerted bymeans of microglial-dependent inflammation butthis hypothesis remains to be experimentally tested
5 Inflammation Associated with Aging andNeurodegenerative Diseases
Inflammation is also commonly associated with normalaging and neurodegenerative diseases and therefore couldrepresent a putative underlying mechanism that explainstheir decrease in hippocampal neurogenesis Nonethelessinflammation is also associated with neurological diseasessuch as epilepsy or stroke where neurogenesis is thought tobe increased although the data from rodents and humans issomewhat conflictive [102] Neurogenesis is well known todecline throughout adulthood and normal aging in rodentsand humans [103 104] but the decay ismore pronounced andoccurs later in life in mice than in humans [105] The aging-associated decrease in neurogenesis has been shown to occurmainly as a consequence of exhaustion of the rNSC popula-tion which after being recruited and activated undergo three
rounds of mitosis in average and then terminally differentiateinto astrocytes [12 106] In addition a reduced mitoticcapacity of the neuroprogenitors could further contribute todecreasing neurogenesis [106] and moreover an age-relatedincrease in the levels of proinflammatory cytokines couldalso hinder neurogenesis in the aging brain Serum levelsof IL-1120573 IL-6 and TNF120572 are elevated in elderly patients[107 108] Aged microglia express higher levels of theseproinflammatory cytokines and show a greater response toLPS inflammatory challenge that is a ldquoprimedrdquo responsethan their younger counterparts [109] The origin of thislow-grade age-related inflammation (ldquoinflamm-agingrdquo [110])remains unknown and may be related to both aging anddamage to the surrounding neurons as well as aging of theimmune system per se
At the cellular level stress to the endoplasmic reticulum(ER) caused by various perturbations such as nutrient deple-tion disturbances in calcium or redox status or increasedlevels of misfolded proteins can induce a cell-autonomousinflammatory response to neurons Stress to the ER a mul-tifunctional organelle which is involved in protein foldinglipid biosynthesis and calcium storage triggers a homeostaticresponse mechanism named the unfolding protein response(UPR) aiming to clear the unfolded proteins in order torestore normal ER homeostasis [111] However if the ERstress cannot be resolved theUPR also initiates inflammatoryand apoptotic pathways via activation of the transcriptionfactor NF-120581B which controls the expression of most proin-flammatory cytokines [112] In the brain ER stress is ofteninitiated by the formation of abnormal protein aggregatesin several neurodegenerative diseases such as Alzheimerrsquosdisease (AD) Parkinsonrsquos disease (PD) amyotrophic lateralsclerosis (ALS) Huntingtonrsquos disease (HD) and prion-relateddisorders [113] This neurodegeneration-associated ER stressis assumed to occur mostly in neurons but there aresome examples of microglial protein misfolding as well Forinstance both microglia and neurons overexpress CHOP(CEBP homologous protein) a transcription factor whichis activated during ER stress in human patients and mousemodels of ALS [114] Inflammation has been speculated tobe a main negative contributor to the pathology of ALS[115] but a direct microglial involvement in mediating theinflammatory response to abnormal protein aggregation inALS and other neurodegenerative conditions remains to betested Finally ER stress has been linked to a variety of inflam-matory conditions [116 117] including chronic stress diet-induced obesity and drug abuse as well as atherosclerosisand arthritis [118ndash120] During normal aging a progressivedecline in expression and activity of key ER molecularchaperones and folding enzymes could also compromise theadaptive response of the UPR thereby contributing to theage-associated decline in cellular functions [118] Thereforeaging is strongly associated with a chronic ER stress whichleads to increased activation of NF-120581B [112] however thecontribution of the different brain cell types to ldquoinflamm-agingrdquo is still poorly understood The detrimental effects onneurogenesis of increased proinflammatory cytokines in theaging brain are not necessarily related to microglia but alsoto stressed neurons Furthermore ER stress may also cause a
6 Neural Plasticity
cell-autonomous response in neural stem cells [121] althoughits impact on neurogenesis remains to be experimentallydetermined
In addition aging is accompanied by an increased levelof mitochondrial oxidative stress which in turn activatesthe ldquoInflammasomerdquo [122] a group of multimeric proteinscomprising the interleukin 1 converting enzyme (ICE cas-pase 1) which serves to release the active form of thecytokine [123] IL-1120573 may act directly on rNSCs (visualisedby labeling with the Sox2 marker) as they express IL-1R1 in the adult hippocampus [91] Treatment with IL-1120573decreases hippocampal proliferation in young mice [91] andpharmacological inhibition of ICE partially restores the num-ber of newborn neurons in aged mice without significantlyaffecting their differentiation rate [124] Transgenic IL-1120573overexpression results in chronic inflammation and deple-tion of doublecortin-labeled neuroblasts thus mimickingthe aging-associated depletion of neurogenesis [125] Theactual mechanism of action of IL-1120573 on neurogenesis inaged mice including decreased proliferation of rNSCsANPsand survival of newborn neurons remains undeterminedMicroglia are a main source of IL-1120573 in the aging brain butthe hypothesis that microglia-derived IL-1120573 is responsiblefor depleting neurogenesis in the aging brain remains to bedirectly tested
The regulation of neurogenesis by IL-1120573 in the agingbrain has been further linked to the activity of anothercytokine the chemokine fractalkine or CX3CL1 Fractalkinehas soluble and membrane-tethered forms and is exclu-sively expressed by neurons while the fractalkine receptor(CX3CR1) is expressed in the brain by microglia alone [126]Thismodule forms a unique neuron-microglia signalling unitthat controls the extent of microglial inflammation in severalneurodegenerative conditions including PD ALS [127] orAD [128] In fact CX3CR1 blocking antibodies increasethe production of hippocampal IL-1120573 when administeredto young adult rats [129] Importantly chronic treatmentwith fractalkine increases hippocampal proliferation and thenumber of neuroblasts in aged (22 months old) but notyoung (3 months old) or middle-aged rats (12 months old)whereas an antagonists of CX3CR1 has the opposite effectsin young but not in middle-aged nor old rats [129] Sincefractalkine expression is decreased during aging [129] areduced neuron-microglia signalling might be releasing thebrake on microglial contribution to inflammatory responsesalthough increased levels of fractalkine were instead reportedin aged rat hippocampus by other studies [68] Additionalinsights into the role of fractalkine signalling come fromknock-in mice in which the endogenous CX3CR1 locus isreplaced by the fluorescent reporter GFP [126] The initialstudies suggested that CX3CR1GFPGFP (ie CX3CR1minusminus)mice have no significant differences in brain development andfunctions [130] but more systematic investigations recentlyrevealed a long list of hippocampal-dependent changes inyoung (3 months old) CX3CR1GFPGFP and CX3CR1GFP+mice compared to wild-type mice These changes notablyincluded decreased neuroprogenitors proliferation and neu-roblasts number impaired LTP performance in contextual
fear conditioning and water maze spatial learning and mem-ory and importantly increased IL-1120573 protein levels [131]Thesignalling pathway of fractalkine-IL-1120573 is functionally rele-vant because IL-1R1 antagonists rescued LTP and cognitivefunction in CX3CR1GFPGFP mice [131] In sum even thoughneuronal fractalkine seems to be sufficient for restrainingthe inflammatory activity of microglia in young rats itsdownregulation during aging could activate the microglialinflammatory response and thereby subsequently reduce theproliferation of remaining neuroprogenitors
In AD inflammatory cytokines such as IL-1120573 are over-expressed in the microglia associated with the amyloid beta(A120573) plaques of postmortem samples [132] and in transgenicmice modeling the disease [133] The loss of synapses (fromhippocampus to frontal cortex) is one of the main patho-logical substrates in this disease but adult neurogenesis isalso severely reduced in most mouse models of AD possiblydue to a decreased proliferation of neuroprogenitors and adecreased survival of newborn cells even though the putativechanges in the neurogenic cascade in postmortem samplesremain controversial (reviewed in [102]) This lack of agree-ment is possibly explained by the fact that the vast majorityof AD cases have a late onset over 65 years of age when littleneurogenesis remains In contrast in most transgenic ADmouse models the A120573 accumulation cognitive deficits andchanges in neurogenesis are already detectable in young ani-mals (2-3 months old) The study of AD is further hinderedby the difficulty in comparing the time course and pathologyacross different mouse models For instance early treatmentwith minocycline can improve cognition and reduce A120573burden in mice expressing the human amyloid precursorprotein (APP) [134] In contrast in mice expressing APP anda mutated form of presenilin 1 (PS1) which is part of the 120574secretase pathway that cleaves A120573 inflammation is reducedwithout any detectable changes in A120573 plaques deposition[135] Concomitantly with a decrease in tissue inflamma-tory cytokines and number of microglial cells minocyclinerestores neurogenesis and hippocampus-dependent memorydeficits in these APPPS1 mice [135] indirectly suggestingthat cognitive decay in AD may be at least in part relatedto a detrimental effect of inflammation on hippocampalneurogenesis Direct evidence that neurogenesis is associatedwith the cognitive performance in AD is still lacking Furtherresearch is also necessary to determine the neurogenic targetsof AD-related inflammation One central open questionfor future therapies aiming at increasing neurogenesis andcognition in AD is whether neuroprogenitors are spared orwhether their age-induced loss becomes accelerated Ratherthan increasing the proliferation and neurogenic output ofthe few rNSCs remaining in an old AD brain it may be morerelevant to develop strategies that prevent the age-related lossof neuroprogenitors in presymptomatic patients
In summary inflammation associated with a wide varietyof experimental models of disease produces strong detri-mental effects on hippocampal neurogenesis These effectson human neurogenesis are however not so well describedand in vitro IL-1120573 increases the proliferation of hip-pocampal embryonic neuroprogenitors but decreases their
Neural Plasticity 7
differentiation into neurons [136] Novel methods to assesshippocampal neurogenesis in the living human brain frommetabolomics of neuroprogenitors to hippocampal bloodbrain volume (reviewed in [102]) will help to determine thecontribution of inflammation to adult neurogenesis in thehealthy and diseased human brain during aging
6 Normal Physiological Conditions
In the healthy mature brain microglia are an essential com-ponent of the neurogenic SGZ niche where they physicallyintermingle with neuroprogenitors neuroblasts and new-born neurons [62] Here surveillant microglia effectively andrapidly phagocytose the excess of newborn cells undergoingapoptosis [62] Importantly microglial phagocytosis in theadult SGZ is not disturbed by inflammation associated withaging or by LPS challenge as the phagocytic index (iethe proportion of apoptotic cells completely engulfed bymicroglia) is maintained over 90 in these conditions [62]Nonetheless the consequences of microglial phagocytosis onadult hippocampal neurogenesis remain elusive Treatment ofmice with annexin V which binds to the phosphatidylserine(PS) receptor and prevents the recognition of PS on thesurface of apoptotic cells presumably blocking phagocytosisincreases the number of apoptotic cells in the SGZ [40] Con-comitantly annexin V reduces neurogenesis by decreasingthe survival of neuroblasts without affecting neuroprogeni-tors proliferation [40] Similar results were obtained in trans-genic mice knock-out for ELMO1 a cytoplasm protein whichpromotes the internalization of apoptotic cells althoughthe effects on neurogenesis were ascribed to a decreasedphagocytic activity of neuroblasts [40]The actual phagocytictarget of the neuroblasts remains undetermined but thenewborn apoptotic cells in the adult SGZ are exclusivelyphagocytosed by microglia at least in physiological condi-tions [62] Nevertheless none of the above manipulationshas specifically tested the role of microglial phagocytosisin hippocampal-dependent learning and memory and thusthe functional impact of microglial phagocytosis in adultneurogenic niches during normal physiological conditionsremains to be elucidated
Microglial phagocytosis of apoptotic cells is activelyanti-inflammatory at least in vitro and thus it has beenhypothesized that anti-inflammatory cytokines produced byphagocytic microglia may further regulate neurogenesis [10]For instance transforming growth factor beta (TGF120573) whichis produced by phagocytic microglia in vitro [137] inhibitsthe proliferation of SGZ neuroprogenitors [138] Microgliaare further able to produce proneurogenic factors in vitro[139] When primed with cytokines associated with T helpercells such as interleukin 4 (IL-4) or low doses of interferongamma (IFN120574) culturedmicroglia support neurogenesis andoligodendrogenesis through decreased production of TNF120572and increased production of insulin-like growth factor 1(IGF-1) [139] an inducer of neuroprogenitor proliferation[26] A list of potential factors produced by microgliaand known to act on neuroprogenitor proliferation can
be found in Table 1 In addition recent observations sug-gest that neuroprogenitor cells may not only regulate theirown environment but also influence microglial functionsFor instance vascular endothelial growth factor (VEGF)produced by cultured neuroprecursor cells directly affectsmicroglial proliferation migration and phagocytosis [20]More potential factors produced by neuroprogenitors shownto be influencing microglial activity and function can befound in Table 2 However it has to be taken into accountthat most of these observations were obtained in culture andthat further research is needed in order to elucidate whetherthose factors are also secreted and have the same regulatoryresponses in vivo
In addition microglial capacity to remodel and eliminatesynaptic structures during normal physiological conditionshas suggested that microglia could also control the synap-tic integration of the newborn neurons generated duringadult hippocampal neurogenesis [140] Three main mech-anisms were proposed (1) the phagocytic elimination ofnonapoptotic axon terminals and dendritic spines (2) theproteolytic remodeling of the perisynaptic environmentand (3) the concomitant structural remodeling of dendriticspines [7 140] Indeed microglial contacts with synapticelements are frequently observed in the cortex during normalphysiological conditions sometimes accompanied by theirengulfment and phagocytic elimination [141ndash143] as in thedeveloping retinogeniculate system [144] Microglial cells aredistinctively surrounded by pockets of extracellular spacecontrarily to all the other cellular elements [142] suggestingthat microglia could remodel the volume and geometryof the extracellular space and thus the concentration ofvarious ions neurotransmitters and signalling moleculesin the synaptic environment Whether microglia create thepockets of extracellular space themselves or not remainsunknown but these pockets could result from microglialrelease of extracellular proteases such as metalloproteinasesand cathepsins [145] which are well known for influencingthe formation structural remodeling and elimination ofdendritic spines in situ and also experience-dependent plas-ticity in vivo [7 146] More recently microglial phagocytosisof synaptic components was also observed in the developinghippocampus in the unique time window of synaptogenesisa process which is notably regulated by fractalkine-CX3CR1signalling [147] Therefore the attractive hypothesis thatmicroglial sculpts the circuitry of newborn cells in the adulthippocampus deserves further attention
Lastly microglia were also involved in increasing adulthippocampal neurogenesis in the enriched environment(EE) experimental paradigm EE is a paradigm mimick-ing some features of the normal living circumstances ofwild animals as it gives them access to social interactionstoys running wheels and edible treats EE has long beenknown to enhance neurogenesis by acting on newborncells survival resulting ultimately in an enlargement ofthe dentate gyrus [148] Functionally these changes areaccompanied by enhanced spatial learning and memoryformation with the water maze paradigm [149] Similarincreases in neurogenesis are obtained by subjecting miceto voluntary running paradigms although in this case the
8 Neural Plasticity
Table 1 Summary of factors secreted by microglia and the potential effect they have on neuroprogenitors in vitro
Microglia secreted factors Reference Modulation of neural progenitor cells ReferenceBDNF [18] Differentiation [19]EGF [20] Survival expansion proliferation differentiation [21]FGF120573 [22] Survival and expansion [23]GDNF [24] Survival migration and differentiation [25]IGF-1 [21] Proliferation [26]IL-1120573 [27] Reduction in migration [27]IL-6 [28] Inhibition of neurogenesis [29]IL-7 [20] Differentiation [30]IL-11 [20] Differentiation [30]NT-4 [24] Differentiation [31]PDGF [32] Expansion and differentiation [33]TGF120573 [34] Inhibition of proliferation [19]
Table 2 Summary of factors secreted by neuroprogenitors and the potential effect they have on microglia in vitro
NPC secreted factors Reference Modulation of microglia ReferenceBDNF [18] Proliferation and induction of phagocytic activity [35]Haptoglobin [24] Neuroprotection [36]IL-1120573 [37] Intracellular Ca+2 elevation and proliferation [22]IL-6 [37] Increase in proliferation [38]M-CSF [20] Mitogen [39]NGF [40] Decrease in LPS-induced NO [41]TGF120573 [37] Inhibition of TNF120572 secretion [42]TNF120572 [37] Upregulation of IL-10 secretion [43]VEGF [20] Induction of chemotaxis and proliferation [20]
effect is mediated by increased neuroprogenitor proliferation[150] During inflammatory conditions EE is antiapoptoticand neuroprotective [151] and it limits the hippocampalresponse to LPS challenge by decreasing the expression ofseveral cytokines and chemokines including IL1-120573 andTNF120572[152] In fact EE is believed to counteract the inflammatoryenvironment and rescue the decreased number of neuroblastsin CX3CR1GFPGFP mice compared to wild-type mice [153]The effects of EE are independent of the IL-1120573 signallingpathway as it increases neurogenesis in mice that are nullfor IL-1R1 [154] EE also induces microglial proliferation andexpression of the proneurogenic IGF-1 [155] but the fullphenotype of microglia in EE compared to standard housingand its impact on the neurogenic cascade remains to bedetermined
The mechanisms behind the anti-inflammatory actionsof EE are unknown but they were suggested to involvemicroglial interactions with T lymphocytes through anincreased expression of themajor histocompatibility complexof class II (MHC-II) during EE [155] MHC-II is responsiblefor presenting the phagocytosed and degraded antigens tothe antibodies expressed on the surface of a subtype ofT lymphocytes (T helper or CD4+ cells) thus initiatingtheir activation and production of antigen-specific antibod-ies Severe combined immunodeficient (SCID) mice lackingeither T and B lymphocytes or nude mice lacking only Tcells have impaired proliferation and neurogenesis in normal
and EE housing compared to wild-type mice [155] as wellas impaired performance in the water maze [156] Similarlyantibody-based depletion of T helper lymphocytes impairsbasal and exercise-induced proliferation and neurogenesis[157] Furthermore a genetic study in heterogeneous stockmice which descend from eight inbred progenitor strainshas found a significant positive correlation between geneticloci associated to hippocampal proliferation and to theproportion of CD4+ cells among blood CD3+ lymphocytes[158] Additional experiments are needed to fully determinethe possible interactions between microglia and T cellsin neurogenesis because at least in normal physiologicalconditions (1) T cell surveillance of the brain parenchymais minimal (2) microglia are poor antigen presenting cellsand (3) antigen presentation by means of MHC-II family ofmolecules is thought to occur outside the brain that is in themeninges and choroid plexus [159] In fact during voluntaryexercise there are no significant changes in T cell surveillanceof the hippocampus nor a direct interaction between T cellsand microglia nor any changes in the gene expression profileof microglia including that of IGF-1 IL-1120573 and TNF120572 [160]The number of microglia is also inversely correlated withthe number of hippocampal proliferating cells rNSCs andneuroblasts in aged (8 months) mice subjected to voluntaryrunning as well as in vitro cocultures of microglia andneuroprogenitors which has been interpreted as resultingfrom an overall inhibitory effect of microglia on adult
Neural Plasticity 9
neurogenesis [161] Even though EE is clearly a more com-plex environmental factor than voluntary running furtherresearch is necessary to disregard nonspecific or indirecteffects of genetic or antibody-based T cells depletion onmicroglia and other brain cell populations including rNSCsFor instance adoptive transfer of T helper cells treated withglatiramer acetate a synthetic analog of myelin basic protein(MBP) approved for the treatment of multiple sclerosis pro-duces a bystander effect on resident astrocytes and microgliaby increasing their expression of anti-inflammatory cytokinessuch as TGF120573 [162] Alternatively it has been suggested thatT cells may mediate an indirect effect on adult hippocampalneurogenesis by increasing the production of brain-derivedneurotrophic factor (BDNF) [157] which is involved in theproneurogenic actions of EE [163] Whether BDNF cancounteract the detrimental effects of T cell depletion on neu-rogenesis remains unknownOverall the roles ofmicroglia inEE and running-induced neurogenesis are unclear and haveto be addressed with more precise experimental designs Insummary surveillant microglia are part of the physical nichesurrounding the neural stem cells and newborn neurons ofthe mature hippocampus where they continuously phagocy-tose the excess of newborn cellsMicroglia were also linked tothe proneurogenic and anti-inflammatory effects of voluntaryrunning and EE but direct evidence is missing The overallcontribution of microglia to neurogenesis and learning andmemory in normal physiological conditions remains largelyunexplored at this early stage in the field
7 Conclusion
In light of these observations microglia are now emergingas important effector cells during normal brain developmentand functions including adult hippocampal neurogenesisMicroglia can exert a positive or negative influence onthe proliferation survival or differentiation of newborncells depending on the inflammatory context For instancemicroglia can compromise the neurogenic cascade duringchronic stress aging and neurodegenerative diseases bytheir release of proinflammatory cytokines such as IL-1120573IL-6 and TNF120572 A reduced fractalkine signalling betweenneurons and microglia could also be involved during normalaging However microglia are not necessarily the only celltype implicated because astrocytes endothelial cells mastcells perivascular and meningeal macrophages and to alesser extent neurons and invading peripheral immune cellscould further contribute by releasing proinflammatorymedi-ators
Additionally microglia were shown to phagocytose theexcess of newborn neurons undergoing apoptosis in thehippocampal neurogenic niche during normal physiologicalconditions while a similar role in the synaptic integrationof newborn cells was also proposed in light of their capacityto phagocytose synaptic elements Lastly microglial interac-tions with T cells leading to the release of anti-inflammatorycytokines neurotrophic factors and other proneurogenicmediators (notably during EE and voluntary running) couldcounteract the detrimental effects of inflammation on adult
hippocampal neurogenesis and their functional implicationsfor learning and memory
However further research is necessary to assess the rela-tive contribution of microglia versus other types of residentand infiltrating inflammatory cells and to determine thenature of the effector cytokines and other inflammatorymediators involved as well as their cellular andmolecular tar-gets in the neurogenic cascade Such research will undoubt-edly help to develop novel strategies aiming at protecting theneurogenic potential and ultimately its essential contributionto learning and memory
The authors declare that there is no conflict of interestsregarding the publication of this paper
Acknowledgments
This work was supported by grants from the Spanish Min-istry of Economy and Competitiveness to Amanda Sierra(BFU2012-32089) and Juan M Encinas (SAF2012-40085)from Basque Government (Saiotek S-PC 12UN014) and Iker-basque start-up funds to JuanM Encinas andAmanda Sierraand fromTheBanting Research Foundation the Scottish RiteCharitable Foundation of Canada and start-up funds fromUniversite Laval andCentre de recherche duCHUdeQuebecto Marie-Eve Tremblay
References
[1] P Rezaie and D Male ldquoMesoglia and microgliamdasha historicalreview of the concept of mononuclear phagocytes within thecentral nervous systemrdquo Journal of the History of the Neuro-sciences vol 11 no 4 pp 325ndash374 2002
[2] F Ginhoux S Lim G Hoeffel D Low and T Huber ldquoOriginand differentiation of microgliardquo Frontiers in Cellular Neuro-science vol 7 article 45 2013
[3] E Gomez Perdiguero C Schulz and F Geissmann ldquoDevelop-ment and homeostasis of ldquoresidentrdquomyeloid cells the case of themicrogliardquo GLIA vol 61 no 1 pp 112ndash120 2013
[4] H Kettenmann F Kirchhoff and A Verkhratsky ldquoMicroglianew roles for the synaptic stripperrdquo Neuron vol 77 no 1 pp10ndash18 2013
[5] A Aguzzi B A Barres and M L Bennett ldquoMicroglia scape-goat saboteur or something elserdquo Science vol 339 no 6116 pp156ndash161 2013
[6] K Helmut U K Hanisch M Noda and A VerkhratskyldquoPhysiology of microgliardquo Physiological Reviews vol 91 no 2pp 461ndash553 2011
[7] M E Tremblay B Stevens A Sierra H Wake A Bessis andA Nimmerjahn ldquoThe role of microglia in the healthy brainrdquoJournal of Neuroscience vol 31 no 45 pp 16064ndash16069 2011
[8] A Miyamoto H Wake A J Moorhouse and J NabekuraldquoMicroglia and synapse interactions fine tuaning neural circuitsand candidate moleculesrdquo Frontiers in Cellular Neurosciencevol 7 article 70 2013
[9] C Bechade Y Cantaut-Belarif and A Bessis ldquoMicroglialcontrol of neuronal activityrdquo Frontiers in Cellular Neurosciencevol 7 article 32 2013
[10] A Sierra O Abiega A Shahraz and H Neumann ldquoJanus-faced microglia beneficial and detrimental consequences ofmicroglial phagocytosisrdquo Frontiers in Cellular Neuroscience vol7 article 6 2013
[11] G Kempermann S Jessberger B Steiner and G KronenbergldquoMilestones of neuronal development in the adult hippocam-pusrdquo Trends in Neurosciences vol 27 no 8 pp 447ndash452 2004
[12] J M Encinas T V Michurina N Peunova et al ldquoDivision-coupled astrocytic differentiation and age-related depletion ofneural stem cells in the adult hippocampusrdquo Cell Stem Cell vol8 no 5 pp 566ndash579 2011
[13] M A Bonaguidi M A Wheeler J S Shapiro et al ldquoIn vivoclonal analysis reveals self-renewing and multipotent adultneural stem cell characteristicsrdquo Cell vol 145 no 7 pp 1142ndash1155 2011
[14] J J Breunig J I Arellano J D Macklis and P RakicldquoEverything that glitters isnrsquot gold a critical review of postnatalneural precursor analysesrdquo Cell Stem Cell vol 1 no 6 pp 612ndash627 2007
[15] L S Overstreet-Wadiche and G L Westbrook ldquoFunctionalmaturation of adult-generated granule cellsrdquoHippocampus vol16 no 3 pp 208ndash215 2006
[16] S Ge C H Yang K S Hsu G L Ming andH Song ldquoA criticalperiod for enhanced synaptic plasticity in newly generatedneurons of the adult brainrdquo Neuron vol 54 no 4 pp 559ndash5662007
[17] E Bruel-Jungerman C Rampon and S Laroche ldquoAdult hip-pocampal neurogenesis synaptic plasticity and memory factsand hypothesesrdquo Reviews in the Neurosciences vol 18 no 2 pp93ndash114 2007
[18] K Nakajima S Honda Y Tohyama Y Imai S Kohsaka andT Kurihara ldquoNeurotrophin secretion from cultured microgliardquoJournal of Neuroscience Research vol 65 no 4 pp 322ndash3312001
[19] M Krampert S R Chirasani F P Wachs et al ldquoSmad7regulates the adult neural stemprogenitor cell pool in a trans-forming growth factor 120573- and bone morphogenetic protein-independent mannerrdquo Molecular and Cellular Biology vol 30no 14 pp 3685ndash3694 2010
[20] K I Mosher R H Andres T Fukuhara et al ldquoNeural pro-genitor cells regulate microglia functions and activityrdquo NatureNeuroscience vol 15 no 11 pp 1485ndash1487 2012
[21] V Tropepe M Sibilia B G Ciruna J Rossant E F Wagnerand D van der Kooy ldquoDistinct neural stem cells proliferatein response to EGF and FGF in the developing mouse telen-cephalonrdquo Developmental Biology vol 208 no 1 pp 166ndash1881999
[22] S U Kim and J De Vellis ldquoMicroglia in health and diseaserdquoJournal of Neuroscience Research vol 81 no 3 pp 302ndash3132005
[23] B A Reynolds and R L Rietze ldquoNeural stem cells andneurospheresmdashre-evaluating the relationshiprdquoNatureMethodsvol 2 no 5 pp 333ndash336 2005
[24] K Satake Y Matsuyama M Kamiya et al ldquoUp-regulation ofglial cell line-derived neurotrophic factor (GDNF) followingtraumatic spinal cord injuryrdquo NeuroReport vol 11 no 17 pp3877ndash3881 2000
[25] Y M Yoo C J Lee and Y J Kim ldquoExogenous GDNF increasesthe migration of the neural stem cells with no protectionagainst kainic acid-induced excitotoxic cell death in ratsrdquo BrainResearch vol 1486 pp 27ndash38 2012
[26] J L Trejo E Carro and I Torres-Aleman ldquoCirculating insulin-like growth factor I mediates exercise-induced increases in thenumber of new neurons in the adult hippocampusrdquo Journal ofNeuroscience vol 21 no 5 pp 1628ndash1634 2001
Neural Plasticity 11
[27] K Striedinger and E Scemes ldquoInterleukin-1120573 affects calciumsignaling and in vitro cell migration of astrocyte progenitorsrdquoJournal of Neuroimmunology vol 196 no 1-2 pp 116ndash123 2008
[28] Y B Lee A Nagai and S U Kim ldquoCytokines chemokines andcytokine receptors in humanmicrogliardquo Journal of NeuroscienceResearch vol 69 no 1 pp 94ndash103 2002
[29] G Kempermann and H Neumann ldquoMicroglia the enemywithinrdquo Science vol 302 no 5651 pp 1689ndash1690 2003
[30] M F Mehler R Rozental M Dougherty D C Spray and JA Kessler ldquoCytokine regulation of neuronal differentiation ofhippocampal progenitor cellsrdquo Nature vol 362 no 6415 pp62ndash65 1993
[31] U Gurok C Steinhoff B Lipkowitz H H Ropers C Scharffand U A Nuber ldquoGene expression changes in the course ofneural progenitor cell differentiationrdquo Journal of Neurosciencevol 24 no 26 pp 5982ndash6002 2004
[32] J B Demoulin M Enarsson J Larsson A Essaghir C HHeldin and K Forsberg-Nilsson ldquoThe gene expression profileof PDGF-treated neural stem cells corresponds to partiallydifferentiated neurons and gliardquo Growth Factors vol 24 no 3pp 184ndash196 2006
[33] F C Mansergh M A Wride and D E Rancourt ldquoNeuronsfrom stem cells implications for understanding nervous systemdevelopment and repairrdquo Biochemistry and Cell Biology vol 78no 5 pp 613ndash628 2000
[34] F C Alcantara Gomes V De Oliveira Sousa and L RomaoldquoEmerging roles for TGF-1205731 in nervous system developmentrdquoInternational Journal of Developmental Neuroscience vol 23 no5 pp 413ndash424 2005
[35] S Elkabes E M DiCicco-Bloom and I B Black ldquoBrainmicrogliamacrophages express neurotrophins that selectivelyregulate microglial proliferation and functionrdquo Journal of Neu-roscience vol 16 no 8 pp 2508ndash2521 1996
[36] U K Hanisch and H Kettenmann ldquoMicroglia active sensorand versatile effector cells in the normal and pathologic brainrdquoNature Neuroscience vol 10 no 11 pp 1387ndash1394 2007
[37] H J Klassen T F Ng Y Kurimoto et al ldquoMultipotent retinalprogenitors express developmental markers differentiate intoretinal neurons and preserve light-mediated behaviorrdquo Inves-tigative Ophthalmology and Visual Science vol 45 no 11 pp4167ndash4173 2004
[38] W J Streit S D Hurley T S McGraw and S L Semple-Rowland ldquoComparative evaluation of cytokine profiles andreactive gliosis supports a critical role for interleukin-6 inneuron-glia signaling during regenerationrdquo Journal of Neuro-science Research vol 61 no 1 pp 10ndash20 2000
[39] A Suzumura M Sawada H Yamamoto and T MarunouchildquoEffects of colony stimulating factors on isolated microglia invitrordquo Journal of Neuroimmunology vol 30 no 2-3 pp 111ndash1201990
[40] Z Lu M R Elliott Y Chen et al ldquoPhagocytic activity ofneuronal progenitors regulates adult neurogenesisrdquoNature CellBiology vol 13 no 9 pp 1076ndash1084 2011
[41] K Nakajima Y Kikuchi E Ikoma et al ldquoNeurotrophinsregulate the function of cultured microgliardquo GLIA vol 24 no3 pp 272ndash289 1998
[42] P A Lodge and S Sriram ldquoRegulation of microglial activationby TGF-120573 IL-10 and CSF-1rdquo Journal of Leukocyte Biology vol60 no 4 pp 502ndash508 1996
[43] W S Sheng S Hu F H Kravitz P K Peterson and C C ChaoldquoTumor necrosis factor alpha upregulates humanmicroglial cell
production of interleukin-10 in vitrordquo Clinical and DiagnosticLaboratory Immunology vol 2 no 5 pp 604ndash608 1995
[44] G LMing andH Song ldquoAdult neurogenesis in themammalianbrain significant answers and significant questionsrdquo Neuronvol 70 no 4 pp 687ndash702 2011
[45] E Bruel-Jungerman S Davis C Rampon and S LarocheldquoLong-term potentiation enhances neurogenesis in the adultdentate gyrusrdquo Journal of Neuroscience vol 26 no 22 pp 5888ndash5893 2006
[46] E Drapeau M F Montaron S Aguerre and D N AbrousldquoLearning-induced survival of new neurons depends on thecognitive status of aged ratsrdquo Journal of Neuroscience vol 27no 22 pp 6037ndash6044 2007
[47] A Mouret G Gheusi M M Gabellec F De Chaumont J COlivo-Marin and P M Lledo ldquoLearning and survival of newlygenerated neurons when timemattersrdquo Journal of Neurosciencevol 28 no 45 pp 11511ndash11516 2008
[48] N Kee C M Teixeira A H Wang and P W FranklandldquoPreferential incorporation of adult-generated granule cellsinto spatial memory networks in the dentate gyrusrdquo NatureNeuroscience vol 10 no 3 pp 355ndash362 2007
[49] F Massa M Koelh T Wiesner et al ldquoConditional reduction ofadult neurogenesis impairs bidirectional hippocampal synapticplasticityrdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 108 no 16 pp 6644ndash6649 2011
[50] T J Shors G Miesegaes A Beylin M Zhao T Rydel and EGould ldquoNeurogenesis in the adult is involved in the formationof tracememoriesrdquoNature vol 410 no 6826 pp 372ndash376 2001
[51] W Deng M D Saxe I S Gallina and F H Gage ldquoAdult-born hippocampal dentate granule cells undergoingmaturationmodulate learning and memory in the brainrdquo Journal of Neuro-science vol 29 no 43 pp 13532ndash13542 2009
[52] M Arruda-Carvalho M Sakaguchi K G Akers S A Josselynand P W Frankland ldquoPosttraining ablation of adult-generatedneurons degrades previously acquired memoriesrdquo Journal ofNeuroscience vol 31 no 42 pp 15113ndash15127 2011
[53] A Sahay K N Scobie A S Hill et al ldquoIncreasing adulthippocampal neurogenesis is sufficient to improve patternseparationrdquo Nature vol 472 no 7344 pp 466ndash470 2011
[54] G LMing andH Song ldquoAdult neurogenesis in themammaliancentral nervous systemrdquoAnnual Review of Neuroscience vol 28pp 223ndash250 2005
[55] K Newton and V M Dixit ldquoSignaling in innate immunity andinflammationrdquo Cold Spring Harbor Perspectives in Biology vol4 no 3 2012
[56] H K Jeong K Ji K Min and E H Joe ldquoBrain inflammationand microglia facts and misconceptionsrdquo Experimental Neuro-biology vol 22 no 2 pp 59ndash67 2013
[57] D Stellwagen and R CMalenka ldquoSynaptic scalingmediated byglial TNF-120572rdquo Nature vol 440 no 7087 pp 1054ndash1059 2006
[58] M Pickering D Cumiskey and J J OrsquoConnor ldquoActions of TNF-120572 on glutamatergic synaptic transmission in the central nervoussystemrdquo Experimental Physiology vol 90 no 5 pp 663ndash6702005
[59] K Belarbi T Jopson D Tweedie et al ldquoTNF-120572 protein synthe-sis inhibitor restores neuronal function and reverses cognitivedeficits induced by chronic neuroinflammationrdquo Journal ofNeuroinflammation vol 9 article 23 2012
[60] C T Ekdahl J H Claasen S Bonde Z Kokaia andO LindvallldquoInflammation is detrimental for neurogenesis in adult brainrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 100 no 23 pp 13632ndash13637 2003
12 Neural Plasticity
[61] M L Monje H Toda and T D Palmer ldquoInflammatoryblockade restores adult hippocampal neurogenesisrdquo Sciencevol 302 no 5651 pp 1760ndash1765 2003
[62] A Sierra J M Encinas J J P Deudero et al ldquoMicroglia shapeadult hippocampal neurogenesis through apoptosis-coupledphagocytosisrdquo Cell Stem Cell vol 7 no 4 pp 483ndash495 2010
[63] D Chugh P Nilsson S A Afjei A Bakochi and C T EkdahlldquoBrain inflammation induces post-synaptic changes duringearly synapse formation in adult-born hippocampal neuronsrdquoExperimental Neurobiology vol 250 pp 176ndash188 2013
[64] K Belarbi C Arellano R Ferguson T Jopson and S RosildquoChronic neuroinflammation impacts the recruitment of adult-born neurons into behaviorally relevant hippocampal net-worksrdquo Brain Behavior and Immunity vol 26 no 1 pp 18ndash232012
[65] S Johann E Kampmann B Denecke et al ldquoExpression ofenzymes involved in the prostanoid metabolism by corticalastrocytes after LPS-induced inflammationrdquo Journal of Molec-ular Neuroscience vol 34 no 2 pp 177ndash185 2008
[66] P V B Reddy K V Rama Rao and M D NorenbergldquoInhibitors of the mitochondrial permeability transition reduceammonia-induced cell swelling in cultured astrocytesrdquo Journalof Neuroscience Research vol 87 no 12 pp 2677ndash2685 2009
[67] H Nie H Zhang and H R Weng ldquoMinocycline preventsimpaired glial glutamate uptake in the spinal sensory synapsesof neuropathic ratsrdquo Neuroscience vol 170 no 3 pp 901ndash9122010
[68] F Cerbai D Lana D Nosi et al ldquoThe neuron-astrocyte-microglia triad in normal brain ageing and in a model ofneuroinflammation in the rat hippocampusrdquo PLoS ONE vol 7no 9 Article ID e45250 2012
[69] W J Jin S W Feng Z Feng S M Lu T Qi and Y N QianldquoMinocycline improves postoperative cognitive impairment inaged mice by inhibiting astrocytic activationrdquo NeuroReport2013
[70] K A Ji M S Yang H K Jeong et al ldquoResident microgliadie and infiltrated neutrophils and monocytes become majorinflammatory cells in lipopolysaccharide-injected brainrdquoGLIAvol 55 no 15 pp 1577ndash1588 2007
[71] N J van Wagoner J W Oh P Repovic and E N BenvenisteldquoInterleukin-6 (IL-6) production by astrocytes autocrine reg-ulation by IL-6 and the soluble IL-6 receptorrdquo Journal ofNeuroscience vol 19 no 13 pp 5236ndash5244 1999
[72] L Vallieres I L Campbell F H Gage and P E SawchenkoldquoReduced hippocampal neurogenesis in adult transgenic micewith chronic astrocytic production of interleukin-6rdquo Journal ofNeuroscience vol 22 no 2 pp 486ndash492 2002
[73] B S McEwen ldquoPhysiology and neurobiology of stress andadaptation central role of the brainrdquo Physiological Reviews vol87 no 3 pp 873ndash904 2007
[74] V LuineMVillegas CMartinez and B SMcEwen ldquoRepeatedstress causes reversible impairments of spatial memory perfor-mancerdquo Brain Research vol 639 no 1 pp 167ndash170 1994
[75] S Rivest ldquoMolecular insights on the cerebral innate immunesystemrdquo Brain Behavior and Immunity vol 17 no 1 pp 13ndash192003
[76] S Nadeau and S Rivest ldquoEndotoxemia prevents the cerebralinflammatory wave induced by intraparenchymal lipopolysac-charide injection role of glucocorticoids and CD14rdquo Journal ofImmunology vol 169 no 6 pp 3370ndash3381 2002
[77] A Sierra A Gottfried-Blackmore T A Milner B S McEwenand K Bulloch ldquoSteroid hormone receptor expression andfunction in microgliardquo GLIA vol 56 no 6 pp 659ndash674 2008
[78] C Liston andW B Gan ldquoGlucocorticoids are critical regulatorsof dendritic spine development and plasticity in vivordquo Proceed-ings of the National Academy of Sciences of the United States ofAmerica vol 108 no 38 pp 16074ndash16079 2011
[79] C Liston J M Cichon F Jeanneteau Z Jia M V Chaoand W B Gan ldquoCircadian glucocorticoid oscillations pro-mote learning-dependent synapse formation andmaintenancerdquoNature Neuroscience vol 16 no 6 pp 698ndash705 2013
[80] M A Carrillo-de Sauvage L Maatouk I Arnoux et al ldquoPotentand multiple regulatory actions of microglial glucocorticoidreceptors during CNS inflammationrdquo Cell Death amp Differenti-ation vol 20 no 11 pp 1546ndash1557 2013
[81] S F Sorrells J R Caso C DMunhoz and RM Sapolsky ldquoThestressed CNS when glucocorticoids aggravate inflammationrdquoNeuron vol 64 no 1 pp 33ndash39 2009
[82] M A Bellavance and S Rivest ldquoThe neuroendocrine controlof the innate immune system in health and brain diseasesrdquoImmunological Reviews vol 248 no 1 pp 36ndash55 2012
[83] R J Tynan S Naicker M Hinwood et al ldquoChronic stress altersthe density and morphology of microglia in a subset of stress-responsive brain regionsrdquo Brain Behavior and Immunity vol24 no 7 pp 1058ndash1068 2010
[84] E S Wohleb N D Powell J P Godbout and J F SheridanldquoStress-induced recruitment of bone marrow-derived mono-cytes to the brain promotes anxiety-like behaviorrdquo The Journalof Neuroscience vol 33 no 34 pp 13820ndash13833 2013
[85] Y Diz-Chaves M Astiz M J Bellini and L M Garcia-SeguraldquoPrenatal stress increases the expression of proinflammatorycytokines and exacerbates the inflammatory response to LPS inthe hippocampal formation of adultmalemicerdquoBrain Behaviorand Immunity vol 28 pp 196ndash206 2013
[86] E S Wohleb A M Fenn A M Pacenta N D Powell J FSheridan and J P Godbout ldquoPeripheral innate immune chal-lenge exaggerated microglia activation increased the numberof inflammatory CNSmacrophages and prolonged social with-drawal in socially defeated micerdquo Psychoneuroendocrinologyvol 37 no 9 pp 1491ndash1505 2012
[87] C Mirescu and E Gould ldquoStress and adult neurogenesisrdquoHippocampus vol 16 no 3 pp 233ndash238 2006
[88] J LWarner-Schmidt andR SDuman ldquoHippocampal neuroge-nesis opposing effects of stress and antidepressant treatmentrdquoHippocampus vol 16 no 3 pp 239ndash249 2006
[89] N D Hanson M J Owens K A Boss-Williams J M Weissand C B Nemeroff ldquoSeveral stressors fail to reduce adulthippocampal neurogenesisrdquo Psychoneuroendocrinology vol 36no 10 pp 1520ndash1529 2011
[90] E Gould B S McEwen P Tanapat L A M Galea and EFuchs ldquoNeurogenesis in the dentate gyrus of the adult treeshrew is regulated by psychosocial stress and NMDA receptoractivationrdquo Journal of Neuroscience vol 17 no 7 pp 2492ndash24981997
[91] JW Koo andR S Duman ldquoIL-1120573 is an essentialmediator of theantineurogenic and anhedonic effects of stressrdquo Proceedings ofthe National Academy of Sciences of the United States of Americavol 105 no 2 pp 751ndash756 2008
[92] D C Lagace M H Donovan N A Decarolis et al ldquoAdulthippocampal neurogenesis is functionally important for stress-induced social avoidancerdquo Proceedings of the National Academy
Neural Plasticity 13
of Sciences of the United States of America vol 107 no 9 pp4436ndash4441 2010
[93] G Kronenberg I Kirste D Inta et al ldquoReduced hippocampalneurogenesis in the GR+- genetic mousemodel of depressionrdquoEuropean Archives of Psychiatry and Clinical Neuroscience vol259 no 8 pp 499ndash504 2009
[94] M B Howren D M Lamkin and J Suls ldquoAssociations ofdepression with c-reactive protein IL-1 and IL-6 a meta-analysisrdquo Psychosomatic Medicine vol 71 no 2 pp 171ndash1862009
[95] J W Koo S J Russo D Ferguson E J Nestler and R SDuman ldquoNuclear factor-120581B is a critical mediator of stress-impaired neurogenesis and depressive behaviorrdquo Proceedings ofthe National Academy of Sciences of the United States of Americavol 107 no 6 pp 2669ndash2674 2010
[96] I Goshen T Kreisel O Ben-Menachem-Zidon et al ldquoBraininterleukin-1 mediates chronic stress-induced depression inmice via adrenocortical activation and hippocampal neuroge-nesis suppressionrdquo Molecular Psychiatry vol 13 no 7 pp 717ndash728 2008
[97] C D Munhoz L B Lepsch E M Kawamoto et al ldquoChronicunpredictable stress exacerbates lipopolysaccharide-inducedactivation of nuclear factor-120581B in the frontal cortex andhippocampus via glucocorticoid secretionrdquo Journal of Neuro-science vol 26 no 14 pp 3813ndash3820 2006
[98] S J Sukoff Rizzo S J Neal Z A Hughes et al ldquoEvidence forsustained elevation of IL-6 in the CNS as a key contributorof depressive-like phenotypesrdquo Translational Psychiatry vol 2article e199 2012
[99] A Garcia B Steiner G Kronenberg A Bick-Sander and GKempermann ldquoAge-dependent expression of glucocorticoid-andmineralocorticoid receptors on neural precursor cell popu-lations in the adult murine hippocampusrdquoAging Cell vol 3 no6 pp 363ndash371 2004
[100] M G Frank B M Thompson L R Watkins and S F MaierldquoGlucocorticoids mediate stress-induced priming of microglialpro-inflammatory responsesrdquo Brain Behavior and Immunityvol 26 no 2 pp 337ndash345 2012
[101] S Sugama M Fujita M Hashimoto and B Conti ldquoStressinduced morphological microglial activation in the rodentbrain involvement of interleukin-18rdquoNeuroscience vol 146 no3 pp 1388ndash1399 2007
[102] A Sierra J M Encinas and M Maletic-Savatic ldquoAdult humanneurogenesis from microscopy to magnetic resonance imag-ingrdquo Frontiers in Neuroscience vol 5 article 47 2011
[103] H G Kuhn H Dickinson-Anson and F H Gage ldquoNeurogen-esis in the dentate gyrus of the adult rat age-related decrease ofneuronal progenitor proliferationrdquo Journal of Neuroscience vol16 no 6 pp 2027ndash2033 1996
[104] L N Manganas X Zhang Y Li et al ldquoMagnetic resonancespectroscopy identifies neural progenitor cells in the live humanbrainrdquo Science vol 318 no 5852 pp 980ndash985 2007
[105] K L Spalding O Bergmann K Alkass et al ldquoDynamics ofhippocampal neurogenesis in adult humansrdquo Cell vol 153 no6 pp 1219ndash1227 2013
[106] J M Encinas and A Sierra ldquoNeural stem cell deforestationas the main force driving the age-related decline in adulthippocampal neurogenesisrdquo Behavioural Brain Research vol227 no 2 pp 433ndash439 2012
[107] K S Krabbe M Pedersen andH Bruunsgaard ldquoInflammatorymediators in the elderlyrdquo Experimental Gerontology vol 39 no5 pp 687ndash699 2004
[108] B S Diniz A L Teixeira L Talib W F Gattaz andO V Forlenza ldquoInterleukin-1120573 serum levels is increased inantidepressant-free elderly depressed patientsrdquo American Jour-nal of Geriatric Psychiatry vol 18 no 2 pp 172ndash176 2010
[109] A Sierra A C Gottfried-Blackmore B S Mcewen and KBulloch ldquoMicroglia derived from aging mice exhibit an alteredinflammatory profilerdquo GLIA vol 55 no 4 pp 412ndash424 2007
[110] C FranceschiM Bonafe S Valensin et al ldquoInflamm-aging Anevolutionary perspective on immunosenescencerdquo Annals of theNew York Academy of Sciences vol 908 pp 244ndash254 2000
[111] R Sano and J C Reed ldquoER stress-induced cell death mecha-nismsrdquoBiochimica et BiophysicaActa vol 1833 no 12 pp 3460ndash3470 2013
[112] S Z Hasnain R Lourie I Das A C H Chen and MA McGuckin ldquoThe interplay between endoplasmic reticulumstress and inflammationrdquo Immunology and Cell Biology vol 90no 3 pp 260ndash270 2012
[113] S Matus L H Glimcher and C Hetz ldquoProtein folding stressin neurodegenerative diseases a glimpse into the ERrdquo CurrentOpinion in Cell Biology vol 23 no 2 pp 239ndash252 2011
[114] Y Ito M Yamada H Tanaka et al ldquoInvolvement of CHOP anER-stress apoptotic mediator in both human sporadic ALS andALS model micerdquo Neurobiology of Disease vol 36 no 3 pp470ndash476 2009
[115] D Papadimitriou V Le Verche A Jacquier B Ikiz S Przed-borski and D B Re ldquoInflammation in ALS and SMA sortingout the good from the evilrdquo Neurobiology of Disease vol 37 no3 pp 493ndash502 2010
[116] A R Johnson J J Milner and LMakowski ldquoThe inflammationhighway metabolism accelerates inflammatory traffic in obe-sityrdquo Immunological Reviews vol 249 no 1 pp 218ndash238 2012
[117] S Buch H Yao M Guo et al ldquoCocaine and HIV-1 interplayin CNS cellular and molecular mechanismsrdquo Current HIVResearch vol 10 no 5 pp 425ndash428 2012
[118] M K Brown and N Naidoo ldquoThe endoplasmic reticulumstress response in aging and age-related diseasesrdquo Frontiers inPhysiology vol 3 article 263 2012
[119] G Castro C Areias MF L Weissmann et al ldquoDiet-inducedobesity induces endoplasmic reticulum stress and insulin resis-tance in the amygdala of ratsrdquo FEBS Open Bio vol 3 pp 443ndash449 2013
[120] A A Pavlovsky D Boehning D Li Y Zhang X Fan andT A Green ldquoPsychological stress cocaine and natural rewardeach induce endoplasmic reticulum stress genes in rat brainrdquoNeuroscience vol 246 pp 160ndash169 2013
[121] G GargiuloM CesaroniM Serresi et al ldquoIn vivo RNAi screenfor BMI1 targets identifies TGF-betaBMP-ER stress pathwaysas key regulators of neural- and malignant glioma-stem cellhomeostasisrdquo Cancer Cell vol 23 no 5 pp 660ndash676 2013
[122] A Salminen K Kaarniranta and A Kauppinen ldquoInflammag-ing disturbed interplay between autophagy and inflamma-somesrdquo Aging vol 4 no 3 pp 166ndash175 2012
[123] E Latz T S Xiao andA Stutz ldquoActivation and regulation of theinflammasomesrdquoNature Reviews Immunology vol 13 no 6 pp397ndash411 2013
[124] C Gemma A D Bachstetter M J Cole M Fister C Hudsonand P C Bickford ldquoBlockade of caspase-1 increases neurogene-sis in the aged hippocampusrdquo European Journal of Neurosciencevol 26 no 10 pp 2795ndash2803 2007
[125] M D Wu A M Hein M J Moravan S S Shaftel J AOlschowka and M K OrsquoBanion ldquoAdult murine hippocampal
14 Neural Plasticity
neurogenesis is inhibited by sustained IL-1120573 and not rescued byvoluntary runningrdquo Brain Behavior and Immunity vol 26 no2 pp 292ndash300 2012
[126] Y Wolf S Yona K W Kim and S Jung ldquoMicroglia seen fromthe CX3CR1 anglerdquo Frontiers in Cellular Neuroscience vol 7article 26 2013
[127] A E Cardona E P Pioro M E Sasse et al ldquoControl ofmicroglial neurotoxicity by the fractalkine receptorrdquo NatureNeuroscience vol 9 no 7 pp 917ndash924 2006
[128] K Bhaskar M Konerth O N Kokiko-Cochran A Cardona RM Ransohoff and B T Lamb ldquoRegulation of tau pathology bythe microglial fractalkine receptorrdquo Neuron vol 68 no 1 pp19ndash31 2010
[129] A D Bachstetter J M Morganti J Jernberg et al ldquoFractalkineand CX3CR1 regulate hippocampal neurogenesis in adult andaged ratsrdquo Neurobiology of Aging vol 32 no 11 pp 2030ndash20442011
[130] S Jung J Aliberti P Graemmel et al ldquoAnalysis of fractalkinereceptor CX3CR1 function by targeted deletion and greenfluorescent protein reporter gene insertionrdquo Molecular andCellular Biology vol 20 no 11 pp 4106ndash4114 2000
[131] J T Rogers J M Morganti A D Bachstetter et al ldquoCX3CR1deficiency leads to impairment of hippocampal cognitive func-tion and synaptic plasticityrdquo Journal of Neuroscience vol 31 no45 pp 16241ndash16250 2011
[132] W S T Griffin L C Stanley C Ling et al ldquoBrain interleukin1 and S-100 immunoreactivity are elevated in Down syndromeand Alzheimer diseaserdquo Proceedings of the National Academy ofSciences of the United States of America vol 86 no 19 pp 7611ndash7615 1989
[133] W C Benzing J RWujek E KWard et al ldquoEvidence for glial-mediated inflammation in aged APP(SW) transgenic micerdquoNeurobiology of Aging vol 20 no 6 pp 581ndash589 1999
[134] T J Seabrook L Jiang M Maier and C A Lemere ldquoMinocy-cline affects microglia activation A120573 deposition and behaviorin APP-tg micerdquo GLIA vol 53 no 7 pp 776ndash782 2006
[135] B Biscaro O Lindvall G Tesco C T Ekdahl and RM NitschldquoInhibition of microglial activation protects hippocampal neu-rogenesis and improves cognitive deficits in a transgenic mousemodel for Alzheimerrsquos diseaserdquoNeurodegenerative Diseases vol9 no 4 pp 187ndash198 2012
[136] P A Zunszain C Anacker A Cattaneo et al ldquoInterleukin-1120573a new regulator of the kynurenine pathway affecting humanhippocampal neurogenesisrdquo Neuropsychopharmacology vol 37no 4 pp 939ndash949 2012
[137] R De Simone M Antonietta Ajmone-Cat P Tirassa and LMinghetti ldquoApoptotic PC12 cells exposing phosphatidylserinepromote the production of anti-inflammatory and neuropro-tective molecules bymicroglial cellsrdquo Journal of Neuropathologyand Experimental Neurology vol 62 no 2 pp 208ndash216 2003
[138] M S Buckwalter M Yamane B S Coleman et al ldquoChroni-cally increased transforming growth factor-1205731 strongly inhibitshippocampal neurogenesis in aged micerdquo American Journal ofPathology vol 169 no 1 pp 154ndash164 2006
[139] O Butovsky Y Ziv A Schwartz et al ldquoMicroglia activatedby IL-4 or IFN-120574 differentially induce neurogenesis and oligo-dendrogenesis from adult stemprogenitor cellsrdquoMolecular andCellular Neuroscience vol 31 no 1 pp 149ndash160 2006
[140] C T Ekdahl ldquoMicroglial activationmdashtuning and pruning adultneurogenesisrdquo Frontiers in Pharmacology vol 3 article 41 2012
[141] HWakeA JMoorhouse S Jinno S Kohsaka and JNabekuraldquoResting microglia directly monitor the functional state ofsynapses in vivo and determine the fate of ischemic terminalsrdquoJournal of Neuroscience vol 29 no 13 pp 3974ndash3980 2009
[142] M E Tremblay R L Lowery and A K Majewska ldquoMicroglialinteractions with synapses are modulated by visual experiencerdquoPLoS Biology vol 8 no 11 Article ID e1000527 2010
[143] M E Tremblay M L Zettel J R Ison P D Allen and A KMajewska ldquoEffects of aging and sensory loss on glial cells inmouse visual and auditory corticesrdquo GLIA vol 60 no 4 pp541ndash558 2012
[144] D P Schafer E K Lehrman A G Kautzman et al ldquoMicrogliasculpt postnatal neural circuits in an activity and complement-dependent mannerrdquo Neuron vol 74 no 4 pp 691ndash705 2012
[145] H Nakanishi ldquoMicroglial functions and proteasesrdquo MolecularNeurobiology vol 27 no 2 pp 163ndash176 2003
[146] M E Tremblay and A K Majewska ldquoA role for microglia insynaptic plasticityrdquoCommunicative and Integrative Biology vol4 no 2 pp 220ndash222 2011
[147] R C Paolicelli G Bolasco F Pagani et al ldquoSynaptic pruning bymicroglia is necessary for normal brain developmentrdquo Sciencevol 333 no 6048 pp 1456ndash1458 2011
[148] GKempermannHGKuhn and FHGage ldquoMore hippocam-pal neurons in adult mice living in an enriched environmentrdquoNature vol 386 no 6624 pp 493ndash495 1997
[149] M Nilsson E Perfilieva U Johansson O Orwar and P SEriksson ldquoEnriched environment increases neurogenesis in theadult rat dentate gyrus and improves spatial memoryrdquo Journalof Neurobiology vol 39 no 4 pp 569ndash578 1999
[150] H van Praag G Kempermann and F H Gage ldquoRunningincreases cell proliferation and neurogenesis in the adult mousedentate gyrusrdquo Nature Neuroscience vol 2 no 3 pp 266ndash2701999
[151] D Young P A Lawlor P Leone M Dragunow and MJ During ldquoEnvironmental enrichment inhibits spontaneousapoptosis prevents seizures and is neuroprotectiverdquo NatureMedicine vol 5 no 4 pp 448ndash453 1999
[152] L L Williamson A Chao and S D Bilbo ldquoEnvironmentalenrichment alters glial antigen expression and neuroimmunefunction in the adult rat hippocampusrdquo Brain Behavior andImmunity vol 26 no 3 pp 500ndash510 2012
[153] L Maggi M Scianni I Branchi I DrsquoAndrea C Lauro and CLimatola ldquoCX(3)CR1 deficiency alters hippocampal-dependentplasticity phenomena blunting the effects of enriched environ-mentrdquo Frontiers in Cellular Neuroscience vol 5 article 22 2011
[154] I Goshen A Avital T Kreisel T Licht M Segal and RYirmiya ldquoEnvironmental enrichment restores memory func-tioning in mice with impaired IL-1 signaling via reinstatementof long-term potentiation and spine size enlargementrdquo Journalof Neuroscience vol 29 no 11 pp 3395ndash3403 2009
[155] Y Ziv N Ron O Butovsky et al ldquoImmune cells contribute tothe maintenance of neurogenesis and spatial learning abilitiesin adulthoodrdquo Nature Neuroscience vol 9 no 2 pp 268ndash2752006
[156] J Kipnis H Cohen M Cardon Y Ziv and M Schwartz ldquoTcell deficiency leads to cognitive dysfunction implications fortherapeutic vaccination for schizophrenia and other psychiatricconditionsrdquo Proceedings of the National Academy of Sciences ofthe United States of America vol 101 no 21 pp 8180ndash8185 2004
[157] S A Wolf B Steiner A Akpinarli et al ldquoCD4-positive Tlymphocytes provide a neuroimmunological link in the control
Neural Plasticity 15
of adult hippocampal neurogenesisrdquo Journal of Immunologyvol 182 no 7 pp 3979ndash3984 2009
[158] G J Huang A L Smith D H D Gray et al ldquoA genetic andfunctional relationship between T cells and cellular prolifera-tion in the adult hippocampusrdquo PLOS Biology vol 8 no 12Article ID e1000561 2010
[159] R M Ransohoff and B Engelhardt ldquoThe anatomical andcellular basis of immune surveillance in the central nervoussystemrdquoNature Reviews Immunology vol 12 no 9 pp 623ndash6352012
[160] M Olah G Ping A H De Haas et al ldquoEnhanced hippocampalneurogenesis in the absence of microglia T cell interactionand microglia activation in the murine running wheel modelrdquoGLIA vol 57 no 10 pp 1046ndash1061 2009
[161] E Gebara S Sultan J Kocher-Braissant and N Toni ldquoAdulthippocampal neurogenesis inversely correlates with microgliain conditions of voluntary running and agingrdquo Frontiers inNeuroscience vol 7 article 145 2013
[162] R Aharoni B Kayhan R Eilam M Sela and R ArnonldquoGlatiramer acetate-specific T cells in the brain express T helper23 cytokines and brain-derived neurotrophic factor in siturdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 100 no 2 pp 14157ndash14162 2003
[163] C Rossi A Angelucci L Costantin et al ldquoBrain-derivedneurotrophic factor (BDNF) is required for the enhancementof hippocampal neurogenesis following environmental enrich-mentrdquo European Journal of Neuroscience vol 24 no 7 pp 1850ndash1856 2006
Neural Plasticity 5
of IL-1120573 and IL-6 are significantly increased in depressedpatients [94] In mice restraint stress leads to a widespreadactivation of NF-120581B in the hippocampus including at thelevel of neuroprogenitors [95] and increased protein levels ofIL-1120573 [96] In addition to the direct role of glucocorticoidsIL-1120573 also seems to mediate some of the effects of mildchronic stress because in vivomanipulations that block IL-1120573(either pharmacologically or in null transgenic mice) preventthe anhedonic stress response and the antineurogenic effectof stress [91 96]Moreover the corticoids and IL-1120573 pathwaysmay regulate each other in a bidirectional manner becausethe administration of a GR antagonist can blunt the LPS-induced production of hippocampal IL-1120573 in stressed mice[97] whereas mice knockout for the IL-1120573 receptor (IL-1R1)fail to display the characteristic elevation of corticosteroneinduced by mild chronic stress [96] Another stress-relatedcytokine IL-6 induces depressive phenotypes and preventsthe antidepressant actions of fluoxetinewhen administered tomice in vivo [98] So far the effects of stress on neurogenesisvia corticosteroids and inflammation have been assumed tobe cell autonomous as neuroprogenitors express both GR[99] and IL-1R1 [95] The potential participation of microgliais yet to be determined but there are some reports of adirect effect of stress on microglial activation For instancemicroglia acutely isolated frommice subjected to acute stress(by inescapable tail shock) showed a primed response to LPSchallenge by producing higher levels of IL-1120573mRNA ex vivo[100] and the specific loss of expression of GR in microglialeads to a blunted inflammatory response in vitro and to adecreased neuronal damage in vivo in response to LPS [80]In stress paradigms these enhanced responses of microgliato inflammatory challenges are similar to their age-relatedldquoprimingrdquo which has been associated with and is possiblydue to an increased basal production of proinflammatorymediators However whether microglia express increasedlevels of IL-1120573 and other proinflammatory cytokines inresponse to stressful events is presently unclear [101] It is thuspossible that some of the antineurogenic effects of stress areexerted bymeans of microglial-dependent inflammation butthis hypothesis remains to be experimentally tested
5 Inflammation Associated with Aging andNeurodegenerative Diseases
Inflammation is also commonly associated with normalaging and neurodegenerative diseases and therefore couldrepresent a putative underlying mechanism that explainstheir decrease in hippocampal neurogenesis Nonethelessinflammation is also associated with neurological diseasessuch as epilepsy or stroke where neurogenesis is thought tobe increased although the data from rodents and humans issomewhat conflictive [102] Neurogenesis is well known todecline throughout adulthood and normal aging in rodentsand humans [103 104] but the decay ismore pronounced andoccurs later in life in mice than in humans [105] The aging-associated decrease in neurogenesis has been shown to occurmainly as a consequence of exhaustion of the rNSC popula-tion which after being recruited and activated undergo three
rounds of mitosis in average and then terminally differentiateinto astrocytes [12 106] In addition a reduced mitoticcapacity of the neuroprogenitors could further contribute todecreasing neurogenesis [106] and moreover an age-relatedincrease in the levels of proinflammatory cytokines couldalso hinder neurogenesis in the aging brain Serum levelsof IL-1120573 IL-6 and TNF120572 are elevated in elderly patients[107 108] Aged microglia express higher levels of theseproinflammatory cytokines and show a greater response toLPS inflammatory challenge that is a ldquoprimedrdquo responsethan their younger counterparts [109] The origin of thislow-grade age-related inflammation (ldquoinflamm-agingrdquo [110])remains unknown and may be related to both aging anddamage to the surrounding neurons as well as aging of theimmune system per se
At the cellular level stress to the endoplasmic reticulum(ER) caused by various perturbations such as nutrient deple-tion disturbances in calcium or redox status or increasedlevels of misfolded proteins can induce a cell-autonomousinflammatory response to neurons Stress to the ER a mul-tifunctional organelle which is involved in protein foldinglipid biosynthesis and calcium storage triggers a homeostaticresponse mechanism named the unfolding protein response(UPR) aiming to clear the unfolded proteins in order torestore normal ER homeostasis [111] However if the ERstress cannot be resolved theUPR also initiates inflammatoryand apoptotic pathways via activation of the transcriptionfactor NF-120581B which controls the expression of most proin-flammatory cytokines [112] In the brain ER stress is ofteninitiated by the formation of abnormal protein aggregatesin several neurodegenerative diseases such as Alzheimerrsquosdisease (AD) Parkinsonrsquos disease (PD) amyotrophic lateralsclerosis (ALS) Huntingtonrsquos disease (HD) and prion-relateddisorders [113] This neurodegeneration-associated ER stressis assumed to occur mostly in neurons but there aresome examples of microglial protein misfolding as well Forinstance both microglia and neurons overexpress CHOP(CEBP homologous protein) a transcription factor whichis activated during ER stress in human patients and mousemodels of ALS [114] Inflammation has been speculated tobe a main negative contributor to the pathology of ALS[115] but a direct microglial involvement in mediating theinflammatory response to abnormal protein aggregation inALS and other neurodegenerative conditions remains to betested Finally ER stress has been linked to a variety of inflam-matory conditions [116 117] including chronic stress diet-induced obesity and drug abuse as well as atherosclerosisand arthritis [118ndash120] During normal aging a progressivedecline in expression and activity of key ER molecularchaperones and folding enzymes could also compromise theadaptive response of the UPR thereby contributing to theage-associated decline in cellular functions [118] Thereforeaging is strongly associated with a chronic ER stress whichleads to increased activation of NF-120581B [112] however thecontribution of the different brain cell types to ldquoinflamm-agingrdquo is still poorly understood The detrimental effects onneurogenesis of increased proinflammatory cytokines in theaging brain are not necessarily related to microglia but alsoto stressed neurons Furthermore ER stress may also cause a
6 Neural Plasticity
cell-autonomous response in neural stem cells [121] althoughits impact on neurogenesis remains to be experimentallydetermined
In addition aging is accompanied by an increased levelof mitochondrial oxidative stress which in turn activatesthe ldquoInflammasomerdquo [122] a group of multimeric proteinscomprising the interleukin 1 converting enzyme (ICE cas-pase 1) which serves to release the active form of thecytokine [123] IL-1120573 may act directly on rNSCs (visualisedby labeling with the Sox2 marker) as they express IL-1R1 in the adult hippocampus [91] Treatment with IL-1120573decreases hippocampal proliferation in young mice [91] andpharmacological inhibition of ICE partially restores the num-ber of newborn neurons in aged mice without significantlyaffecting their differentiation rate [124] Transgenic IL-1120573overexpression results in chronic inflammation and deple-tion of doublecortin-labeled neuroblasts thus mimickingthe aging-associated depletion of neurogenesis [125] Theactual mechanism of action of IL-1120573 on neurogenesis inaged mice including decreased proliferation of rNSCsANPsand survival of newborn neurons remains undeterminedMicroglia are a main source of IL-1120573 in the aging brain butthe hypothesis that microglia-derived IL-1120573 is responsiblefor depleting neurogenesis in the aging brain remains to bedirectly tested
The regulation of neurogenesis by IL-1120573 in the agingbrain has been further linked to the activity of anothercytokine the chemokine fractalkine or CX3CL1 Fractalkinehas soluble and membrane-tethered forms and is exclu-sively expressed by neurons while the fractalkine receptor(CX3CR1) is expressed in the brain by microglia alone [126]Thismodule forms a unique neuron-microglia signalling unitthat controls the extent of microglial inflammation in severalneurodegenerative conditions including PD ALS [127] orAD [128] In fact CX3CR1 blocking antibodies increasethe production of hippocampal IL-1120573 when administeredto young adult rats [129] Importantly chronic treatmentwith fractalkine increases hippocampal proliferation and thenumber of neuroblasts in aged (22 months old) but notyoung (3 months old) or middle-aged rats (12 months old)whereas an antagonists of CX3CR1 has the opposite effectsin young but not in middle-aged nor old rats [129] Sincefractalkine expression is decreased during aging [129] areduced neuron-microglia signalling might be releasing thebrake on microglial contribution to inflammatory responsesalthough increased levels of fractalkine were instead reportedin aged rat hippocampus by other studies [68] Additionalinsights into the role of fractalkine signalling come fromknock-in mice in which the endogenous CX3CR1 locus isreplaced by the fluorescent reporter GFP [126] The initialstudies suggested that CX3CR1GFPGFP (ie CX3CR1minusminus)mice have no significant differences in brain development andfunctions [130] but more systematic investigations recentlyrevealed a long list of hippocampal-dependent changes inyoung (3 months old) CX3CR1GFPGFP and CX3CR1GFP+mice compared to wild-type mice These changes notablyincluded decreased neuroprogenitors proliferation and neu-roblasts number impaired LTP performance in contextual
fear conditioning and water maze spatial learning and mem-ory and importantly increased IL-1120573 protein levels [131]Thesignalling pathway of fractalkine-IL-1120573 is functionally rele-vant because IL-1R1 antagonists rescued LTP and cognitivefunction in CX3CR1GFPGFP mice [131] In sum even thoughneuronal fractalkine seems to be sufficient for restrainingthe inflammatory activity of microglia in young rats itsdownregulation during aging could activate the microglialinflammatory response and thereby subsequently reduce theproliferation of remaining neuroprogenitors
In AD inflammatory cytokines such as IL-1120573 are over-expressed in the microglia associated with the amyloid beta(A120573) plaques of postmortem samples [132] and in transgenicmice modeling the disease [133] The loss of synapses (fromhippocampus to frontal cortex) is one of the main patho-logical substrates in this disease but adult neurogenesis isalso severely reduced in most mouse models of AD possiblydue to a decreased proliferation of neuroprogenitors and adecreased survival of newborn cells even though the putativechanges in the neurogenic cascade in postmortem samplesremain controversial (reviewed in [102]) This lack of agree-ment is possibly explained by the fact that the vast majorityof AD cases have a late onset over 65 years of age when littleneurogenesis remains In contrast in most transgenic ADmouse models the A120573 accumulation cognitive deficits andchanges in neurogenesis are already detectable in young ani-mals (2-3 months old) The study of AD is further hinderedby the difficulty in comparing the time course and pathologyacross different mouse models For instance early treatmentwith minocycline can improve cognition and reduce A120573burden in mice expressing the human amyloid precursorprotein (APP) [134] In contrast in mice expressing APP anda mutated form of presenilin 1 (PS1) which is part of the 120574secretase pathway that cleaves A120573 inflammation is reducedwithout any detectable changes in A120573 plaques deposition[135] Concomitantly with a decrease in tissue inflamma-tory cytokines and number of microglial cells minocyclinerestores neurogenesis and hippocampus-dependent memorydeficits in these APPPS1 mice [135] indirectly suggestingthat cognitive decay in AD may be at least in part relatedto a detrimental effect of inflammation on hippocampalneurogenesis Direct evidence that neurogenesis is associatedwith the cognitive performance in AD is still lacking Furtherresearch is also necessary to determine the neurogenic targetsof AD-related inflammation One central open questionfor future therapies aiming at increasing neurogenesis andcognition in AD is whether neuroprogenitors are spared orwhether their age-induced loss becomes accelerated Ratherthan increasing the proliferation and neurogenic output ofthe few rNSCs remaining in an old AD brain it may be morerelevant to develop strategies that prevent the age-related lossof neuroprogenitors in presymptomatic patients
In summary inflammation associated with a wide varietyof experimental models of disease produces strong detri-mental effects on hippocampal neurogenesis These effectson human neurogenesis are however not so well describedand in vitro IL-1120573 increases the proliferation of hip-pocampal embryonic neuroprogenitors but decreases their
Neural Plasticity 7
differentiation into neurons [136] Novel methods to assesshippocampal neurogenesis in the living human brain frommetabolomics of neuroprogenitors to hippocampal bloodbrain volume (reviewed in [102]) will help to determine thecontribution of inflammation to adult neurogenesis in thehealthy and diseased human brain during aging
6 Normal Physiological Conditions
In the healthy mature brain microglia are an essential com-ponent of the neurogenic SGZ niche where they physicallyintermingle with neuroprogenitors neuroblasts and new-born neurons [62] Here surveillant microglia effectively andrapidly phagocytose the excess of newborn cells undergoingapoptosis [62] Importantly microglial phagocytosis in theadult SGZ is not disturbed by inflammation associated withaging or by LPS challenge as the phagocytic index (iethe proportion of apoptotic cells completely engulfed bymicroglia) is maintained over 90 in these conditions [62]Nonetheless the consequences of microglial phagocytosis onadult hippocampal neurogenesis remain elusive Treatment ofmice with annexin V which binds to the phosphatidylserine(PS) receptor and prevents the recognition of PS on thesurface of apoptotic cells presumably blocking phagocytosisincreases the number of apoptotic cells in the SGZ [40] Con-comitantly annexin V reduces neurogenesis by decreasingthe survival of neuroblasts without affecting neuroprogeni-tors proliferation [40] Similar results were obtained in trans-genic mice knock-out for ELMO1 a cytoplasm protein whichpromotes the internalization of apoptotic cells althoughthe effects on neurogenesis were ascribed to a decreasedphagocytic activity of neuroblasts [40]The actual phagocytictarget of the neuroblasts remains undetermined but thenewborn apoptotic cells in the adult SGZ are exclusivelyphagocytosed by microglia at least in physiological condi-tions [62] Nevertheless none of the above manipulationshas specifically tested the role of microglial phagocytosisin hippocampal-dependent learning and memory and thusthe functional impact of microglial phagocytosis in adultneurogenic niches during normal physiological conditionsremains to be elucidated
Microglial phagocytosis of apoptotic cells is activelyanti-inflammatory at least in vitro and thus it has beenhypothesized that anti-inflammatory cytokines produced byphagocytic microglia may further regulate neurogenesis [10]For instance transforming growth factor beta (TGF120573) whichis produced by phagocytic microglia in vitro [137] inhibitsthe proliferation of SGZ neuroprogenitors [138] Microgliaare further able to produce proneurogenic factors in vitro[139] When primed with cytokines associated with T helpercells such as interleukin 4 (IL-4) or low doses of interferongamma (IFN120574) culturedmicroglia support neurogenesis andoligodendrogenesis through decreased production of TNF120572and increased production of insulin-like growth factor 1(IGF-1) [139] an inducer of neuroprogenitor proliferation[26] A list of potential factors produced by microgliaand known to act on neuroprogenitor proliferation can
be found in Table 1 In addition recent observations sug-gest that neuroprogenitor cells may not only regulate theirown environment but also influence microglial functionsFor instance vascular endothelial growth factor (VEGF)produced by cultured neuroprecursor cells directly affectsmicroglial proliferation migration and phagocytosis [20]More potential factors produced by neuroprogenitors shownto be influencing microglial activity and function can befound in Table 2 However it has to be taken into accountthat most of these observations were obtained in culture andthat further research is needed in order to elucidate whetherthose factors are also secreted and have the same regulatoryresponses in vivo
In addition microglial capacity to remodel and eliminatesynaptic structures during normal physiological conditionshas suggested that microglia could also control the synap-tic integration of the newborn neurons generated duringadult hippocampal neurogenesis [140] Three main mech-anisms were proposed (1) the phagocytic elimination ofnonapoptotic axon terminals and dendritic spines (2) theproteolytic remodeling of the perisynaptic environmentand (3) the concomitant structural remodeling of dendriticspines [7 140] Indeed microglial contacts with synapticelements are frequently observed in the cortex during normalphysiological conditions sometimes accompanied by theirengulfment and phagocytic elimination [141ndash143] as in thedeveloping retinogeniculate system [144] Microglial cells aredistinctively surrounded by pockets of extracellular spacecontrarily to all the other cellular elements [142] suggestingthat microglia could remodel the volume and geometryof the extracellular space and thus the concentration ofvarious ions neurotransmitters and signalling moleculesin the synaptic environment Whether microglia create thepockets of extracellular space themselves or not remainsunknown but these pockets could result from microglialrelease of extracellular proteases such as metalloproteinasesand cathepsins [145] which are well known for influencingthe formation structural remodeling and elimination ofdendritic spines in situ and also experience-dependent plas-ticity in vivo [7 146] More recently microglial phagocytosisof synaptic components was also observed in the developinghippocampus in the unique time window of synaptogenesisa process which is notably regulated by fractalkine-CX3CR1signalling [147] Therefore the attractive hypothesis thatmicroglial sculpts the circuitry of newborn cells in the adulthippocampus deserves further attention
Lastly microglia were also involved in increasing adulthippocampal neurogenesis in the enriched environment(EE) experimental paradigm EE is a paradigm mimick-ing some features of the normal living circumstances ofwild animals as it gives them access to social interactionstoys running wheels and edible treats EE has long beenknown to enhance neurogenesis by acting on newborncells survival resulting ultimately in an enlargement ofthe dentate gyrus [148] Functionally these changes areaccompanied by enhanced spatial learning and memoryformation with the water maze paradigm [149] Similarincreases in neurogenesis are obtained by subjecting miceto voluntary running paradigms although in this case the
8 Neural Plasticity
Table 1 Summary of factors secreted by microglia and the potential effect they have on neuroprogenitors in vitro
Microglia secreted factors Reference Modulation of neural progenitor cells ReferenceBDNF [18] Differentiation [19]EGF [20] Survival expansion proliferation differentiation [21]FGF120573 [22] Survival and expansion [23]GDNF [24] Survival migration and differentiation [25]IGF-1 [21] Proliferation [26]IL-1120573 [27] Reduction in migration [27]IL-6 [28] Inhibition of neurogenesis [29]IL-7 [20] Differentiation [30]IL-11 [20] Differentiation [30]NT-4 [24] Differentiation [31]PDGF [32] Expansion and differentiation [33]TGF120573 [34] Inhibition of proliferation [19]
Table 2 Summary of factors secreted by neuroprogenitors and the potential effect they have on microglia in vitro
NPC secreted factors Reference Modulation of microglia ReferenceBDNF [18] Proliferation and induction of phagocytic activity [35]Haptoglobin [24] Neuroprotection [36]IL-1120573 [37] Intracellular Ca+2 elevation and proliferation [22]IL-6 [37] Increase in proliferation [38]M-CSF [20] Mitogen [39]NGF [40] Decrease in LPS-induced NO [41]TGF120573 [37] Inhibition of TNF120572 secretion [42]TNF120572 [37] Upregulation of IL-10 secretion [43]VEGF [20] Induction of chemotaxis and proliferation [20]
effect is mediated by increased neuroprogenitor proliferation[150] During inflammatory conditions EE is antiapoptoticand neuroprotective [151] and it limits the hippocampalresponse to LPS challenge by decreasing the expression ofseveral cytokines and chemokines including IL1-120573 andTNF120572[152] In fact EE is believed to counteract the inflammatoryenvironment and rescue the decreased number of neuroblastsin CX3CR1GFPGFP mice compared to wild-type mice [153]The effects of EE are independent of the IL-1120573 signallingpathway as it increases neurogenesis in mice that are nullfor IL-1R1 [154] EE also induces microglial proliferation andexpression of the proneurogenic IGF-1 [155] but the fullphenotype of microglia in EE compared to standard housingand its impact on the neurogenic cascade remains to bedetermined
The mechanisms behind the anti-inflammatory actionsof EE are unknown but they were suggested to involvemicroglial interactions with T lymphocytes through anincreased expression of themajor histocompatibility complexof class II (MHC-II) during EE [155] MHC-II is responsiblefor presenting the phagocytosed and degraded antigens tothe antibodies expressed on the surface of a subtype ofT lymphocytes (T helper or CD4+ cells) thus initiatingtheir activation and production of antigen-specific antibod-ies Severe combined immunodeficient (SCID) mice lackingeither T and B lymphocytes or nude mice lacking only Tcells have impaired proliferation and neurogenesis in normal
and EE housing compared to wild-type mice [155] as wellas impaired performance in the water maze [156] Similarlyantibody-based depletion of T helper lymphocytes impairsbasal and exercise-induced proliferation and neurogenesis[157] Furthermore a genetic study in heterogeneous stockmice which descend from eight inbred progenitor strainshas found a significant positive correlation between geneticloci associated to hippocampal proliferation and to theproportion of CD4+ cells among blood CD3+ lymphocytes[158] Additional experiments are needed to fully determinethe possible interactions between microglia and T cellsin neurogenesis because at least in normal physiologicalconditions (1) T cell surveillance of the brain parenchymais minimal (2) microglia are poor antigen presenting cellsand (3) antigen presentation by means of MHC-II family ofmolecules is thought to occur outside the brain that is in themeninges and choroid plexus [159] In fact during voluntaryexercise there are no significant changes in T cell surveillanceof the hippocampus nor a direct interaction between T cellsand microglia nor any changes in the gene expression profileof microglia including that of IGF-1 IL-1120573 and TNF120572 [160]The number of microglia is also inversely correlated withthe number of hippocampal proliferating cells rNSCs andneuroblasts in aged (8 months) mice subjected to voluntaryrunning as well as in vitro cocultures of microglia andneuroprogenitors which has been interpreted as resultingfrom an overall inhibitory effect of microglia on adult
Neural Plasticity 9
neurogenesis [161] Even though EE is clearly a more com-plex environmental factor than voluntary running furtherresearch is necessary to disregard nonspecific or indirecteffects of genetic or antibody-based T cells depletion onmicroglia and other brain cell populations including rNSCsFor instance adoptive transfer of T helper cells treated withglatiramer acetate a synthetic analog of myelin basic protein(MBP) approved for the treatment of multiple sclerosis pro-duces a bystander effect on resident astrocytes and microgliaby increasing their expression of anti-inflammatory cytokinessuch as TGF120573 [162] Alternatively it has been suggested thatT cells may mediate an indirect effect on adult hippocampalneurogenesis by increasing the production of brain-derivedneurotrophic factor (BDNF) [157] which is involved in theproneurogenic actions of EE [163] Whether BDNF cancounteract the detrimental effects of T cell depletion on neu-rogenesis remains unknownOverall the roles ofmicroglia inEE and running-induced neurogenesis are unclear and haveto be addressed with more precise experimental designs Insummary surveillant microglia are part of the physical nichesurrounding the neural stem cells and newborn neurons ofthe mature hippocampus where they continuously phagocy-tose the excess of newborn cellsMicroglia were also linked tothe proneurogenic and anti-inflammatory effects of voluntaryrunning and EE but direct evidence is missing The overallcontribution of microglia to neurogenesis and learning andmemory in normal physiological conditions remains largelyunexplored at this early stage in the field
7 Conclusion
In light of these observations microglia are now emergingas important effector cells during normal brain developmentand functions including adult hippocampal neurogenesisMicroglia can exert a positive or negative influence onthe proliferation survival or differentiation of newborncells depending on the inflammatory context For instancemicroglia can compromise the neurogenic cascade duringchronic stress aging and neurodegenerative diseases bytheir release of proinflammatory cytokines such as IL-1120573IL-6 and TNF120572 A reduced fractalkine signalling betweenneurons and microglia could also be involved during normalaging However microglia are not necessarily the only celltype implicated because astrocytes endothelial cells mastcells perivascular and meningeal macrophages and to alesser extent neurons and invading peripheral immune cellscould further contribute by releasing proinflammatorymedi-ators
Additionally microglia were shown to phagocytose theexcess of newborn neurons undergoing apoptosis in thehippocampal neurogenic niche during normal physiologicalconditions while a similar role in the synaptic integrationof newborn cells was also proposed in light of their capacityto phagocytose synaptic elements Lastly microglial interac-tions with T cells leading to the release of anti-inflammatorycytokines neurotrophic factors and other proneurogenicmediators (notably during EE and voluntary running) couldcounteract the detrimental effects of inflammation on adult
hippocampal neurogenesis and their functional implicationsfor learning and memory
However further research is necessary to assess the rela-tive contribution of microglia versus other types of residentand infiltrating inflammatory cells and to determine thenature of the effector cytokines and other inflammatorymediators involved as well as their cellular andmolecular tar-gets in the neurogenic cascade Such research will undoubt-edly help to develop novel strategies aiming at protecting theneurogenic potential and ultimately its essential contributionto learning and memory
The authors declare that there is no conflict of interestsregarding the publication of this paper
Acknowledgments
This work was supported by grants from the Spanish Min-istry of Economy and Competitiveness to Amanda Sierra(BFU2012-32089) and Juan M Encinas (SAF2012-40085)from Basque Government (Saiotek S-PC 12UN014) and Iker-basque start-up funds to JuanM Encinas andAmanda Sierraand fromTheBanting Research Foundation the Scottish RiteCharitable Foundation of Canada and start-up funds fromUniversite Laval andCentre de recherche duCHUdeQuebecto Marie-Eve Tremblay
References
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[2] F Ginhoux S Lim G Hoeffel D Low and T Huber ldquoOriginand differentiation of microgliardquo Frontiers in Cellular Neuro-science vol 7 article 45 2013
[3] E Gomez Perdiguero C Schulz and F Geissmann ldquoDevelop-ment and homeostasis of ldquoresidentrdquomyeloid cells the case of themicrogliardquo GLIA vol 61 no 1 pp 112ndash120 2013
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[5] A Aguzzi B A Barres and M L Bennett ldquoMicroglia scape-goat saboteur or something elserdquo Science vol 339 no 6116 pp156ndash161 2013
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[7] M E Tremblay B Stevens A Sierra H Wake A Bessis andA Nimmerjahn ldquoThe role of microglia in the healthy brainrdquoJournal of Neuroscience vol 31 no 45 pp 16064ndash16069 2011
[8] A Miyamoto H Wake A J Moorhouse and J NabekuraldquoMicroglia and synapse interactions fine tuaning neural circuitsand candidate moleculesrdquo Frontiers in Cellular Neurosciencevol 7 article 70 2013
[9] C Bechade Y Cantaut-Belarif and A Bessis ldquoMicroglialcontrol of neuronal activityrdquo Frontiers in Cellular Neurosciencevol 7 article 32 2013
[10] A Sierra O Abiega A Shahraz and H Neumann ldquoJanus-faced microglia beneficial and detrimental consequences ofmicroglial phagocytosisrdquo Frontiers in Cellular Neuroscience vol7 article 6 2013
[11] G Kempermann S Jessberger B Steiner and G KronenbergldquoMilestones of neuronal development in the adult hippocam-pusrdquo Trends in Neurosciences vol 27 no 8 pp 447ndash452 2004
[12] J M Encinas T V Michurina N Peunova et al ldquoDivision-coupled astrocytic differentiation and age-related depletion ofneural stem cells in the adult hippocampusrdquo Cell Stem Cell vol8 no 5 pp 566ndash579 2011
[13] M A Bonaguidi M A Wheeler J S Shapiro et al ldquoIn vivoclonal analysis reveals self-renewing and multipotent adultneural stem cell characteristicsrdquo Cell vol 145 no 7 pp 1142ndash1155 2011
[14] J J Breunig J I Arellano J D Macklis and P RakicldquoEverything that glitters isnrsquot gold a critical review of postnatalneural precursor analysesrdquo Cell Stem Cell vol 1 no 6 pp 612ndash627 2007
[15] L S Overstreet-Wadiche and G L Westbrook ldquoFunctionalmaturation of adult-generated granule cellsrdquoHippocampus vol16 no 3 pp 208ndash215 2006
[16] S Ge C H Yang K S Hsu G L Ming andH Song ldquoA criticalperiod for enhanced synaptic plasticity in newly generatedneurons of the adult brainrdquo Neuron vol 54 no 4 pp 559ndash5662007
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[18] K Nakajima S Honda Y Tohyama Y Imai S Kohsaka andT Kurihara ldquoNeurotrophin secretion from cultured microgliardquoJournal of Neuroscience Research vol 65 no 4 pp 322ndash3312001
[19] M Krampert S R Chirasani F P Wachs et al ldquoSmad7regulates the adult neural stemprogenitor cell pool in a trans-forming growth factor 120573- and bone morphogenetic protein-independent mannerrdquo Molecular and Cellular Biology vol 30no 14 pp 3685ndash3694 2010
[20] K I Mosher R H Andres T Fukuhara et al ldquoNeural pro-genitor cells regulate microglia functions and activityrdquo NatureNeuroscience vol 15 no 11 pp 1485ndash1487 2012
[21] V Tropepe M Sibilia B G Ciruna J Rossant E F Wagnerand D van der Kooy ldquoDistinct neural stem cells proliferatein response to EGF and FGF in the developing mouse telen-cephalonrdquo Developmental Biology vol 208 no 1 pp 166ndash1881999
[22] S U Kim and J De Vellis ldquoMicroglia in health and diseaserdquoJournal of Neuroscience Research vol 81 no 3 pp 302ndash3132005
[23] B A Reynolds and R L Rietze ldquoNeural stem cells andneurospheresmdashre-evaluating the relationshiprdquoNatureMethodsvol 2 no 5 pp 333ndash336 2005
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Neural Plasticity 11
[27] K Striedinger and E Scemes ldquoInterleukin-1120573 affects calciumsignaling and in vitro cell migration of astrocyte progenitorsrdquoJournal of Neuroimmunology vol 196 no 1-2 pp 116ndash123 2008
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[30] M F Mehler R Rozental M Dougherty D C Spray and JA Kessler ldquoCytokine regulation of neuronal differentiation ofhippocampal progenitor cellsrdquo Nature vol 362 no 6415 pp62ndash65 1993
[31] U Gurok C Steinhoff B Lipkowitz H H Ropers C Scharffand U A Nuber ldquoGene expression changes in the course ofneural progenitor cell differentiationrdquo Journal of Neurosciencevol 24 no 26 pp 5982ndash6002 2004
[32] J B Demoulin M Enarsson J Larsson A Essaghir C HHeldin and K Forsberg-Nilsson ldquoThe gene expression profileof PDGF-treated neural stem cells corresponds to partiallydifferentiated neurons and gliardquo Growth Factors vol 24 no 3pp 184ndash196 2006
[33] F C Mansergh M A Wride and D E Rancourt ldquoNeuronsfrom stem cells implications for understanding nervous systemdevelopment and repairrdquo Biochemistry and Cell Biology vol 78no 5 pp 613ndash628 2000
[34] F C Alcantara Gomes V De Oliveira Sousa and L RomaoldquoEmerging roles for TGF-1205731 in nervous system developmentrdquoInternational Journal of Developmental Neuroscience vol 23 no5 pp 413ndash424 2005
[35] S Elkabes E M DiCicco-Bloom and I B Black ldquoBrainmicrogliamacrophages express neurotrophins that selectivelyregulate microglial proliferation and functionrdquo Journal of Neu-roscience vol 16 no 8 pp 2508ndash2521 1996
[36] U K Hanisch and H Kettenmann ldquoMicroglia active sensorand versatile effector cells in the normal and pathologic brainrdquoNature Neuroscience vol 10 no 11 pp 1387ndash1394 2007
[37] H J Klassen T F Ng Y Kurimoto et al ldquoMultipotent retinalprogenitors express developmental markers differentiate intoretinal neurons and preserve light-mediated behaviorrdquo Inves-tigative Ophthalmology and Visual Science vol 45 no 11 pp4167ndash4173 2004
[38] W J Streit S D Hurley T S McGraw and S L Semple-Rowland ldquoComparative evaluation of cytokine profiles andreactive gliosis supports a critical role for interleukin-6 inneuron-glia signaling during regenerationrdquo Journal of Neuro-science Research vol 61 no 1 pp 10ndash20 2000
[39] A Suzumura M Sawada H Yamamoto and T MarunouchildquoEffects of colony stimulating factors on isolated microglia invitrordquo Journal of Neuroimmunology vol 30 no 2-3 pp 111ndash1201990
[40] Z Lu M R Elliott Y Chen et al ldquoPhagocytic activity ofneuronal progenitors regulates adult neurogenesisrdquoNature CellBiology vol 13 no 9 pp 1076ndash1084 2011
[41] K Nakajima Y Kikuchi E Ikoma et al ldquoNeurotrophinsregulate the function of cultured microgliardquo GLIA vol 24 no3 pp 272ndash289 1998
[42] P A Lodge and S Sriram ldquoRegulation of microglial activationby TGF-120573 IL-10 and CSF-1rdquo Journal of Leukocyte Biology vol60 no 4 pp 502ndash508 1996
[43] W S Sheng S Hu F H Kravitz P K Peterson and C C ChaoldquoTumor necrosis factor alpha upregulates humanmicroglial cell
production of interleukin-10 in vitrordquo Clinical and DiagnosticLaboratory Immunology vol 2 no 5 pp 604ndash608 1995
[44] G LMing andH Song ldquoAdult neurogenesis in themammalianbrain significant answers and significant questionsrdquo Neuronvol 70 no 4 pp 687ndash702 2011
[45] E Bruel-Jungerman S Davis C Rampon and S LarocheldquoLong-term potentiation enhances neurogenesis in the adultdentate gyrusrdquo Journal of Neuroscience vol 26 no 22 pp 5888ndash5893 2006
[46] E Drapeau M F Montaron S Aguerre and D N AbrousldquoLearning-induced survival of new neurons depends on thecognitive status of aged ratsrdquo Journal of Neuroscience vol 27no 22 pp 6037ndash6044 2007
[47] A Mouret G Gheusi M M Gabellec F De Chaumont J COlivo-Marin and P M Lledo ldquoLearning and survival of newlygenerated neurons when timemattersrdquo Journal of Neurosciencevol 28 no 45 pp 11511ndash11516 2008
[48] N Kee C M Teixeira A H Wang and P W FranklandldquoPreferential incorporation of adult-generated granule cellsinto spatial memory networks in the dentate gyrusrdquo NatureNeuroscience vol 10 no 3 pp 355ndash362 2007
[49] F Massa M Koelh T Wiesner et al ldquoConditional reduction ofadult neurogenesis impairs bidirectional hippocampal synapticplasticityrdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 108 no 16 pp 6644ndash6649 2011
[50] T J Shors G Miesegaes A Beylin M Zhao T Rydel and EGould ldquoNeurogenesis in the adult is involved in the formationof tracememoriesrdquoNature vol 410 no 6826 pp 372ndash376 2001
[51] W Deng M D Saxe I S Gallina and F H Gage ldquoAdult-born hippocampal dentate granule cells undergoingmaturationmodulate learning and memory in the brainrdquo Journal of Neuro-science vol 29 no 43 pp 13532ndash13542 2009
[52] M Arruda-Carvalho M Sakaguchi K G Akers S A Josselynand P W Frankland ldquoPosttraining ablation of adult-generatedneurons degrades previously acquired memoriesrdquo Journal ofNeuroscience vol 31 no 42 pp 15113ndash15127 2011
[53] A Sahay K N Scobie A S Hill et al ldquoIncreasing adulthippocampal neurogenesis is sufficient to improve patternseparationrdquo Nature vol 472 no 7344 pp 466ndash470 2011
[54] G LMing andH Song ldquoAdult neurogenesis in themammaliancentral nervous systemrdquoAnnual Review of Neuroscience vol 28pp 223ndash250 2005
[55] K Newton and V M Dixit ldquoSignaling in innate immunity andinflammationrdquo Cold Spring Harbor Perspectives in Biology vol4 no 3 2012
[56] H K Jeong K Ji K Min and E H Joe ldquoBrain inflammationand microglia facts and misconceptionsrdquo Experimental Neuro-biology vol 22 no 2 pp 59ndash67 2013
[57] D Stellwagen and R CMalenka ldquoSynaptic scalingmediated byglial TNF-120572rdquo Nature vol 440 no 7087 pp 1054ndash1059 2006
[58] M Pickering D Cumiskey and J J OrsquoConnor ldquoActions of TNF-120572 on glutamatergic synaptic transmission in the central nervoussystemrdquo Experimental Physiology vol 90 no 5 pp 663ndash6702005
[59] K Belarbi T Jopson D Tweedie et al ldquoTNF-120572 protein synthe-sis inhibitor restores neuronal function and reverses cognitivedeficits induced by chronic neuroinflammationrdquo Journal ofNeuroinflammation vol 9 article 23 2012
[60] C T Ekdahl J H Claasen S Bonde Z Kokaia andO LindvallldquoInflammation is detrimental for neurogenesis in adult brainrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 100 no 23 pp 13632ndash13637 2003
12 Neural Plasticity
[61] M L Monje H Toda and T D Palmer ldquoInflammatoryblockade restores adult hippocampal neurogenesisrdquo Sciencevol 302 no 5651 pp 1760ndash1765 2003
[62] A Sierra J M Encinas J J P Deudero et al ldquoMicroglia shapeadult hippocampal neurogenesis through apoptosis-coupledphagocytosisrdquo Cell Stem Cell vol 7 no 4 pp 483ndash495 2010
[63] D Chugh P Nilsson S A Afjei A Bakochi and C T EkdahlldquoBrain inflammation induces post-synaptic changes duringearly synapse formation in adult-born hippocampal neuronsrdquoExperimental Neurobiology vol 250 pp 176ndash188 2013
[64] K Belarbi C Arellano R Ferguson T Jopson and S RosildquoChronic neuroinflammation impacts the recruitment of adult-born neurons into behaviorally relevant hippocampal net-worksrdquo Brain Behavior and Immunity vol 26 no 1 pp 18ndash232012
[65] S Johann E Kampmann B Denecke et al ldquoExpression ofenzymes involved in the prostanoid metabolism by corticalastrocytes after LPS-induced inflammationrdquo Journal of Molec-ular Neuroscience vol 34 no 2 pp 177ndash185 2008
[66] P V B Reddy K V Rama Rao and M D NorenbergldquoInhibitors of the mitochondrial permeability transition reduceammonia-induced cell swelling in cultured astrocytesrdquo Journalof Neuroscience Research vol 87 no 12 pp 2677ndash2685 2009
[67] H Nie H Zhang and H R Weng ldquoMinocycline preventsimpaired glial glutamate uptake in the spinal sensory synapsesof neuropathic ratsrdquo Neuroscience vol 170 no 3 pp 901ndash9122010
[68] F Cerbai D Lana D Nosi et al ldquoThe neuron-astrocyte-microglia triad in normal brain ageing and in a model ofneuroinflammation in the rat hippocampusrdquo PLoS ONE vol 7no 9 Article ID e45250 2012
[69] W J Jin S W Feng Z Feng S M Lu T Qi and Y N QianldquoMinocycline improves postoperative cognitive impairment inaged mice by inhibiting astrocytic activationrdquo NeuroReport2013
[70] K A Ji M S Yang H K Jeong et al ldquoResident microgliadie and infiltrated neutrophils and monocytes become majorinflammatory cells in lipopolysaccharide-injected brainrdquoGLIAvol 55 no 15 pp 1577ndash1588 2007
[71] N J van Wagoner J W Oh P Repovic and E N BenvenisteldquoInterleukin-6 (IL-6) production by astrocytes autocrine reg-ulation by IL-6 and the soluble IL-6 receptorrdquo Journal ofNeuroscience vol 19 no 13 pp 5236ndash5244 1999
[72] L Vallieres I L Campbell F H Gage and P E SawchenkoldquoReduced hippocampal neurogenesis in adult transgenic micewith chronic astrocytic production of interleukin-6rdquo Journal ofNeuroscience vol 22 no 2 pp 486ndash492 2002
[73] B S McEwen ldquoPhysiology and neurobiology of stress andadaptation central role of the brainrdquo Physiological Reviews vol87 no 3 pp 873ndash904 2007
[74] V LuineMVillegas CMartinez and B SMcEwen ldquoRepeatedstress causes reversible impairments of spatial memory perfor-mancerdquo Brain Research vol 639 no 1 pp 167ndash170 1994
[75] S Rivest ldquoMolecular insights on the cerebral innate immunesystemrdquo Brain Behavior and Immunity vol 17 no 1 pp 13ndash192003
[76] S Nadeau and S Rivest ldquoEndotoxemia prevents the cerebralinflammatory wave induced by intraparenchymal lipopolysac-charide injection role of glucocorticoids and CD14rdquo Journal ofImmunology vol 169 no 6 pp 3370ndash3381 2002
[77] A Sierra A Gottfried-Blackmore T A Milner B S McEwenand K Bulloch ldquoSteroid hormone receptor expression andfunction in microgliardquo GLIA vol 56 no 6 pp 659ndash674 2008
[78] C Liston andW B Gan ldquoGlucocorticoids are critical regulatorsof dendritic spine development and plasticity in vivordquo Proceed-ings of the National Academy of Sciences of the United States ofAmerica vol 108 no 38 pp 16074ndash16079 2011
[79] C Liston J M Cichon F Jeanneteau Z Jia M V Chaoand W B Gan ldquoCircadian glucocorticoid oscillations pro-mote learning-dependent synapse formation andmaintenancerdquoNature Neuroscience vol 16 no 6 pp 698ndash705 2013
[80] M A Carrillo-de Sauvage L Maatouk I Arnoux et al ldquoPotentand multiple regulatory actions of microglial glucocorticoidreceptors during CNS inflammationrdquo Cell Death amp Differenti-ation vol 20 no 11 pp 1546ndash1557 2013
[81] S F Sorrells J R Caso C DMunhoz and RM Sapolsky ldquoThestressed CNS when glucocorticoids aggravate inflammationrdquoNeuron vol 64 no 1 pp 33ndash39 2009
[82] M A Bellavance and S Rivest ldquoThe neuroendocrine controlof the innate immune system in health and brain diseasesrdquoImmunological Reviews vol 248 no 1 pp 36ndash55 2012
[83] R J Tynan S Naicker M Hinwood et al ldquoChronic stress altersthe density and morphology of microglia in a subset of stress-responsive brain regionsrdquo Brain Behavior and Immunity vol24 no 7 pp 1058ndash1068 2010
[84] E S Wohleb N D Powell J P Godbout and J F SheridanldquoStress-induced recruitment of bone marrow-derived mono-cytes to the brain promotes anxiety-like behaviorrdquo The Journalof Neuroscience vol 33 no 34 pp 13820ndash13833 2013
[85] Y Diz-Chaves M Astiz M J Bellini and L M Garcia-SeguraldquoPrenatal stress increases the expression of proinflammatorycytokines and exacerbates the inflammatory response to LPS inthe hippocampal formation of adultmalemicerdquoBrain Behaviorand Immunity vol 28 pp 196ndash206 2013
[86] E S Wohleb A M Fenn A M Pacenta N D Powell J FSheridan and J P Godbout ldquoPeripheral innate immune chal-lenge exaggerated microglia activation increased the numberof inflammatory CNSmacrophages and prolonged social with-drawal in socially defeated micerdquo Psychoneuroendocrinologyvol 37 no 9 pp 1491ndash1505 2012
[87] C Mirescu and E Gould ldquoStress and adult neurogenesisrdquoHippocampus vol 16 no 3 pp 233ndash238 2006
[88] J LWarner-Schmidt andR SDuman ldquoHippocampal neuroge-nesis opposing effects of stress and antidepressant treatmentrdquoHippocampus vol 16 no 3 pp 239ndash249 2006
[89] N D Hanson M J Owens K A Boss-Williams J M Weissand C B Nemeroff ldquoSeveral stressors fail to reduce adulthippocampal neurogenesisrdquo Psychoneuroendocrinology vol 36no 10 pp 1520ndash1529 2011
[90] E Gould B S McEwen P Tanapat L A M Galea and EFuchs ldquoNeurogenesis in the dentate gyrus of the adult treeshrew is regulated by psychosocial stress and NMDA receptoractivationrdquo Journal of Neuroscience vol 17 no 7 pp 2492ndash24981997
[91] JW Koo andR S Duman ldquoIL-1120573 is an essentialmediator of theantineurogenic and anhedonic effects of stressrdquo Proceedings ofthe National Academy of Sciences of the United States of Americavol 105 no 2 pp 751ndash756 2008
[92] D C Lagace M H Donovan N A Decarolis et al ldquoAdulthippocampal neurogenesis is functionally important for stress-induced social avoidancerdquo Proceedings of the National Academy
Neural Plasticity 13
of Sciences of the United States of America vol 107 no 9 pp4436ndash4441 2010
[93] G Kronenberg I Kirste D Inta et al ldquoReduced hippocampalneurogenesis in the GR+- genetic mousemodel of depressionrdquoEuropean Archives of Psychiatry and Clinical Neuroscience vol259 no 8 pp 499ndash504 2009
[94] M B Howren D M Lamkin and J Suls ldquoAssociations ofdepression with c-reactive protein IL-1 and IL-6 a meta-analysisrdquo Psychosomatic Medicine vol 71 no 2 pp 171ndash1862009
[95] J W Koo S J Russo D Ferguson E J Nestler and R SDuman ldquoNuclear factor-120581B is a critical mediator of stress-impaired neurogenesis and depressive behaviorrdquo Proceedings ofthe National Academy of Sciences of the United States of Americavol 107 no 6 pp 2669ndash2674 2010
[96] I Goshen T Kreisel O Ben-Menachem-Zidon et al ldquoBraininterleukin-1 mediates chronic stress-induced depression inmice via adrenocortical activation and hippocampal neuroge-nesis suppressionrdquo Molecular Psychiatry vol 13 no 7 pp 717ndash728 2008
[97] C D Munhoz L B Lepsch E M Kawamoto et al ldquoChronicunpredictable stress exacerbates lipopolysaccharide-inducedactivation of nuclear factor-120581B in the frontal cortex andhippocampus via glucocorticoid secretionrdquo Journal of Neuro-science vol 26 no 14 pp 3813ndash3820 2006
[98] S J Sukoff Rizzo S J Neal Z A Hughes et al ldquoEvidence forsustained elevation of IL-6 in the CNS as a key contributorof depressive-like phenotypesrdquo Translational Psychiatry vol 2article e199 2012
[99] A Garcia B Steiner G Kronenberg A Bick-Sander and GKempermann ldquoAge-dependent expression of glucocorticoid-andmineralocorticoid receptors on neural precursor cell popu-lations in the adult murine hippocampusrdquoAging Cell vol 3 no6 pp 363ndash371 2004
[100] M G Frank B M Thompson L R Watkins and S F MaierldquoGlucocorticoids mediate stress-induced priming of microglialpro-inflammatory responsesrdquo Brain Behavior and Immunityvol 26 no 2 pp 337ndash345 2012
[101] S Sugama M Fujita M Hashimoto and B Conti ldquoStressinduced morphological microglial activation in the rodentbrain involvement of interleukin-18rdquoNeuroscience vol 146 no3 pp 1388ndash1399 2007
[102] A Sierra J M Encinas and M Maletic-Savatic ldquoAdult humanneurogenesis from microscopy to magnetic resonance imag-ingrdquo Frontiers in Neuroscience vol 5 article 47 2011
[103] H G Kuhn H Dickinson-Anson and F H Gage ldquoNeurogen-esis in the dentate gyrus of the adult rat age-related decrease ofneuronal progenitor proliferationrdquo Journal of Neuroscience vol16 no 6 pp 2027ndash2033 1996
[104] L N Manganas X Zhang Y Li et al ldquoMagnetic resonancespectroscopy identifies neural progenitor cells in the live humanbrainrdquo Science vol 318 no 5852 pp 980ndash985 2007
[105] K L Spalding O Bergmann K Alkass et al ldquoDynamics ofhippocampal neurogenesis in adult humansrdquo Cell vol 153 no6 pp 1219ndash1227 2013
[106] J M Encinas and A Sierra ldquoNeural stem cell deforestationas the main force driving the age-related decline in adulthippocampal neurogenesisrdquo Behavioural Brain Research vol227 no 2 pp 433ndash439 2012
[107] K S Krabbe M Pedersen andH Bruunsgaard ldquoInflammatorymediators in the elderlyrdquo Experimental Gerontology vol 39 no5 pp 687ndash699 2004
[108] B S Diniz A L Teixeira L Talib W F Gattaz andO V Forlenza ldquoInterleukin-1120573 serum levels is increased inantidepressant-free elderly depressed patientsrdquo American Jour-nal of Geriatric Psychiatry vol 18 no 2 pp 172ndash176 2010
[109] A Sierra A C Gottfried-Blackmore B S Mcewen and KBulloch ldquoMicroglia derived from aging mice exhibit an alteredinflammatory profilerdquo GLIA vol 55 no 4 pp 412ndash424 2007
[110] C FranceschiM Bonafe S Valensin et al ldquoInflamm-aging Anevolutionary perspective on immunosenescencerdquo Annals of theNew York Academy of Sciences vol 908 pp 244ndash254 2000
[111] R Sano and J C Reed ldquoER stress-induced cell death mecha-nismsrdquoBiochimica et BiophysicaActa vol 1833 no 12 pp 3460ndash3470 2013
[112] S Z Hasnain R Lourie I Das A C H Chen and MA McGuckin ldquoThe interplay between endoplasmic reticulumstress and inflammationrdquo Immunology and Cell Biology vol 90no 3 pp 260ndash270 2012
[113] S Matus L H Glimcher and C Hetz ldquoProtein folding stressin neurodegenerative diseases a glimpse into the ERrdquo CurrentOpinion in Cell Biology vol 23 no 2 pp 239ndash252 2011
[114] Y Ito M Yamada H Tanaka et al ldquoInvolvement of CHOP anER-stress apoptotic mediator in both human sporadic ALS andALS model micerdquo Neurobiology of Disease vol 36 no 3 pp470ndash476 2009
[115] D Papadimitriou V Le Verche A Jacquier B Ikiz S Przed-borski and D B Re ldquoInflammation in ALS and SMA sortingout the good from the evilrdquo Neurobiology of Disease vol 37 no3 pp 493ndash502 2010
[116] A R Johnson J J Milner and LMakowski ldquoThe inflammationhighway metabolism accelerates inflammatory traffic in obe-sityrdquo Immunological Reviews vol 249 no 1 pp 218ndash238 2012
[117] S Buch H Yao M Guo et al ldquoCocaine and HIV-1 interplayin CNS cellular and molecular mechanismsrdquo Current HIVResearch vol 10 no 5 pp 425ndash428 2012
[118] M K Brown and N Naidoo ldquoThe endoplasmic reticulumstress response in aging and age-related diseasesrdquo Frontiers inPhysiology vol 3 article 263 2012
[119] G Castro C Areias MF L Weissmann et al ldquoDiet-inducedobesity induces endoplasmic reticulum stress and insulin resis-tance in the amygdala of ratsrdquo FEBS Open Bio vol 3 pp 443ndash449 2013
[120] A A Pavlovsky D Boehning D Li Y Zhang X Fan andT A Green ldquoPsychological stress cocaine and natural rewardeach induce endoplasmic reticulum stress genes in rat brainrdquoNeuroscience vol 246 pp 160ndash169 2013
[121] G GargiuloM CesaroniM Serresi et al ldquoIn vivo RNAi screenfor BMI1 targets identifies TGF-betaBMP-ER stress pathwaysas key regulators of neural- and malignant glioma-stem cellhomeostasisrdquo Cancer Cell vol 23 no 5 pp 660ndash676 2013
[122] A Salminen K Kaarniranta and A Kauppinen ldquoInflammag-ing disturbed interplay between autophagy and inflamma-somesrdquo Aging vol 4 no 3 pp 166ndash175 2012
[123] E Latz T S Xiao andA Stutz ldquoActivation and regulation of theinflammasomesrdquoNature Reviews Immunology vol 13 no 6 pp397ndash411 2013
[124] C Gemma A D Bachstetter M J Cole M Fister C Hudsonand P C Bickford ldquoBlockade of caspase-1 increases neurogene-sis in the aged hippocampusrdquo European Journal of Neurosciencevol 26 no 10 pp 2795ndash2803 2007
[125] M D Wu A M Hein M J Moravan S S Shaftel J AOlschowka and M K OrsquoBanion ldquoAdult murine hippocampal
14 Neural Plasticity
neurogenesis is inhibited by sustained IL-1120573 and not rescued byvoluntary runningrdquo Brain Behavior and Immunity vol 26 no2 pp 292ndash300 2012
[126] Y Wolf S Yona K W Kim and S Jung ldquoMicroglia seen fromthe CX3CR1 anglerdquo Frontiers in Cellular Neuroscience vol 7article 26 2013
[127] A E Cardona E P Pioro M E Sasse et al ldquoControl ofmicroglial neurotoxicity by the fractalkine receptorrdquo NatureNeuroscience vol 9 no 7 pp 917ndash924 2006
[128] K Bhaskar M Konerth O N Kokiko-Cochran A Cardona RM Ransohoff and B T Lamb ldquoRegulation of tau pathology bythe microglial fractalkine receptorrdquo Neuron vol 68 no 1 pp19ndash31 2010
[129] A D Bachstetter J M Morganti J Jernberg et al ldquoFractalkineand CX3CR1 regulate hippocampal neurogenesis in adult andaged ratsrdquo Neurobiology of Aging vol 32 no 11 pp 2030ndash20442011
[130] S Jung J Aliberti P Graemmel et al ldquoAnalysis of fractalkinereceptor CX3CR1 function by targeted deletion and greenfluorescent protein reporter gene insertionrdquo Molecular andCellular Biology vol 20 no 11 pp 4106ndash4114 2000
[131] J T Rogers J M Morganti A D Bachstetter et al ldquoCX3CR1deficiency leads to impairment of hippocampal cognitive func-tion and synaptic plasticityrdquo Journal of Neuroscience vol 31 no45 pp 16241ndash16250 2011
[132] W S T Griffin L C Stanley C Ling et al ldquoBrain interleukin1 and S-100 immunoreactivity are elevated in Down syndromeand Alzheimer diseaserdquo Proceedings of the National Academy ofSciences of the United States of America vol 86 no 19 pp 7611ndash7615 1989
[133] W C Benzing J RWujek E KWard et al ldquoEvidence for glial-mediated inflammation in aged APP(SW) transgenic micerdquoNeurobiology of Aging vol 20 no 6 pp 581ndash589 1999
[134] T J Seabrook L Jiang M Maier and C A Lemere ldquoMinocy-cline affects microglia activation A120573 deposition and behaviorin APP-tg micerdquo GLIA vol 53 no 7 pp 776ndash782 2006
[135] B Biscaro O Lindvall G Tesco C T Ekdahl and RM NitschldquoInhibition of microglial activation protects hippocampal neu-rogenesis and improves cognitive deficits in a transgenic mousemodel for Alzheimerrsquos diseaserdquoNeurodegenerative Diseases vol9 no 4 pp 187ndash198 2012
[136] P A Zunszain C Anacker A Cattaneo et al ldquoInterleukin-1120573a new regulator of the kynurenine pathway affecting humanhippocampal neurogenesisrdquo Neuropsychopharmacology vol 37no 4 pp 939ndash949 2012
[137] R De Simone M Antonietta Ajmone-Cat P Tirassa and LMinghetti ldquoApoptotic PC12 cells exposing phosphatidylserinepromote the production of anti-inflammatory and neuropro-tective molecules bymicroglial cellsrdquo Journal of Neuropathologyand Experimental Neurology vol 62 no 2 pp 208ndash216 2003
[138] M S Buckwalter M Yamane B S Coleman et al ldquoChroni-cally increased transforming growth factor-1205731 strongly inhibitshippocampal neurogenesis in aged micerdquo American Journal ofPathology vol 169 no 1 pp 154ndash164 2006
[139] O Butovsky Y Ziv A Schwartz et al ldquoMicroglia activatedby IL-4 or IFN-120574 differentially induce neurogenesis and oligo-dendrogenesis from adult stemprogenitor cellsrdquoMolecular andCellular Neuroscience vol 31 no 1 pp 149ndash160 2006
[140] C T Ekdahl ldquoMicroglial activationmdashtuning and pruning adultneurogenesisrdquo Frontiers in Pharmacology vol 3 article 41 2012
[141] HWakeA JMoorhouse S Jinno S Kohsaka and JNabekuraldquoResting microglia directly monitor the functional state ofsynapses in vivo and determine the fate of ischemic terminalsrdquoJournal of Neuroscience vol 29 no 13 pp 3974ndash3980 2009
[142] M E Tremblay R L Lowery and A K Majewska ldquoMicroglialinteractions with synapses are modulated by visual experiencerdquoPLoS Biology vol 8 no 11 Article ID e1000527 2010
[143] M E Tremblay M L Zettel J R Ison P D Allen and A KMajewska ldquoEffects of aging and sensory loss on glial cells inmouse visual and auditory corticesrdquo GLIA vol 60 no 4 pp541ndash558 2012
[144] D P Schafer E K Lehrman A G Kautzman et al ldquoMicrogliasculpt postnatal neural circuits in an activity and complement-dependent mannerrdquo Neuron vol 74 no 4 pp 691ndash705 2012
[145] H Nakanishi ldquoMicroglial functions and proteasesrdquo MolecularNeurobiology vol 27 no 2 pp 163ndash176 2003
[146] M E Tremblay and A K Majewska ldquoA role for microglia insynaptic plasticityrdquoCommunicative and Integrative Biology vol4 no 2 pp 220ndash222 2011
[147] R C Paolicelli G Bolasco F Pagani et al ldquoSynaptic pruning bymicroglia is necessary for normal brain developmentrdquo Sciencevol 333 no 6048 pp 1456ndash1458 2011
[148] GKempermannHGKuhn and FHGage ldquoMore hippocam-pal neurons in adult mice living in an enriched environmentrdquoNature vol 386 no 6624 pp 493ndash495 1997
[149] M Nilsson E Perfilieva U Johansson O Orwar and P SEriksson ldquoEnriched environment increases neurogenesis in theadult rat dentate gyrus and improves spatial memoryrdquo Journalof Neurobiology vol 39 no 4 pp 569ndash578 1999
[150] H van Praag G Kempermann and F H Gage ldquoRunningincreases cell proliferation and neurogenesis in the adult mousedentate gyrusrdquo Nature Neuroscience vol 2 no 3 pp 266ndash2701999
[151] D Young P A Lawlor P Leone M Dragunow and MJ During ldquoEnvironmental enrichment inhibits spontaneousapoptosis prevents seizures and is neuroprotectiverdquo NatureMedicine vol 5 no 4 pp 448ndash453 1999
[152] L L Williamson A Chao and S D Bilbo ldquoEnvironmentalenrichment alters glial antigen expression and neuroimmunefunction in the adult rat hippocampusrdquo Brain Behavior andImmunity vol 26 no 3 pp 500ndash510 2012
[153] L Maggi M Scianni I Branchi I DrsquoAndrea C Lauro and CLimatola ldquoCX(3)CR1 deficiency alters hippocampal-dependentplasticity phenomena blunting the effects of enriched environ-mentrdquo Frontiers in Cellular Neuroscience vol 5 article 22 2011
[154] I Goshen A Avital T Kreisel T Licht M Segal and RYirmiya ldquoEnvironmental enrichment restores memory func-tioning in mice with impaired IL-1 signaling via reinstatementof long-term potentiation and spine size enlargementrdquo Journalof Neuroscience vol 29 no 11 pp 3395ndash3403 2009
[155] Y Ziv N Ron O Butovsky et al ldquoImmune cells contribute tothe maintenance of neurogenesis and spatial learning abilitiesin adulthoodrdquo Nature Neuroscience vol 9 no 2 pp 268ndash2752006
[156] J Kipnis H Cohen M Cardon Y Ziv and M Schwartz ldquoTcell deficiency leads to cognitive dysfunction implications fortherapeutic vaccination for schizophrenia and other psychiatricconditionsrdquo Proceedings of the National Academy of Sciences ofthe United States of America vol 101 no 21 pp 8180ndash8185 2004
[157] S A Wolf B Steiner A Akpinarli et al ldquoCD4-positive Tlymphocytes provide a neuroimmunological link in the control
Neural Plasticity 15
of adult hippocampal neurogenesisrdquo Journal of Immunologyvol 182 no 7 pp 3979ndash3984 2009
[158] G J Huang A L Smith D H D Gray et al ldquoA genetic andfunctional relationship between T cells and cellular prolifera-tion in the adult hippocampusrdquo PLOS Biology vol 8 no 12Article ID e1000561 2010
[159] R M Ransohoff and B Engelhardt ldquoThe anatomical andcellular basis of immune surveillance in the central nervoussystemrdquoNature Reviews Immunology vol 12 no 9 pp 623ndash6352012
[160] M Olah G Ping A H De Haas et al ldquoEnhanced hippocampalneurogenesis in the absence of microglia T cell interactionand microglia activation in the murine running wheel modelrdquoGLIA vol 57 no 10 pp 1046ndash1061 2009
[161] E Gebara S Sultan J Kocher-Braissant and N Toni ldquoAdulthippocampal neurogenesis inversely correlates with microgliain conditions of voluntary running and agingrdquo Frontiers inNeuroscience vol 7 article 145 2013
[162] R Aharoni B Kayhan R Eilam M Sela and R ArnonldquoGlatiramer acetate-specific T cells in the brain express T helper23 cytokines and brain-derived neurotrophic factor in siturdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 100 no 2 pp 14157ndash14162 2003
[163] C Rossi A Angelucci L Costantin et al ldquoBrain-derivedneurotrophic factor (BDNF) is required for the enhancementof hippocampal neurogenesis following environmental enrich-mentrdquo European Journal of Neuroscience vol 24 no 7 pp 1850ndash1856 2006
6 Neural Plasticity
cell-autonomous response in neural stem cells [121] althoughits impact on neurogenesis remains to be experimentallydetermined
In addition aging is accompanied by an increased levelof mitochondrial oxidative stress which in turn activatesthe ldquoInflammasomerdquo [122] a group of multimeric proteinscomprising the interleukin 1 converting enzyme (ICE cas-pase 1) which serves to release the active form of thecytokine [123] IL-1120573 may act directly on rNSCs (visualisedby labeling with the Sox2 marker) as they express IL-1R1 in the adult hippocampus [91] Treatment with IL-1120573decreases hippocampal proliferation in young mice [91] andpharmacological inhibition of ICE partially restores the num-ber of newborn neurons in aged mice without significantlyaffecting their differentiation rate [124] Transgenic IL-1120573overexpression results in chronic inflammation and deple-tion of doublecortin-labeled neuroblasts thus mimickingthe aging-associated depletion of neurogenesis [125] Theactual mechanism of action of IL-1120573 on neurogenesis inaged mice including decreased proliferation of rNSCsANPsand survival of newborn neurons remains undeterminedMicroglia are a main source of IL-1120573 in the aging brain butthe hypothesis that microglia-derived IL-1120573 is responsiblefor depleting neurogenesis in the aging brain remains to bedirectly tested
The regulation of neurogenesis by IL-1120573 in the agingbrain has been further linked to the activity of anothercytokine the chemokine fractalkine or CX3CL1 Fractalkinehas soluble and membrane-tethered forms and is exclu-sively expressed by neurons while the fractalkine receptor(CX3CR1) is expressed in the brain by microglia alone [126]Thismodule forms a unique neuron-microglia signalling unitthat controls the extent of microglial inflammation in severalneurodegenerative conditions including PD ALS [127] orAD [128] In fact CX3CR1 blocking antibodies increasethe production of hippocampal IL-1120573 when administeredto young adult rats [129] Importantly chronic treatmentwith fractalkine increases hippocampal proliferation and thenumber of neuroblasts in aged (22 months old) but notyoung (3 months old) or middle-aged rats (12 months old)whereas an antagonists of CX3CR1 has the opposite effectsin young but not in middle-aged nor old rats [129] Sincefractalkine expression is decreased during aging [129] areduced neuron-microglia signalling might be releasing thebrake on microglial contribution to inflammatory responsesalthough increased levels of fractalkine were instead reportedin aged rat hippocampus by other studies [68] Additionalinsights into the role of fractalkine signalling come fromknock-in mice in which the endogenous CX3CR1 locus isreplaced by the fluorescent reporter GFP [126] The initialstudies suggested that CX3CR1GFPGFP (ie CX3CR1minusminus)mice have no significant differences in brain development andfunctions [130] but more systematic investigations recentlyrevealed a long list of hippocampal-dependent changes inyoung (3 months old) CX3CR1GFPGFP and CX3CR1GFP+mice compared to wild-type mice These changes notablyincluded decreased neuroprogenitors proliferation and neu-roblasts number impaired LTP performance in contextual
fear conditioning and water maze spatial learning and mem-ory and importantly increased IL-1120573 protein levels [131]Thesignalling pathway of fractalkine-IL-1120573 is functionally rele-vant because IL-1R1 antagonists rescued LTP and cognitivefunction in CX3CR1GFPGFP mice [131] In sum even thoughneuronal fractalkine seems to be sufficient for restrainingthe inflammatory activity of microglia in young rats itsdownregulation during aging could activate the microglialinflammatory response and thereby subsequently reduce theproliferation of remaining neuroprogenitors
In AD inflammatory cytokines such as IL-1120573 are over-expressed in the microglia associated with the amyloid beta(A120573) plaques of postmortem samples [132] and in transgenicmice modeling the disease [133] The loss of synapses (fromhippocampus to frontal cortex) is one of the main patho-logical substrates in this disease but adult neurogenesis isalso severely reduced in most mouse models of AD possiblydue to a decreased proliferation of neuroprogenitors and adecreased survival of newborn cells even though the putativechanges in the neurogenic cascade in postmortem samplesremain controversial (reviewed in [102]) This lack of agree-ment is possibly explained by the fact that the vast majorityof AD cases have a late onset over 65 years of age when littleneurogenesis remains In contrast in most transgenic ADmouse models the A120573 accumulation cognitive deficits andchanges in neurogenesis are already detectable in young ani-mals (2-3 months old) The study of AD is further hinderedby the difficulty in comparing the time course and pathologyacross different mouse models For instance early treatmentwith minocycline can improve cognition and reduce A120573burden in mice expressing the human amyloid precursorprotein (APP) [134] In contrast in mice expressing APP anda mutated form of presenilin 1 (PS1) which is part of the 120574secretase pathway that cleaves A120573 inflammation is reducedwithout any detectable changes in A120573 plaques deposition[135] Concomitantly with a decrease in tissue inflamma-tory cytokines and number of microglial cells minocyclinerestores neurogenesis and hippocampus-dependent memorydeficits in these APPPS1 mice [135] indirectly suggestingthat cognitive decay in AD may be at least in part relatedto a detrimental effect of inflammation on hippocampalneurogenesis Direct evidence that neurogenesis is associatedwith the cognitive performance in AD is still lacking Furtherresearch is also necessary to determine the neurogenic targetsof AD-related inflammation One central open questionfor future therapies aiming at increasing neurogenesis andcognition in AD is whether neuroprogenitors are spared orwhether their age-induced loss becomes accelerated Ratherthan increasing the proliferation and neurogenic output ofthe few rNSCs remaining in an old AD brain it may be morerelevant to develop strategies that prevent the age-related lossof neuroprogenitors in presymptomatic patients
In summary inflammation associated with a wide varietyof experimental models of disease produces strong detri-mental effects on hippocampal neurogenesis These effectson human neurogenesis are however not so well describedand in vitro IL-1120573 increases the proliferation of hip-pocampal embryonic neuroprogenitors but decreases their
Neural Plasticity 7
differentiation into neurons [136] Novel methods to assesshippocampal neurogenesis in the living human brain frommetabolomics of neuroprogenitors to hippocampal bloodbrain volume (reviewed in [102]) will help to determine thecontribution of inflammation to adult neurogenesis in thehealthy and diseased human brain during aging
6 Normal Physiological Conditions
In the healthy mature brain microglia are an essential com-ponent of the neurogenic SGZ niche where they physicallyintermingle with neuroprogenitors neuroblasts and new-born neurons [62] Here surveillant microglia effectively andrapidly phagocytose the excess of newborn cells undergoingapoptosis [62] Importantly microglial phagocytosis in theadult SGZ is not disturbed by inflammation associated withaging or by LPS challenge as the phagocytic index (iethe proportion of apoptotic cells completely engulfed bymicroglia) is maintained over 90 in these conditions [62]Nonetheless the consequences of microglial phagocytosis onadult hippocampal neurogenesis remain elusive Treatment ofmice with annexin V which binds to the phosphatidylserine(PS) receptor and prevents the recognition of PS on thesurface of apoptotic cells presumably blocking phagocytosisincreases the number of apoptotic cells in the SGZ [40] Con-comitantly annexin V reduces neurogenesis by decreasingthe survival of neuroblasts without affecting neuroprogeni-tors proliferation [40] Similar results were obtained in trans-genic mice knock-out for ELMO1 a cytoplasm protein whichpromotes the internalization of apoptotic cells althoughthe effects on neurogenesis were ascribed to a decreasedphagocytic activity of neuroblasts [40]The actual phagocytictarget of the neuroblasts remains undetermined but thenewborn apoptotic cells in the adult SGZ are exclusivelyphagocytosed by microglia at least in physiological condi-tions [62] Nevertheless none of the above manipulationshas specifically tested the role of microglial phagocytosisin hippocampal-dependent learning and memory and thusthe functional impact of microglial phagocytosis in adultneurogenic niches during normal physiological conditionsremains to be elucidated
Microglial phagocytosis of apoptotic cells is activelyanti-inflammatory at least in vitro and thus it has beenhypothesized that anti-inflammatory cytokines produced byphagocytic microglia may further regulate neurogenesis [10]For instance transforming growth factor beta (TGF120573) whichis produced by phagocytic microglia in vitro [137] inhibitsthe proliferation of SGZ neuroprogenitors [138] Microgliaare further able to produce proneurogenic factors in vitro[139] When primed with cytokines associated with T helpercells such as interleukin 4 (IL-4) or low doses of interferongamma (IFN120574) culturedmicroglia support neurogenesis andoligodendrogenesis through decreased production of TNF120572and increased production of insulin-like growth factor 1(IGF-1) [139] an inducer of neuroprogenitor proliferation[26] A list of potential factors produced by microgliaand known to act on neuroprogenitor proliferation can
be found in Table 1 In addition recent observations sug-gest that neuroprogenitor cells may not only regulate theirown environment but also influence microglial functionsFor instance vascular endothelial growth factor (VEGF)produced by cultured neuroprecursor cells directly affectsmicroglial proliferation migration and phagocytosis [20]More potential factors produced by neuroprogenitors shownto be influencing microglial activity and function can befound in Table 2 However it has to be taken into accountthat most of these observations were obtained in culture andthat further research is needed in order to elucidate whetherthose factors are also secreted and have the same regulatoryresponses in vivo
In addition microglial capacity to remodel and eliminatesynaptic structures during normal physiological conditionshas suggested that microglia could also control the synap-tic integration of the newborn neurons generated duringadult hippocampal neurogenesis [140] Three main mech-anisms were proposed (1) the phagocytic elimination ofnonapoptotic axon terminals and dendritic spines (2) theproteolytic remodeling of the perisynaptic environmentand (3) the concomitant structural remodeling of dendriticspines [7 140] Indeed microglial contacts with synapticelements are frequently observed in the cortex during normalphysiological conditions sometimes accompanied by theirengulfment and phagocytic elimination [141ndash143] as in thedeveloping retinogeniculate system [144] Microglial cells aredistinctively surrounded by pockets of extracellular spacecontrarily to all the other cellular elements [142] suggestingthat microglia could remodel the volume and geometryof the extracellular space and thus the concentration ofvarious ions neurotransmitters and signalling moleculesin the synaptic environment Whether microglia create thepockets of extracellular space themselves or not remainsunknown but these pockets could result from microglialrelease of extracellular proteases such as metalloproteinasesand cathepsins [145] which are well known for influencingthe formation structural remodeling and elimination ofdendritic spines in situ and also experience-dependent plas-ticity in vivo [7 146] More recently microglial phagocytosisof synaptic components was also observed in the developinghippocampus in the unique time window of synaptogenesisa process which is notably regulated by fractalkine-CX3CR1signalling [147] Therefore the attractive hypothesis thatmicroglial sculpts the circuitry of newborn cells in the adulthippocampus deserves further attention
Lastly microglia were also involved in increasing adulthippocampal neurogenesis in the enriched environment(EE) experimental paradigm EE is a paradigm mimick-ing some features of the normal living circumstances ofwild animals as it gives them access to social interactionstoys running wheels and edible treats EE has long beenknown to enhance neurogenesis by acting on newborncells survival resulting ultimately in an enlargement ofthe dentate gyrus [148] Functionally these changes areaccompanied by enhanced spatial learning and memoryformation with the water maze paradigm [149] Similarincreases in neurogenesis are obtained by subjecting miceto voluntary running paradigms although in this case the
8 Neural Plasticity
Table 1 Summary of factors secreted by microglia and the potential effect they have on neuroprogenitors in vitro
Microglia secreted factors Reference Modulation of neural progenitor cells ReferenceBDNF [18] Differentiation [19]EGF [20] Survival expansion proliferation differentiation [21]FGF120573 [22] Survival and expansion [23]GDNF [24] Survival migration and differentiation [25]IGF-1 [21] Proliferation [26]IL-1120573 [27] Reduction in migration [27]IL-6 [28] Inhibition of neurogenesis [29]IL-7 [20] Differentiation [30]IL-11 [20] Differentiation [30]NT-4 [24] Differentiation [31]PDGF [32] Expansion and differentiation [33]TGF120573 [34] Inhibition of proliferation [19]
Table 2 Summary of factors secreted by neuroprogenitors and the potential effect they have on microglia in vitro
NPC secreted factors Reference Modulation of microglia ReferenceBDNF [18] Proliferation and induction of phagocytic activity [35]Haptoglobin [24] Neuroprotection [36]IL-1120573 [37] Intracellular Ca+2 elevation and proliferation [22]IL-6 [37] Increase in proliferation [38]M-CSF [20] Mitogen [39]NGF [40] Decrease in LPS-induced NO [41]TGF120573 [37] Inhibition of TNF120572 secretion [42]TNF120572 [37] Upregulation of IL-10 secretion [43]VEGF [20] Induction of chemotaxis and proliferation [20]
effect is mediated by increased neuroprogenitor proliferation[150] During inflammatory conditions EE is antiapoptoticand neuroprotective [151] and it limits the hippocampalresponse to LPS challenge by decreasing the expression ofseveral cytokines and chemokines including IL1-120573 andTNF120572[152] In fact EE is believed to counteract the inflammatoryenvironment and rescue the decreased number of neuroblastsin CX3CR1GFPGFP mice compared to wild-type mice [153]The effects of EE are independent of the IL-1120573 signallingpathway as it increases neurogenesis in mice that are nullfor IL-1R1 [154] EE also induces microglial proliferation andexpression of the proneurogenic IGF-1 [155] but the fullphenotype of microglia in EE compared to standard housingand its impact on the neurogenic cascade remains to bedetermined
The mechanisms behind the anti-inflammatory actionsof EE are unknown but they were suggested to involvemicroglial interactions with T lymphocytes through anincreased expression of themajor histocompatibility complexof class II (MHC-II) during EE [155] MHC-II is responsiblefor presenting the phagocytosed and degraded antigens tothe antibodies expressed on the surface of a subtype ofT lymphocytes (T helper or CD4+ cells) thus initiatingtheir activation and production of antigen-specific antibod-ies Severe combined immunodeficient (SCID) mice lackingeither T and B lymphocytes or nude mice lacking only Tcells have impaired proliferation and neurogenesis in normal
and EE housing compared to wild-type mice [155] as wellas impaired performance in the water maze [156] Similarlyantibody-based depletion of T helper lymphocytes impairsbasal and exercise-induced proliferation and neurogenesis[157] Furthermore a genetic study in heterogeneous stockmice which descend from eight inbred progenitor strainshas found a significant positive correlation between geneticloci associated to hippocampal proliferation and to theproportion of CD4+ cells among blood CD3+ lymphocytes[158] Additional experiments are needed to fully determinethe possible interactions between microglia and T cellsin neurogenesis because at least in normal physiologicalconditions (1) T cell surveillance of the brain parenchymais minimal (2) microglia are poor antigen presenting cellsand (3) antigen presentation by means of MHC-II family ofmolecules is thought to occur outside the brain that is in themeninges and choroid plexus [159] In fact during voluntaryexercise there are no significant changes in T cell surveillanceof the hippocampus nor a direct interaction between T cellsand microglia nor any changes in the gene expression profileof microglia including that of IGF-1 IL-1120573 and TNF120572 [160]The number of microglia is also inversely correlated withthe number of hippocampal proliferating cells rNSCs andneuroblasts in aged (8 months) mice subjected to voluntaryrunning as well as in vitro cocultures of microglia andneuroprogenitors which has been interpreted as resultingfrom an overall inhibitory effect of microglia on adult
Neural Plasticity 9
neurogenesis [161] Even though EE is clearly a more com-plex environmental factor than voluntary running furtherresearch is necessary to disregard nonspecific or indirecteffects of genetic or antibody-based T cells depletion onmicroglia and other brain cell populations including rNSCsFor instance adoptive transfer of T helper cells treated withglatiramer acetate a synthetic analog of myelin basic protein(MBP) approved for the treatment of multiple sclerosis pro-duces a bystander effect on resident astrocytes and microgliaby increasing their expression of anti-inflammatory cytokinessuch as TGF120573 [162] Alternatively it has been suggested thatT cells may mediate an indirect effect on adult hippocampalneurogenesis by increasing the production of brain-derivedneurotrophic factor (BDNF) [157] which is involved in theproneurogenic actions of EE [163] Whether BDNF cancounteract the detrimental effects of T cell depletion on neu-rogenesis remains unknownOverall the roles ofmicroglia inEE and running-induced neurogenesis are unclear and haveto be addressed with more precise experimental designs Insummary surveillant microglia are part of the physical nichesurrounding the neural stem cells and newborn neurons ofthe mature hippocampus where they continuously phagocy-tose the excess of newborn cellsMicroglia were also linked tothe proneurogenic and anti-inflammatory effects of voluntaryrunning and EE but direct evidence is missing The overallcontribution of microglia to neurogenesis and learning andmemory in normal physiological conditions remains largelyunexplored at this early stage in the field
7 Conclusion
In light of these observations microglia are now emergingas important effector cells during normal brain developmentand functions including adult hippocampal neurogenesisMicroglia can exert a positive or negative influence onthe proliferation survival or differentiation of newborncells depending on the inflammatory context For instancemicroglia can compromise the neurogenic cascade duringchronic stress aging and neurodegenerative diseases bytheir release of proinflammatory cytokines such as IL-1120573IL-6 and TNF120572 A reduced fractalkine signalling betweenneurons and microglia could also be involved during normalaging However microglia are not necessarily the only celltype implicated because astrocytes endothelial cells mastcells perivascular and meningeal macrophages and to alesser extent neurons and invading peripheral immune cellscould further contribute by releasing proinflammatorymedi-ators
Additionally microglia were shown to phagocytose theexcess of newborn neurons undergoing apoptosis in thehippocampal neurogenic niche during normal physiologicalconditions while a similar role in the synaptic integrationof newborn cells was also proposed in light of their capacityto phagocytose synaptic elements Lastly microglial interac-tions with T cells leading to the release of anti-inflammatorycytokines neurotrophic factors and other proneurogenicmediators (notably during EE and voluntary running) couldcounteract the detrimental effects of inflammation on adult
hippocampal neurogenesis and their functional implicationsfor learning and memory
However further research is necessary to assess the rela-tive contribution of microglia versus other types of residentand infiltrating inflammatory cells and to determine thenature of the effector cytokines and other inflammatorymediators involved as well as their cellular andmolecular tar-gets in the neurogenic cascade Such research will undoubt-edly help to develop novel strategies aiming at protecting theneurogenic potential and ultimately its essential contributionto learning and memory
The authors declare that there is no conflict of interestsregarding the publication of this paper
Acknowledgments
This work was supported by grants from the Spanish Min-istry of Economy and Competitiveness to Amanda Sierra(BFU2012-32089) and Juan M Encinas (SAF2012-40085)from Basque Government (Saiotek S-PC 12UN014) and Iker-basque start-up funds to JuanM Encinas andAmanda Sierraand fromTheBanting Research Foundation the Scottish RiteCharitable Foundation of Canada and start-up funds fromUniversite Laval andCentre de recherche duCHUdeQuebecto Marie-Eve Tremblay
References
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[2] F Ginhoux S Lim G Hoeffel D Low and T Huber ldquoOriginand differentiation of microgliardquo Frontiers in Cellular Neuro-science vol 7 article 45 2013
[3] E Gomez Perdiguero C Schulz and F Geissmann ldquoDevelop-ment and homeostasis of ldquoresidentrdquomyeloid cells the case of themicrogliardquo GLIA vol 61 no 1 pp 112ndash120 2013
[4] H Kettenmann F Kirchhoff and A Verkhratsky ldquoMicroglianew roles for the synaptic stripperrdquo Neuron vol 77 no 1 pp10ndash18 2013
[5] A Aguzzi B A Barres and M L Bennett ldquoMicroglia scape-goat saboteur or something elserdquo Science vol 339 no 6116 pp156ndash161 2013
[6] K Helmut U K Hanisch M Noda and A VerkhratskyldquoPhysiology of microgliardquo Physiological Reviews vol 91 no 2pp 461ndash553 2011
[7] M E Tremblay B Stevens A Sierra H Wake A Bessis andA Nimmerjahn ldquoThe role of microglia in the healthy brainrdquoJournal of Neuroscience vol 31 no 45 pp 16064ndash16069 2011
[8] A Miyamoto H Wake A J Moorhouse and J NabekuraldquoMicroglia and synapse interactions fine tuaning neural circuitsand candidate moleculesrdquo Frontiers in Cellular Neurosciencevol 7 article 70 2013
[9] C Bechade Y Cantaut-Belarif and A Bessis ldquoMicroglialcontrol of neuronal activityrdquo Frontiers in Cellular Neurosciencevol 7 article 32 2013
[10] A Sierra O Abiega A Shahraz and H Neumann ldquoJanus-faced microglia beneficial and detrimental consequences ofmicroglial phagocytosisrdquo Frontiers in Cellular Neuroscience vol7 article 6 2013
[11] G Kempermann S Jessberger B Steiner and G KronenbergldquoMilestones of neuronal development in the adult hippocam-pusrdquo Trends in Neurosciences vol 27 no 8 pp 447ndash452 2004
[12] J M Encinas T V Michurina N Peunova et al ldquoDivision-coupled astrocytic differentiation and age-related depletion ofneural stem cells in the adult hippocampusrdquo Cell Stem Cell vol8 no 5 pp 566ndash579 2011
[13] M A Bonaguidi M A Wheeler J S Shapiro et al ldquoIn vivoclonal analysis reveals self-renewing and multipotent adultneural stem cell characteristicsrdquo Cell vol 145 no 7 pp 1142ndash1155 2011
[14] J J Breunig J I Arellano J D Macklis and P RakicldquoEverything that glitters isnrsquot gold a critical review of postnatalneural precursor analysesrdquo Cell Stem Cell vol 1 no 6 pp 612ndash627 2007
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[19] M Krampert S R Chirasani F P Wachs et al ldquoSmad7regulates the adult neural stemprogenitor cell pool in a trans-forming growth factor 120573- and bone morphogenetic protein-independent mannerrdquo Molecular and Cellular Biology vol 30no 14 pp 3685ndash3694 2010
[20] K I Mosher R H Andres T Fukuhara et al ldquoNeural pro-genitor cells regulate microglia functions and activityrdquo NatureNeuroscience vol 15 no 11 pp 1485ndash1487 2012
[21] V Tropepe M Sibilia B G Ciruna J Rossant E F Wagnerand D van der Kooy ldquoDistinct neural stem cells proliferatein response to EGF and FGF in the developing mouse telen-cephalonrdquo Developmental Biology vol 208 no 1 pp 166ndash1881999
[22] S U Kim and J De Vellis ldquoMicroglia in health and diseaserdquoJournal of Neuroscience Research vol 81 no 3 pp 302ndash3132005
[23] B A Reynolds and R L Rietze ldquoNeural stem cells andneurospheresmdashre-evaluating the relationshiprdquoNatureMethodsvol 2 no 5 pp 333ndash336 2005
[24] K Satake Y Matsuyama M Kamiya et al ldquoUp-regulation ofglial cell line-derived neurotrophic factor (GDNF) followingtraumatic spinal cord injuryrdquo NeuroReport vol 11 no 17 pp3877ndash3881 2000
[25] Y M Yoo C J Lee and Y J Kim ldquoExogenous GDNF increasesthe migration of the neural stem cells with no protectionagainst kainic acid-induced excitotoxic cell death in ratsrdquo BrainResearch vol 1486 pp 27ndash38 2012
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Neural Plasticity 11
[27] K Striedinger and E Scemes ldquoInterleukin-1120573 affects calciumsignaling and in vitro cell migration of astrocyte progenitorsrdquoJournal of Neuroimmunology vol 196 no 1-2 pp 116ndash123 2008
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[30] M F Mehler R Rozental M Dougherty D C Spray and JA Kessler ldquoCytokine regulation of neuronal differentiation ofhippocampal progenitor cellsrdquo Nature vol 362 no 6415 pp62ndash65 1993
[31] U Gurok C Steinhoff B Lipkowitz H H Ropers C Scharffand U A Nuber ldquoGene expression changes in the course ofneural progenitor cell differentiationrdquo Journal of Neurosciencevol 24 no 26 pp 5982ndash6002 2004
[32] J B Demoulin M Enarsson J Larsson A Essaghir C HHeldin and K Forsberg-Nilsson ldquoThe gene expression profileof PDGF-treated neural stem cells corresponds to partiallydifferentiated neurons and gliardquo Growth Factors vol 24 no 3pp 184ndash196 2006
[33] F C Mansergh M A Wride and D E Rancourt ldquoNeuronsfrom stem cells implications for understanding nervous systemdevelopment and repairrdquo Biochemistry and Cell Biology vol 78no 5 pp 613ndash628 2000
[34] F C Alcantara Gomes V De Oliveira Sousa and L RomaoldquoEmerging roles for TGF-1205731 in nervous system developmentrdquoInternational Journal of Developmental Neuroscience vol 23 no5 pp 413ndash424 2005
[35] S Elkabes E M DiCicco-Bloom and I B Black ldquoBrainmicrogliamacrophages express neurotrophins that selectivelyregulate microglial proliferation and functionrdquo Journal of Neu-roscience vol 16 no 8 pp 2508ndash2521 1996
[36] U K Hanisch and H Kettenmann ldquoMicroglia active sensorand versatile effector cells in the normal and pathologic brainrdquoNature Neuroscience vol 10 no 11 pp 1387ndash1394 2007
[37] H J Klassen T F Ng Y Kurimoto et al ldquoMultipotent retinalprogenitors express developmental markers differentiate intoretinal neurons and preserve light-mediated behaviorrdquo Inves-tigative Ophthalmology and Visual Science vol 45 no 11 pp4167ndash4173 2004
[38] W J Streit S D Hurley T S McGraw and S L Semple-Rowland ldquoComparative evaluation of cytokine profiles andreactive gliosis supports a critical role for interleukin-6 inneuron-glia signaling during regenerationrdquo Journal of Neuro-science Research vol 61 no 1 pp 10ndash20 2000
[39] A Suzumura M Sawada H Yamamoto and T MarunouchildquoEffects of colony stimulating factors on isolated microglia invitrordquo Journal of Neuroimmunology vol 30 no 2-3 pp 111ndash1201990
[40] Z Lu M R Elliott Y Chen et al ldquoPhagocytic activity ofneuronal progenitors regulates adult neurogenesisrdquoNature CellBiology vol 13 no 9 pp 1076ndash1084 2011
[41] K Nakajima Y Kikuchi E Ikoma et al ldquoNeurotrophinsregulate the function of cultured microgliardquo GLIA vol 24 no3 pp 272ndash289 1998
[42] P A Lodge and S Sriram ldquoRegulation of microglial activationby TGF-120573 IL-10 and CSF-1rdquo Journal of Leukocyte Biology vol60 no 4 pp 502ndash508 1996
[43] W S Sheng S Hu F H Kravitz P K Peterson and C C ChaoldquoTumor necrosis factor alpha upregulates humanmicroglial cell
production of interleukin-10 in vitrordquo Clinical and DiagnosticLaboratory Immunology vol 2 no 5 pp 604ndash608 1995
[44] G LMing andH Song ldquoAdult neurogenesis in themammalianbrain significant answers and significant questionsrdquo Neuronvol 70 no 4 pp 687ndash702 2011
[45] E Bruel-Jungerman S Davis C Rampon and S LarocheldquoLong-term potentiation enhances neurogenesis in the adultdentate gyrusrdquo Journal of Neuroscience vol 26 no 22 pp 5888ndash5893 2006
[46] E Drapeau M F Montaron S Aguerre and D N AbrousldquoLearning-induced survival of new neurons depends on thecognitive status of aged ratsrdquo Journal of Neuroscience vol 27no 22 pp 6037ndash6044 2007
[47] A Mouret G Gheusi M M Gabellec F De Chaumont J COlivo-Marin and P M Lledo ldquoLearning and survival of newlygenerated neurons when timemattersrdquo Journal of Neurosciencevol 28 no 45 pp 11511ndash11516 2008
[48] N Kee C M Teixeira A H Wang and P W FranklandldquoPreferential incorporation of adult-generated granule cellsinto spatial memory networks in the dentate gyrusrdquo NatureNeuroscience vol 10 no 3 pp 355ndash362 2007
[49] F Massa M Koelh T Wiesner et al ldquoConditional reduction ofadult neurogenesis impairs bidirectional hippocampal synapticplasticityrdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 108 no 16 pp 6644ndash6649 2011
[50] T J Shors G Miesegaes A Beylin M Zhao T Rydel and EGould ldquoNeurogenesis in the adult is involved in the formationof tracememoriesrdquoNature vol 410 no 6826 pp 372ndash376 2001
[51] W Deng M D Saxe I S Gallina and F H Gage ldquoAdult-born hippocampal dentate granule cells undergoingmaturationmodulate learning and memory in the brainrdquo Journal of Neuro-science vol 29 no 43 pp 13532ndash13542 2009
[52] M Arruda-Carvalho M Sakaguchi K G Akers S A Josselynand P W Frankland ldquoPosttraining ablation of adult-generatedneurons degrades previously acquired memoriesrdquo Journal ofNeuroscience vol 31 no 42 pp 15113ndash15127 2011
[53] A Sahay K N Scobie A S Hill et al ldquoIncreasing adulthippocampal neurogenesis is sufficient to improve patternseparationrdquo Nature vol 472 no 7344 pp 466ndash470 2011
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[55] K Newton and V M Dixit ldquoSignaling in innate immunity andinflammationrdquo Cold Spring Harbor Perspectives in Biology vol4 no 3 2012
[56] H K Jeong K Ji K Min and E H Joe ldquoBrain inflammationand microglia facts and misconceptionsrdquo Experimental Neuro-biology vol 22 no 2 pp 59ndash67 2013
[57] D Stellwagen and R CMalenka ldquoSynaptic scalingmediated byglial TNF-120572rdquo Nature vol 440 no 7087 pp 1054ndash1059 2006
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12 Neural Plasticity
[61] M L Monje H Toda and T D Palmer ldquoInflammatoryblockade restores adult hippocampal neurogenesisrdquo Sciencevol 302 no 5651 pp 1760ndash1765 2003
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[68] F Cerbai D Lana D Nosi et al ldquoThe neuron-astrocyte-microglia triad in normal brain ageing and in a model ofneuroinflammation in the rat hippocampusrdquo PLoS ONE vol 7no 9 Article ID e45250 2012
[69] W J Jin S W Feng Z Feng S M Lu T Qi and Y N QianldquoMinocycline improves postoperative cognitive impairment inaged mice by inhibiting astrocytic activationrdquo NeuroReport2013
[70] K A Ji M S Yang H K Jeong et al ldquoResident microgliadie and infiltrated neutrophils and monocytes become majorinflammatory cells in lipopolysaccharide-injected brainrdquoGLIAvol 55 no 15 pp 1577ndash1588 2007
[71] N J van Wagoner J W Oh P Repovic and E N BenvenisteldquoInterleukin-6 (IL-6) production by astrocytes autocrine reg-ulation by IL-6 and the soluble IL-6 receptorrdquo Journal ofNeuroscience vol 19 no 13 pp 5236ndash5244 1999
[72] L Vallieres I L Campbell F H Gage and P E SawchenkoldquoReduced hippocampal neurogenesis in adult transgenic micewith chronic astrocytic production of interleukin-6rdquo Journal ofNeuroscience vol 22 no 2 pp 486ndash492 2002
[73] B S McEwen ldquoPhysiology and neurobiology of stress andadaptation central role of the brainrdquo Physiological Reviews vol87 no 3 pp 873ndash904 2007
[74] V LuineMVillegas CMartinez and B SMcEwen ldquoRepeatedstress causes reversible impairments of spatial memory perfor-mancerdquo Brain Research vol 639 no 1 pp 167ndash170 1994
[75] S Rivest ldquoMolecular insights on the cerebral innate immunesystemrdquo Brain Behavior and Immunity vol 17 no 1 pp 13ndash192003
[76] S Nadeau and S Rivest ldquoEndotoxemia prevents the cerebralinflammatory wave induced by intraparenchymal lipopolysac-charide injection role of glucocorticoids and CD14rdquo Journal ofImmunology vol 169 no 6 pp 3370ndash3381 2002
[77] A Sierra A Gottfried-Blackmore T A Milner B S McEwenand K Bulloch ldquoSteroid hormone receptor expression andfunction in microgliardquo GLIA vol 56 no 6 pp 659ndash674 2008
[78] C Liston andW B Gan ldquoGlucocorticoids are critical regulatorsof dendritic spine development and plasticity in vivordquo Proceed-ings of the National Academy of Sciences of the United States ofAmerica vol 108 no 38 pp 16074ndash16079 2011
[79] C Liston J M Cichon F Jeanneteau Z Jia M V Chaoand W B Gan ldquoCircadian glucocorticoid oscillations pro-mote learning-dependent synapse formation andmaintenancerdquoNature Neuroscience vol 16 no 6 pp 698ndash705 2013
[80] M A Carrillo-de Sauvage L Maatouk I Arnoux et al ldquoPotentand multiple regulatory actions of microglial glucocorticoidreceptors during CNS inflammationrdquo Cell Death amp Differenti-ation vol 20 no 11 pp 1546ndash1557 2013
[81] S F Sorrells J R Caso C DMunhoz and RM Sapolsky ldquoThestressed CNS when glucocorticoids aggravate inflammationrdquoNeuron vol 64 no 1 pp 33ndash39 2009
[82] M A Bellavance and S Rivest ldquoThe neuroendocrine controlof the innate immune system in health and brain diseasesrdquoImmunological Reviews vol 248 no 1 pp 36ndash55 2012
[83] R J Tynan S Naicker M Hinwood et al ldquoChronic stress altersthe density and morphology of microglia in a subset of stress-responsive brain regionsrdquo Brain Behavior and Immunity vol24 no 7 pp 1058ndash1068 2010
[84] E S Wohleb N D Powell J P Godbout and J F SheridanldquoStress-induced recruitment of bone marrow-derived mono-cytes to the brain promotes anxiety-like behaviorrdquo The Journalof Neuroscience vol 33 no 34 pp 13820ndash13833 2013
[85] Y Diz-Chaves M Astiz M J Bellini and L M Garcia-SeguraldquoPrenatal stress increases the expression of proinflammatorycytokines and exacerbates the inflammatory response to LPS inthe hippocampal formation of adultmalemicerdquoBrain Behaviorand Immunity vol 28 pp 196ndash206 2013
[86] E S Wohleb A M Fenn A M Pacenta N D Powell J FSheridan and J P Godbout ldquoPeripheral innate immune chal-lenge exaggerated microglia activation increased the numberof inflammatory CNSmacrophages and prolonged social with-drawal in socially defeated micerdquo Psychoneuroendocrinologyvol 37 no 9 pp 1491ndash1505 2012
[87] C Mirescu and E Gould ldquoStress and adult neurogenesisrdquoHippocampus vol 16 no 3 pp 233ndash238 2006
[88] J LWarner-Schmidt andR SDuman ldquoHippocampal neuroge-nesis opposing effects of stress and antidepressant treatmentrdquoHippocampus vol 16 no 3 pp 239ndash249 2006
[89] N D Hanson M J Owens K A Boss-Williams J M Weissand C B Nemeroff ldquoSeveral stressors fail to reduce adulthippocampal neurogenesisrdquo Psychoneuroendocrinology vol 36no 10 pp 1520ndash1529 2011
[90] E Gould B S McEwen P Tanapat L A M Galea and EFuchs ldquoNeurogenesis in the dentate gyrus of the adult treeshrew is regulated by psychosocial stress and NMDA receptoractivationrdquo Journal of Neuroscience vol 17 no 7 pp 2492ndash24981997
[91] JW Koo andR S Duman ldquoIL-1120573 is an essentialmediator of theantineurogenic and anhedonic effects of stressrdquo Proceedings ofthe National Academy of Sciences of the United States of Americavol 105 no 2 pp 751ndash756 2008
[92] D C Lagace M H Donovan N A Decarolis et al ldquoAdulthippocampal neurogenesis is functionally important for stress-induced social avoidancerdquo Proceedings of the National Academy
Neural Plasticity 13
of Sciences of the United States of America vol 107 no 9 pp4436ndash4441 2010
[93] G Kronenberg I Kirste D Inta et al ldquoReduced hippocampalneurogenesis in the GR+- genetic mousemodel of depressionrdquoEuropean Archives of Psychiatry and Clinical Neuroscience vol259 no 8 pp 499ndash504 2009
[94] M B Howren D M Lamkin and J Suls ldquoAssociations ofdepression with c-reactive protein IL-1 and IL-6 a meta-analysisrdquo Psychosomatic Medicine vol 71 no 2 pp 171ndash1862009
[95] J W Koo S J Russo D Ferguson E J Nestler and R SDuman ldquoNuclear factor-120581B is a critical mediator of stress-impaired neurogenesis and depressive behaviorrdquo Proceedings ofthe National Academy of Sciences of the United States of Americavol 107 no 6 pp 2669ndash2674 2010
[96] I Goshen T Kreisel O Ben-Menachem-Zidon et al ldquoBraininterleukin-1 mediates chronic stress-induced depression inmice via adrenocortical activation and hippocampal neuroge-nesis suppressionrdquo Molecular Psychiatry vol 13 no 7 pp 717ndash728 2008
[97] C D Munhoz L B Lepsch E M Kawamoto et al ldquoChronicunpredictable stress exacerbates lipopolysaccharide-inducedactivation of nuclear factor-120581B in the frontal cortex andhippocampus via glucocorticoid secretionrdquo Journal of Neuro-science vol 26 no 14 pp 3813ndash3820 2006
[98] S J Sukoff Rizzo S J Neal Z A Hughes et al ldquoEvidence forsustained elevation of IL-6 in the CNS as a key contributorof depressive-like phenotypesrdquo Translational Psychiatry vol 2article e199 2012
[99] A Garcia B Steiner G Kronenberg A Bick-Sander and GKempermann ldquoAge-dependent expression of glucocorticoid-andmineralocorticoid receptors on neural precursor cell popu-lations in the adult murine hippocampusrdquoAging Cell vol 3 no6 pp 363ndash371 2004
[100] M G Frank B M Thompson L R Watkins and S F MaierldquoGlucocorticoids mediate stress-induced priming of microglialpro-inflammatory responsesrdquo Brain Behavior and Immunityvol 26 no 2 pp 337ndash345 2012
[101] S Sugama M Fujita M Hashimoto and B Conti ldquoStressinduced morphological microglial activation in the rodentbrain involvement of interleukin-18rdquoNeuroscience vol 146 no3 pp 1388ndash1399 2007
[102] A Sierra J M Encinas and M Maletic-Savatic ldquoAdult humanneurogenesis from microscopy to magnetic resonance imag-ingrdquo Frontiers in Neuroscience vol 5 article 47 2011
[103] H G Kuhn H Dickinson-Anson and F H Gage ldquoNeurogen-esis in the dentate gyrus of the adult rat age-related decrease ofneuronal progenitor proliferationrdquo Journal of Neuroscience vol16 no 6 pp 2027ndash2033 1996
[104] L N Manganas X Zhang Y Li et al ldquoMagnetic resonancespectroscopy identifies neural progenitor cells in the live humanbrainrdquo Science vol 318 no 5852 pp 980ndash985 2007
[105] K L Spalding O Bergmann K Alkass et al ldquoDynamics ofhippocampal neurogenesis in adult humansrdquo Cell vol 153 no6 pp 1219ndash1227 2013
[106] J M Encinas and A Sierra ldquoNeural stem cell deforestationas the main force driving the age-related decline in adulthippocampal neurogenesisrdquo Behavioural Brain Research vol227 no 2 pp 433ndash439 2012
[107] K S Krabbe M Pedersen andH Bruunsgaard ldquoInflammatorymediators in the elderlyrdquo Experimental Gerontology vol 39 no5 pp 687ndash699 2004
[108] B S Diniz A L Teixeira L Talib W F Gattaz andO V Forlenza ldquoInterleukin-1120573 serum levels is increased inantidepressant-free elderly depressed patientsrdquo American Jour-nal of Geriatric Psychiatry vol 18 no 2 pp 172ndash176 2010
[109] A Sierra A C Gottfried-Blackmore B S Mcewen and KBulloch ldquoMicroglia derived from aging mice exhibit an alteredinflammatory profilerdquo GLIA vol 55 no 4 pp 412ndash424 2007
[110] C FranceschiM Bonafe S Valensin et al ldquoInflamm-aging Anevolutionary perspective on immunosenescencerdquo Annals of theNew York Academy of Sciences vol 908 pp 244ndash254 2000
[111] R Sano and J C Reed ldquoER stress-induced cell death mecha-nismsrdquoBiochimica et BiophysicaActa vol 1833 no 12 pp 3460ndash3470 2013
[112] S Z Hasnain R Lourie I Das A C H Chen and MA McGuckin ldquoThe interplay between endoplasmic reticulumstress and inflammationrdquo Immunology and Cell Biology vol 90no 3 pp 260ndash270 2012
[113] S Matus L H Glimcher and C Hetz ldquoProtein folding stressin neurodegenerative diseases a glimpse into the ERrdquo CurrentOpinion in Cell Biology vol 23 no 2 pp 239ndash252 2011
[114] Y Ito M Yamada H Tanaka et al ldquoInvolvement of CHOP anER-stress apoptotic mediator in both human sporadic ALS andALS model micerdquo Neurobiology of Disease vol 36 no 3 pp470ndash476 2009
[115] D Papadimitriou V Le Verche A Jacquier B Ikiz S Przed-borski and D B Re ldquoInflammation in ALS and SMA sortingout the good from the evilrdquo Neurobiology of Disease vol 37 no3 pp 493ndash502 2010
[116] A R Johnson J J Milner and LMakowski ldquoThe inflammationhighway metabolism accelerates inflammatory traffic in obe-sityrdquo Immunological Reviews vol 249 no 1 pp 218ndash238 2012
[117] S Buch H Yao M Guo et al ldquoCocaine and HIV-1 interplayin CNS cellular and molecular mechanismsrdquo Current HIVResearch vol 10 no 5 pp 425ndash428 2012
[118] M K Brown and N Naidoo ldquoThe endoplasmic reticulumstress response in aging and age-related diseasesrdquo Frontiers inPhysiology vol 3 article 263 2012
[119] G Castro C Areias MF L Weissmann et al ldquoDiet-inducedobesity induces endoplasmic reticulum stress and insulin resis-tance in the amygdala of ratsrdquo FEBS Open Bio vol 3 pp 443ndash449 2013
[120] A A Pavlovsky D Boehning D Li Y Zhang X Fan andT A Green ldquoPsychological stress cocaine and natural rewardeach induce endoplasmic reticulum stress genes in rat brainrdquoNeuroscience vol 246 pp 160ndash169 2013
[121] G GargiuloM CesaroniM Serresi et al ldquoIn vivo RNAi screenfor BMI1 targets identifies TGF-betaBMP-ER stress pathwaysas key regulators of neural- and malignant glioma-stem cellhomeostasisrdquo Cancer Cell vol 23 no 5 pp 660ndash676 2013
[122] A Salminen K Kaarniranta and A Kauppinen ldquoInflammag-ing disturbed interplay between autophagy and inflamma-somesrdquo Aging vol 4 no 3 pp 166ndash175 2012
[123] E Latz T S Xiao andA Stutz ldquoActivation and regulation of theinflammasomesrdquoNature Reviews Immunology vol 13 no 6 pp397ndash411 2013
[124] C Gemma A D Bachstetter M J Cole M Fister C Hudsonand P C Bickford ldquoBlockade of caspase-1 increases neurogene-sis in the aged hippocampusrdquo European Journal of Neurosciencevol 26 no 10 pp 2795ndash2803 2007
[125] M D Wu A M Hein M J Moravan S S Shaftel J AOlschowka and M K OrsquoBanion ldquoAdult murine hippocampal
14 Neural Plasticity
neurogenesis is inhibited by sustained IL-1120573 and not rescued byvoluntary runningrdquo Brain Behavior and Immunity vol 26 no2 pp 292ndash300 2012
[126] Y Wolf S Yona K W Kim and S Jung ldquoMicroglia seen fromthe CX3CR1 anglerdquo Frontiers in Cellular Neuroscience vol 7article 26 2013
[127] A E Cardona E P Pioro M E Sasse et al ldquoControl ofmicroglial neurotoxicity by the fractalkine receptorrdquo NatureNeuroscience vol 9 no 7 pp 917ndash924 2006
[128] K Bhaskar M Konerth O N Kokiko-Cochran A Cardona RM Ransohoff and B T Lamb ldquoRegulation of tau pathology bythe microglial fractalkine receptorrdquo Neuron vol 68 no 1 pp19ndash31 2010
[129] A D Bachstetter J M Morganti J Jernberg et al ldquoFractalkineand CX3CR1 regulate hippocampal neurogenesis in adult andaged ratsrdquo Neurobiology of Aging vol 32 no 11 pp 2030ndash20442011
[130] S Jung J Aliberti P Graemmel et al ldquoAnalysis of fractalkinereceptor CX3CR1 function by targeted deletion and greenfluorescent protein reporter gene insertionrdquo Molecular andCellular Biology vol 20 no 11 pp 4106ndash4114 2000
[131] J T Rogers J M Morganti A D Bachstetter et al ldquoCX3CR1deficiency leads to impairment of hippocampal cognitive func-tion and synaptic plasticityrdquo Journal of Neuroscience vol 31 no45 pp 16241ndash16250 2011
[132] W S T Griffin L C Stanley C Ling et al ldquoBrain interleukin1 and S-100 immunoreactivity are elevated in Down syndromeand Alzheimer diseaserdquo Proceedings of the National Academy ofSciences of the United States of America vol 86 no 19 pp 7611ndash7615 1989
[133] W C Benzing J RWujek E KWard et al ldquoEvidence for glial-mediated inflammation in aged APP(SW) transgenic micerdquoNeurobiology of Aging vol 20 no 6 pp 581ndash589 1999
[134] T J Seabrook L Jiang M Maier and C A Lemere ldquoMinocy-cline affects microglia activation A120573 deposition and behaviorin APP-tg micerdquo GLIA vol 53 no 7 pp 776ndash782 2006
[135] B Biscaro O Lindvall G Tesco C T Ekdahl and RM NitschldquoInhibition of microglial activation protects hippocampal neu-rogenesis and improves cognitive deficits in a transgenic mousemodel for Alzheimerrsquos diseaserdquoNeurodegenerative Diseases vol9 no 4 pp 187ndash198 2012
[136] P A Zunszain C Anacker A Cattaneo et al ldquoInterleukin-1120573a new regulator of the kynurenine pathway affecting humanhippocampal neurogenesisrdquo Neuropsychopharmacology vol 37no 4 pp 939ndash949 2012
[137] R De Simone M Antonietta Ajmone-Cat P Tirassa and LMinghetti ldquoApoptotic PC12 cells exposing phosphatidylserinepromote the production of anti-inflammatory and neuropro-tective molecules bymicroglial cellsrdquo Journal of Neuropathologyand Experimental Neurology vol 62 no 2 pp 208ndash216 2003
[138] M S Buckwalter M Yamane B S Coleman et al ldquoChroni-cally increased transforming growth factor-1205731 strongly inhibitshippocampal neurogenesis in aged micerdquo American Journal ofPathology vol 169 no 1 pp 154ndash164 2006
[139] O Butovsky Y Ziv A Schwartz et al ldquoMicroglia activatedby IL-4 or IFN-120574 differentially induce neurogenesis and oligo-dendrogenesis from adult stemprogenitor cellsrdquoMolecular andCellular Neuroscience vol 31 no 1 pp 149ndash160 2006
[140] C T Ekdahl ldquoMicroglial activationmdashtuning and pruning adultneurogenesisrdquo Frontiers in Pharmacology vol 3 article 41 2012
[141] HWakeA JMoorhouse S Jinno S Kohsaka and JNabekuraldquoResting microglia directly monitor the functional state ofsynapses in vivo and determine the fate of ischemic terminalsrdquoJournal of Neuroscience vol 29 no 13 pp 3974ndash3980 2009
[142] M E Tremblay R L Lowery and A K Majewska ldquoMicroglialinteractions with synapses are modulated by visual experiencerdquoPLoS Biology vol 8 no 11 Article ID e1000527 2010
[143] M E Tremblay M L Zettel J R Ison P D Allen and A KMajewska ldquoEffects of aging and sensory loss on glial cells inmouse visual and auditory corticesrdquo GLIA vol 60 no 4 pp541ndash558 2012
[144] D P Schafer E K Lehrman A G Kautzman et al ldquoMicrogliasculpt postnatal neural circuits in an activity and complement-dependent mannerrdquo Neuron vol 74 no 4 pp 691ndash705 2012
[145] H Nakanishi ldquoMicroglial functions and proteasesrdquo MolecularNeurobiology vol 27 no 2 pp 163ndash176 2003
[146] M E Tremblay and A K Majewska ldquoA role for microglia insynaptic plasticityrdquoCommunicative and Integrative Biology vol4 no 2 pp 220ndash222 2011
[147] R C Paolicelli G Bolasco F Pagani et al ldquoSynaptic pruning bymicroglia is necessary for normal brain developmentrdquo Sciencevol 333 no 6048 pp 1456ndash1458 2011
[148] GKempermannHGKuhn and FHGage ldquoMore hippocam-pal neurons in adult mice living in an enriched environmentrdquoNature vol 386 no 6624 pp 493ndash495 1997
[149] M Nilsson E Perfilieva U Johansson O Orwar and P SEriksson ldquoEnriched environment increases neurogenesis in theadult rat dentate gyrus and improves spatial memoryrdquo Journalof Neurobiology vol 39 no 4 pp 569ndash578 1999
[150] H van Praag G Kempermann and F H Gage ldquoRunningincreases cell proliferation and neurogenesis in the adult mousedentate gyrusrdquo Nature Neuroscience vol 2 no 3 pp 266ndash2701999
[151] D Young P A Lawlor P Leone M Dragunow and MJ During ldquoEnvironmental enrichment inhibits spontaneousapoptosis prevents seizures and is neuroprotectiverdquo NatureMedicine vol 5 no 4 pp 448ndash453 1999
[152] L L Williamson A Chao and S D Bilbo ldquoEnvironmentalenrichment alters glial antigen expression and neuroimmunefunction in the adult rat hippocampusrdquo Brain Behavior andImmunity vol 26 no 3 pp 500ndash510 2012
[153] L Maggi M Scianni I Branchi I DrsquoAndrea C Lauro and CLimatola ldquoCX(3)CR1 deficiency alters hippocampal-dependentplasticity phenomena blunting the effects of enriched environ-mentrdquo Frontiers in Cellular Neuroscience vol 5 article 22 2011
[154] I Goshen A Avital T Kreisel T Licht M Segal and RYirmiya ldquoEnvironmental enrichment restores memory func-tioning in mice with impaired IL-1 signaling via reinstatementof long-term potentiation and spine size enlargementrdquo Journalof Neuroscience vol 29 no 11 pp 3395ndash3403 2009
[155] Y Ziv N Ron O Butovsky et al ldquoImmune cells contribute tothe maintenance of neurogenesis and spatial learning abilitiesin adulthoodrdquo Nature Neuroscience vol 9 no 2 pp 268ndash2752006
[156] J Kipnis H Cohen M Cardon Y Ziv and M Schwartz ldquoTcell deficiency leads to cognitive dysfunction implications fortherapeutic vaccination for schizophrenia and other psychiatricconditionsrdquo Proceedings of the National Academy of Sciences ofthe United States of America vol 101 no 21 pp 8180ndash8185 2004
[157] S A Wolf B Steiner A Akpinarli et al ldquoCD4-positive Tlymphocytes provide a neuroimmunological link in the control
Neural Plasticity 15
of adult hippocampal neurogenesisrdquo Journal of Immunologyvol 182 no 7 pp 3979ndash3984 2009
[158] G J Huang A L Smith D H D Gray et al ldquoA genetic andfunctional relationship between T cells and cellular prolifera-tion in the adult hippocampusrdquo PLOS Biology vol 8 no 12Article ID e1000561 2010
[159] R M Ransohoff and B Engelhardt ldquoThe anatomical andcellular basis of immune surveillance in the central nervoussystemrdquoNature Reviews Immunology vol 12 no 9 pp 623ndash6352012
[160] M Olah G Ping A H De Haas et al ldquoEnhanced hippocampalneurogenesis in the absence of microglia T cell interactionand microglia activation in the murine running wheel modelrdquoGLIA vol 57 no 10 pp 1046ndash1061 2009
[161] E Gebara S Sultan J Kocher-Braissant and N Toni ldquoAdulthippocampal neurogenesis inversely correlates with microgliain conditions of voluntary running and agingrdquo Frontiers inNeuroscience vol 7 article 145 2013
[162] R Aharoni B Kayhan R Eilam M Sela and R ArnonldquoGlatiramer acetate-specific T cells in the brain express T helper23 cytokines and brain-derived neurotrophic factor in siturdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 100 no 2 pp 14157ndash14162 2003
[163] C Rossi A Angelucci L Costantin et al ldquoBrain-derivedneurotrophic factor (BDNF) is required for the enhancementof hippocampal neurogenesis following environmental enrich-mentrdquo European Journal of Neuroscience vol 24 no 7 pp 1850ndash1856 2006
Neural Plasticity 7
differentiation into neurons [136] Novel methods to assesshippocampal neurogenesis in the living human brain frommetabolomics of neuroprogenitors to hippocampal bloodbrain volume (reviewed in [102]) will help to determine thecontribution of inflammation to adult neurogenesis in thehealthy and diseased human brain during aging
6 Normal Physiological Conditions
In the healthy mature brain microglia are an essential com-ponent of the neurogenic SGZ niche where they physicallyintermingle with neuroprogenitors neuroblasts and new-born neurons [62] Here surveillant microglia effectively andrapidly phagocytose the excess of newborn cells undergoingapoptosis [62] Importantly microglial phagocytosis in theadult SGZ is not disturbed by inflammation associated withaging or by LPS challenge as the phagocytic index (iethe proportion of apoptotic cells completely engulfed bymicroglia) is maintained over 90 in these conditions [62]Nonetheless the consequences of microglial phagocytosis onadult hippocampal neurogenesis remain elusive Treatment ofmice with annexin V which binds to the phosphatidylserine(PS) receptor and prevents the recognition of PS on thesurface of apoptotic cells presumably blocking phagocytosisincreases the number of apoptotic cells in the SGZ [40] Con-comitantly annexin V reduces neurogenesis by decreasingthe survival of neuroblasts without affecting neuroprogeni-tors proliferation [40] Similar results were obtained in trans-genic mice knock-out for ELMO1 a cytoplasm protein whichpromotes the internalization of apoptotic cells althoughthe effects on neurogenesis were ascribed to a decreasedphagocytic activity of neuroblasts [40]The actual phagocytictarget of the neuroblasts remains undetermined but thenewborn apoptotic cells in the adult SGZ are exclusivelyphagocytosed by microglia at least in physiological condi-tions [62] Nevertheless none of the above manipulationshas specifically tested the role of microglial phagocytosisin hippocampal-dependent learning and memory and thusthe functional impact of microglial phagocytosis in adultneurogenic niches during normal physiological conditionsremains to be elucidated
Microglial phagocytosis of apoptotic cells is activelyanti-inflammatory at least in vitro and thus it has beenhypothesized that anti-inflammatory cytokines produced byphagocytic microglia may further regulate neurogenesis [10]For instance transforming growth factor beta (TGF120573) whichis produced by phagocytic microglia in vitro [137] inhibitsthe proliferation of SGZ neuroprogenitors [138] Microgliaare further able to produce proneurogenic factors in vitro[139] When primed with cytokines associated with T helpercells such as interleukin 4 (IL-4) or low doses of interferongamma (IFN120574) culturedmicroglia support neurogenesis andoligodendrogenesis through decreased production of TNF120572and increased production of insulin-like growth factor 1(IGF-1) [139] an inducer of neuroprogenitor proliferation[26] A list of potential factors produced by microgliaand known to act on neuroprogenitor proliferation can
be found in Table 1 In addition recent observations sug-gest that neuroprogenitor cells may not only regulate theirown environment but also influence microglial functionsFor instance vascular endothelial growth factor (VEGF)produced by cultured neuroprecursor cells directly affectsmicroglial proliferation migration and phagocytosis [20]More potential factors produced by neuroprogenitors shownto be influencing microglial activity and function can befound in Table 2 However it has to be taken into accountthat most of these observations were obtained in culture andthat further research is needed in order to elucidate whetherthose factors are also secreted and have the same regulatoryresponses in vivo
In addition microglial capacity to remodel and eliminatesynaptic structures during normal physiological conditionshas suggested that microglia could also control the synap-tic integration of the newborn neurons generated duringadult hippocampal neurogenesis [140] Three main mech-anisms were proposed (1) the phagocytic elimination ofnonapoptotic axon terminals and dendritic spines (2) theproteolytic remodeling of the perisynaptic environmentand (3) the concomitant structural remodeling of dendriticspines [7 140] Indeed microglial contacts with synapticelements are frequently observed in the cortex during normalphysiological conditions sometimes accompanied by theirengulfment and phagocytic elimination [141ndash143] as in thedeveloping retinogeniculate system [144] Microglial cells aredistinctively surrounded by pockets of extracellular spacecontrarily to all the other cellular elements [142] suggestingthat microglia could remodel the volume and geometryof the extracellular space and thus the concentration ofvarious ions neurotransmitters and signalling moleculesin the synaptic environment Whether microglia create thepockets of extracellular space themselves or not remainsunknown but these pockets could result from microglialrelease of extracellular proteases such as metalloproteinasesand cathepsins [145] which are well known for influencingthe formation structural remodeling and elimination ofdendritic spines in situ and also experience-dependent plas-ticity in vivo [7 146] More recently microglial phagocytosisof synaptic components was also observed in the developinghippocampus in the unique time window of synaptogenesisa process which is notably regulated by fractalkine-CX3CR1signalling [147] Therefore the attractive hypothesis thatmicroglial sculpts the circuitry of newborn cells in the adulthippocampus deserves further attention
Lastly microglia were also involved in increasing adulthippocampal neurogenesis in the enriched environment(EE) experimental paradigm EE is a paradigm mimick-ing some features of the normal living circumstances ofwild animals as it gives them access to social interactionstoys running wheels and edible treats EE has long beenknown to enhance neurogenesis by acting on newborncells survival resulting ultimately in an enlargement ofthe dentate gyrus [148] Functionally these changes areaccompanied by enhanced spatial learning and memoryformation with the water maze paradigm [149] Similarincreases in neurogenesis are obtained by subjecting miceto voluntary running paradigms although in this case the
8 Neural Plasticity
Table 1 Summary of factors secreted by microglia and the potential effect they have on neuroprogenitors in vitro
Microglia secreted factors Reference Modulation of neural progenitor cells ReferenceBDNF [18] Differentiation [19]EGF [20] Survival expansion proliferation differentiation [21]FGF120573 [22] Survival and expansion [23]GDNF [24] Survival migration and differentiation [25]IGF-1 [21] Proliferation [26]IL-1120573 [27] Reduction in migration [27]IL-6 [28] Inhibition of neurogenesis [29]IL-7 [20] Differentiation [30]IL-11 [20] Differentiation [30]NT-4 [24] Differentiation [31]PDGF [32] Expansion and differentiation [33]TGF120573 [34] Inhibition of proliferation [19]
Table 2 Summary of factors secreted by neuroprogenitors and the potential effect they have on microglia in vitro
NPC secreted factors Reference Modulation of microglia ReferenceBDNF [18] Proliferation and induction of phagocytic activity [35]Haptoglobin [24] Neuroprotection [36]IL-1120573 [37] Intracellular Ca+2 elevation and proliferation [22]IL-6 [37] Increase in proliferation [38]M-CSF [20] Mitogen [39]NGF [40] Decrease in LPS-induced NO [41]TGF120573 [37] Inhibition of TNF120572 secretion [42]TNF120572 [37] Upregulation of IL-10 secretion [43]VEGF [20] Induction of chemotaxis and proliferation [20]
effect is mediated by increased neuroprogenitor proliferation[150] During inflammatory conditions EE is antiapoptoticand neuroprotective [151] and it limits the hippocampalresponse to LPS challenge by decreasing the expression ofseveral cytokines and chemokines including IL1-120573 andTNF120572[152] In fact EE is believed to counteract the inflammatoryenvironment and rescue the decreased number of neuroblastsin CX3CR1GFPGFP mice compared to wild-type mice [153]The effects of EE are independent of the IL-1120573 signallingpathway as it increases neurogenesis in mice that are nullfor IL-1R1 [154] EE also induces microglial proliferation andexpression of the proneurogenic IGF-1 [155] but the fullphenotype of microglia in EE compared to standard housingand its impact on the neurogenic cascade remains to bedetermined
The mechanisms behind the anti-inflammatory actionsof EE are unknown but they were suggested to involvemicroglial interactions with T lymphocytes through anincreased expression of themajor histocompatibility complexof class II (MHC-II) during EE [155] MHC-II is responsiblefor presenting the phagocytosed and degraded antigens tothe antibodies expressed on the surface of a subtype ofT lymphocytes (T helper or CD4+ cells) thus initiatingtheir activation and production of antigen-specific antibod-ies Severe combined immunodeficient (SCID) mice lackingeither T and B lymphocytes or nude mice lacking only Tcells have impaired proliferation and neurogenesis in normal
and EE housing compared to wild-type mice [155] as wellas impaired performance in the water maze [156] Similarlyantibody-based depletion of T helper lymphocytes impairsbasal and exercise-induced proliferation and neurogenesis[157] Furthermore a genetic study in heterogeneous stockmice which descend from eight inbred progenitor strainshas found a significant positive correlation between geneticloci associated to hippocampal proliferation and to theproportion of CD4+ cells among blood CD3+ lymphocytes[158] Additional experiments are needed to fully determinethe possible interactions between microglia and T cellsin neurogenesis because at least in normal physiologicalconditions (1) T cell surveillance of the brain parenchymais minimal (2) microglia are poor antigen presenting cellsand (3) antigen presentation by means of MHC-II family ofmolecules is thought to occur outside the brain that is in themeninges and choroid plexus [159] In fact during voluntaryexercise there are no significant changes in T cell surveillanceof the hippocampus nor a direct interaction between T cellsand microglia nor any changes in the gene expression profileof microglia including that of IGF-1 IL-1120573 and TNF120572 [160]The number of microglia is also inversely correlated withthe number of hippocampal proliferating cells rNSCs andneuroblasts in aged (8 months) mice subjected to voluntaryrunning as well as in vitro cocultures of microglia andneuroprogenitors which has been interpreted as resultingfrom an overall inhibitory effect of microglia on adult
Neural Plasticity 9
neurogenesis [161] Even though EE is clearly a more com-plex environmental factor than voluntary running furtherresearch is necessary to disregard nonspecific or indirecteffects of genetic or antibody-based T cells depletion onmicroglia and other brain cell populations including rNSCsFor instance adoptive transfer of T helper cells treated withglatiramer acetate a synthetic analog of myelin basic protein(MBP) approved for the treatment of multiple sclerosis pro-duces a bystander effect on resident astrocytes and microgliaby increasing their expression of anti-inflammatory cytokinessuch as TGF120573 [162] Alternatively it has been suggested thatT cells may mediate an indirect effect on adult hippocampalneurogenesis by increasing the production of brain-derivedneurotrophic factor (BDNF) [157] which is involved in theproneurogenic actions of EE [163] Whether BDNF cancounteract the detrimental effects of T cell depletion on neu-rogenesis remains unknownOverall the roles ofmicroglia inEE and running-induced neurogenesis are unclear and haveto be addressed with more precise experimental designs Insummary surveillant microglia are part of the physical nichesurrounding the neural stem cells and newborn neurons ofthe mature hippocampus where they continuously phagocy-tose the excess of newborn cellsMicroglia were also linked tothe proneurogenic and anti-inflammatory effects of voluntaryrunning and EE but direct evidence is missing The overallcontribution of microglia to neurogenesis and learning andmemory in normal physiological conditions remains largelyunexplored at this early stage in the field
7 Conclusion
In light of these observations microglia are now emergingas important effector cells during normal brain developmentand functions including adult hippocampal neurogenesisMicroglia can exert a positive or negative influence onthe proliferation survival or differentiation of newborncells depending on the inflammatory context For instancemicroglia can compromise the neurogenic cascade duringchronic stress aging and neurodegenerative diseases bytheir release of proinflammatory cytokines such as IL-1120573IL-6 and TNF120572 A reduced fractalkine signalling betweenneurons and microglia could also be involved during normalaging However microglia are not necessarily the only celltype implicated because astrocytes endothelial cells mastcells perivascular and meningeal macrophages and to alesser extent neurons and invading peripheral immune cellscould further contribute by releasing proinflammatorymedi-ators
Additionally microglia were shown to phagocytose theexcess of newborn neurons undergoing apoptosis in thehippocampal neurogenic niche during normal physiologicalconditions while a similar role in the synaptic integrationof newborn cells was also proposed in light of their capacityto phagocytose synaptic elements Lastly microglial interac-tions with T cells leading to the release of anti-inflammatorycytokines neurotrophic factors and other proneurogenicmediators (notably during EE and voluntary running) couldcounteract the detrimental effects of inflammation on adult
hippocampal neurogenesis and their functional implicationsfor learning and memory
However further research is necessary to assess the rela-tive contribution of microglia versus other types of residentand infiltrating inflammatory cells and to determine thenature of the effector cytokines and other inflammatorymediators involved as well as their cellular andmolecular tar-gets in the neurogenic cascade Such research will undoubt-edly help to develop novel strategies aiming at protecting theneurogenic potential and ultimately its essential contributionto learning and memory
The authors declare that there is no conflict of interestsregarding the publication of this paper
Acknowledgments
This work was supported by grants from the Spanish Min-istry of Economy and Competitiveness to Amanda Sierra(BFU2012-32089) and Juan M Encinas (SAF2012-40085)from Basque Government (Saiotek S-PC 12UN014) and Iker-basque start-up funds to JuanM Encinas andAmanda Sierraand fromTheBanting Research Foundation the Scottish RiteCharitable Foundation of Canada and start-up funds fromUniversite Laval andCentre de recherche duCHUdeQuebecto Marie-Eve Tremblay
References
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[114] Y Ito M Yamada H Tanaka et al ldquoInvolvement of CHOP anER-stress apoptotic mediator in both human sporadic ALS andALS model micerdquo Neurobiology of Disease vol 36 no 3 pp470ndash476 2009
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14 Neural Plasticity
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[134] T J Seabrook L Jiang M Maier and C A Lemere ldquoMinocy-cline affects microglia activation A120573 deposition and behaviorin APP-tg micerdquo GLIA vol 53 no 7 pp 776ndash782 2006
[135] B Biscaro O Lindvall G Tesco C T Ekdahl and RM NitschldquoInhibition of microglial activation protects hippocampal neu-rogenesis and improves cognitive deficits in a transgenic mousemodel for Alzheimerrsquos diseaserdquoNeurodegenerative Diseases vol9 no 4 pp 187ndash198 2012
[136] P A Zunszain C Anacker A Cattaneo et al ldquoInterleukin-1120573a new regulator of the kynurenine pathway affecting humanhippocampal neurogenesisrdquo Neuropsychopharmacology vol 37no 4 pp 939ndash949 2012
[137] R De Simone M Antonietta Ajmone-Cat P Tirassa and LMinghetti ldquoApoptotic PC12 cells exposing phosphatidylserinepromote the production of anti-inflammatory and neuropro-tective molecules bymicroglial cellsrdquo Journal of Neuropathologyand Experimental Neurology vol 62 no 2 pp 208ndash216 2003
[138] M S Buckwalter M Yamane B S Coleman et al ldquoChroni-cally increased transforming growth factor-1205731 strongly inhibitshippocampal neurogenesis in aged micerdquo American Journal ofPathology vol 169 no 1 pp 154ndash164 2006
[139] O Butovsky Y Ziv A Schwartz et al ldquoMicroglia activatedby IL-4 or IFN-120574 differentially induce neurogenesis and oligo-dendrogenesis from adult stemprogenitor cellsrdquoMolecular andCellular Neuroscience vol 31 no 1 pp 149ndash160 2006
[140] C T Ekdahl ldquoMicroglial activationmdashtuning and pruning adultneurogenesisrdquo Frontiers in Pharmacology vol 3 article 41 2012
[141] HWakeA JMoorhouse S Jinno S Kohsaka and JNabekuraldquoResting microglia directly monitor the functional state ofsynapses in vivo and determine the fate of ischemic terminalsrdquoJournal of Neuroscience vol 29 no 13 pp 3974ndash3980 2009
[142] M E Tremblay R L Lowery and A K Majewska ldquoMicroglialinteractions with synapses are modulated by visual experiencerdquoPLoS Biology vol 8 no 11 Article ID e1000527 2010
[143] M E Tremblay M L Zettel J R Ison P D Allen and A KMajewska ldquoEffects of aging and sensory loss on glial cells inmouse visual and auditory corticesrdquo GLIA vol 60 no 4 pp541ndash558 2012
[144] D P Schafer E K Lehrman A G Kautzman et al ldquoMicrogliasculpt postnatal neural circuits in an activity and complement-dependent mannerrdquo Neuron vol 74 no 4 pp 691ndash705 2012
[145] H Nakanishi ldquoMicroglial functions and proteasesrdquo MolecularNeurobiology vol 27 no 2 pp 163ndash176 2003
[146] M E Tremblay and A K Majewska ldquoA role for microglia insynaptic plasticityrdquoCommunicative and Integrative Biology vol4 no 2 pp 220ndash222 2011
[147] R C Paolicelli G Bolasco F Pagani et al ldquoSynaptic pruning bymicroglia is necessary for normal brain developmentrdquo Sciencevol 333 no 6048 pp 1456ndash1458 2011
[148] GKempermannHGKuhn and FHGage ldquoMore hippocam-pal neurons in adult mice living in an enriched environmentrdquoNature vol 386 no 6624 pp 493ndash495 1997
[149] M Nilsson E Perfilieva U Johansson O Orwar and P SEriksson ldquoEnriched environment increases neurogenesis in theadult rat dentate gyrus and improves spatial memoryrdquo Journalof Neurobiology vol 39 no 4 pp 569ndash578 1999
[150] H van Praag G Kempermann and F H Gage ldquoRunningincreases cell proliferation and neurogenesis in the adult mousedentate gyrusrdquo Nature Neuroscience vol 2 no 3 pp 266ndash2701999
[151] D Young P A Lawlor P Leone M Dragunow and MJ During ldquoEnvironmental enrichment inhibits spontaneousapoptosis prevents seizures and is neuroprotectiverdquo NatureMedicine vol 5 no 4 pp 448ndash453 1999
[152] L L Williamson A Chao and S D Bilbo ldquoEnvironmentalenrichment alters glial antigen expression and neuroimmunefunction in the adult rat hippocampusrdquo Brain Behavior andImmunity vol 26 no 3 pp 500ndash510 2012
[153] L Maggi M Scianni I Branchi I DrsquoAndrea C Lauro and CLimatola ldquoCX(3)CR1 deficiency alters hippocampal-dependentplasticity phenomena blunting the effects of enriched environ-mentrdquo Frontiers in Cellular Neuroscience vol 5 article 22 2011
[154] I Goshen A Avital T Kreisel T Licht M Segal and RYirmiya ldquoEnvironmental enrichment restores memory func-tioning in mice with impaired IL-1 signaling via reinstatementof long-term potentiation and spine size enlargementrdquo Journalof Neuroscience vol 29 no 11 pp 3395ndash3403 2009
[155] Y Ziv N Ron O Butovsky et al ldquoImmune cells contribute tothe maintenance of neurogenesis and spatial learning abilitiesin adulthoodrdquo Nature Neuroscience vol 9 no 2 pp 268ndash2752006
[156] J Kipnis H Cohen M Cardon Y Ziv and M Schwartz ldquoTcell deficiency leads to cognitive dysfunction implications fortherapeutic vaccination for schizophrenia and other psychiatricconditionsrdquo Proceedings of the National Academy of Sciences ofthe United States of America vol 101 no 21 pp 8180ndash8185 2004
[157] S A Wolf B Steiner A Akpinarli et al ldquoCD4-positive Tlymphocytes provide a neuroimmunological link in the control
Neural Plasticity 15
of adult hippocampal neurogenesisrdquo Journal of Immunologyvol 182 no 7 pp 3979ndash3984 2009
[158] G J Huang A L Smith D H D Gray et al ldquoA genetic andfunctional relationship between T cells and cellular prolifera-tion in the adult hippocampusrdquo PLOS Biology vol 8 no 12Article ID e1000561 2010
[159] R M Ransohoff and B Engelhardt ldquoThe anatomical andcellular basis of immune surveillance in the central nervoussystemrdquoNature Reviews Immunology vol 12 no 9 pp 623ndash6352012
[160] M Olah G Ping A H De Haas et al ldquoEnhanced hippocampalneurogenesis in the absence of microglia T cell interactionand microglia activation in the murine running wheel modelrdquoGLIA vol 57 no 10 pp 1046ndash1061 2009
[161] E Gebara S Sultan J Kocher-Braissant and N Toni ldquoAdulthippocampal neurogenesis inversely correlates with microgliain conditions of voluntary running and agingrdquo Frontiers inNeuroscience vol 7 article 145 2013
[162] R Aharoni B Kayhan R Eilam M Sela and R ArnonldquoGlatiramer acetate-specific T cells in the brain express T helper23 cytokines and brain-derived neurotrophic factor in siturdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 100 no 2 pp 14157ndash14162 2003
[163] C Rossi A Angelucci L Costantin et al ldquoBrain-derivedneurotrophic factor (BDNF) is required for the enhancementof hippocampal neurogenesis following environmental enrich-mentrdquo European Journal of Neuroscience vol 24 no 7 pp 1850ndash1856 2006
8 Neural Plasticity
Table 1 Summary of factors secreted by microglia and the potential effect they have on neuroprogenitors in vitro
Microglia secreted factors Reference Modulation of neural progenitor cells ReferenceBDNF [18] Differentiation [19]EGF [20] Survival expansion proliferation differentiation [21]FGF120573 [22] Survival and expansion [23]GDNF [24] Survival migration and differentiation [25]IGF-1 [21] Proliferation [26]IL-1120573 [27] Reduction in migration [27]IL-6 [28] Inhibition of neurogenesis [29]IL-7 [20] Differentiation [30]IL-11 [20] Differentiation [30]NT-4 [24] Differentiation [31]PDGF [32] Expansion and differentiation [33]TGF120573 [34] Inhibition of proliferation [19]
Table 2 Summary of factors secreted by neuroprogenitors and the potential effect they have on microglia in vitro
NPC secreted factors Reference Modulation of microglia ReferenceBDNF [18] Proliferation and induction of phagocytic activity [35]Haptoglobin [24] Neuroprotection [36]IL-1120573 [37] Intracellular Ca+2 elevation and proliferation [22]IL-6 [37] Increase in proliferation [38]M-CSF [20] Mitogen [39]NGF [40] Decrease in LPS-induced NO [41]TGF120573 [37] Inhibition of TNF120572 secretion [42]TNF120572 [37] Upregulation of IL-10 secretion [43]VEGF [20] Induction of chemotaxis and proliferation [20]
effect is mediated by increased neuroprogenitor proliferation[150] During inflammatory conditions EE is antiapoptoticand neuroprotective [151] and it limits the hippocampalresponse to LPS challenge by decreasing the expression ofseveral cytokines and chemokines including IL1-120573 andTNF120572[152] In fact EE is believed to counteract the inflammatoryenvironment and rescue the decreased number of neuroblastsin CX3CR1GFPGFP mice compared to wild-type mice [153]The effects of EE are independent of the IL-1120573 signallingpathway as it increases neurogenesis in mice that are nullfor IL-1R1 [154] EE also induces microglial proliferation andexpression of the proneurogenic IGF-1 [155] but the fullphenotype of microglia in EE compared to standard housingand its impact on the neurogenic cascade remains to bedetermined
The mechanisms behind the anti-inflammatory actionsof EE are unknown but they were suggested to involvemicroglial interactions with T lymphocytes through anincreased expression of themajor histocompatibility complexof class II (MHC-II) during EE [155] MHC-II is responsiblefor presenting the phagocytosed and degraded antigens tothe antibodies expressed on the surface of a subtype ofT lymphocytes (T helper or CD4+ cells) thus initiatingtheir activation and production of antigen-specific antibod-ies Severe combined immunodeficient (SCID) mice lackingeither T and B lymphocytes or nude mice lacking only Tcells have impaired proliferation and neurogenesis in normal
and EE housing compared to wild-type mice [155] as wellas impaired performance in the water maze [156] Similarlyantibody-based depletion of T helper lymphocytes impairsbasal and exercise-induced proliferation and neurogenesis[157] Furthermore a genetic study in heterogeneous stockmice which descend from eight inbred progenitor strainshas found a significant positive correlation between geneticloci associated to hippocampal proliferation and to theproportion of CD4+ cells among blood CD3+ lymphocytes[158] Additional experiments are needed to fully determinethe possible interactions between microglia and T cellsin neurogenesis because at least in normal physiologicalconditions (1) T cell surveillance of the brain parenchymais minimal (2) microglia are poor antigen presenting cellsand (3) antigen presentation by means of MHC-II family ofmolecules is thought to occur outside the brain that is in themeninges and choroid plexus [159] In fact during voluntaryexercise there are no significant changes in T cell surveillanceof the hippocampus nor a direct interaction between T cellsand microglia nor any changes in the gene expression profileof microglia including that of IGF-1 IL-1120573 and TNF120572 [160]The number of microglia is also inversely correlated withthe number of hippocampal proliferating cells rNSCs andneuroblasts in aged (8 months) mice subjected to voluntaryrunning as well as in vitro cocultures of microglia andneuroprogenitors which has been interpreted as resultingfrom an overall inhibitory effect of microglia on adult
Neural Plasticity 9
neurogenesis [161] Even though EE is clearly a more com-plex environmental factor than voluntary running furtherresearch is necessary to disregard nonspecific or indirecteffects of genetic or antibody-based T cells depletion onmicroglia and other brain cell populations including rNSCsFor instance adoptive transfer of T helper cells treated withglatiramer acetate a synthetic analog of myelin basic protein(MBP) approved for the treatment of multiple sclerosis pro-duces a bystander effect on resident astrocytes and microgliaby increasing their expression of anti-inflammatory cytokinessuch as TGF120573 [162] Alternatively it has been suggested thatT cells may mediate an indirect effect on adult hippocampalneurogenesis by increasing the production of brain-derivedneurotrophic factor (BDNF) [157] which is involved in theproneurogenic actions of EE [163] Whether BDNF cancounteract the detrimental effects of T cell depletion on neu-rogenesis remains unknownOverall the roles ofmicroglia inEE and running-induced neurogenesis are unclear and haveto be addressed with more precise experimental designs Insummary surveillant microglia are part of the physical nichesurrounding the neural stem cells and newborn neurons ofthe mature hippocampus where they continuously phagocy-tose the excess of newborn cellsMicroglia were also linked tothe proneurogenic and anti-inflammatory effects of voluntaryrunning and EE but direct evidence is missing The overallcontribution of microglia to neurogenesis and learning andmemory in normal physiological conditions remains largelyunexplored at this early stage in the field
7 Conclusion
In light of these observations microglia are now emergingas important effector cells during normal brain developmentand functions including adult hippocampal neurogenesisMicroglia can exert a positive or negative influence onthe proliferation survival or differentiation of newborncells depending on the inflammatory context For instancemicroglia can compromise the neurogenic cascade duringchronic stress aging and neurodegenerative diseases bytheir release of proinflammatory cytokines such as IL-1120573IL-6 and TNF120572 A reduced fractalkine signalling betweenneurons and microglia could also be involved during normalaging However microglia are not necessarily the only celltype implicated because astrocytes endothelial cells mastcells perivascular and meningeal macrophages and to alesser extent neurons and invading peripheral immune cellscould further contribute by releasing proinflammatorymedi-ators
Additionally microglia were shown to phagocytose theexcess of newborn neurons undergoing apoptosis in thehippocampal neurogenic niche during normal physiologicalconditions while a similar role in the synaptic integrationof newborn cells was also proposed in light of their capacityto phagocytose synaptic elements Lastly microglial interac-tions with T cells leading to the release of anti-inflammatorycytokines neurotrophic factors and other proneurogenicmediators (notably during EE and voluntary running) couldcounteract the detrimental effects of inflammation on adult
hippocampal neurogenesis and their functional implicationsfor learning and memory
However further research is necessary to assess the rela-tive contribution of microglia versus other types of residentand infiltrating inflammatory cells and to determine thenature of the effector cytokines and other inflammatorymediators involved as well as their cellular andmolecular tar-gets in the neurogenic cascade Such research will undoubt-edly help to develop novel strategies aiming at protecting theneurogenic potential and ultimately its essential contributionto learning and memory
The authors declare that there is no conflict of interestsregarding the publication of this paper
Acknowledgments
This work was supported by grants from the Spanish Min-istry of Economy and Competitiveness to Amanda Sierra(BFU2012-32089) and Juan M Encinas (SAF2012-40085)from Basque Government (Saiotek S-PC 12UN014) and Iker-basque start-up funds to JuanM Encinas andAmanda Sierraand fromTheBanting Research Foundation the Scottish RiteCharitable Foundation of Canada and start-up funds fromUniversite Laval andCentre de recherche duCHUdeQuebecto Marie-Eve Tremblay
References
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[2] F Ginhoux S Lim G Hoeffel D Low and T Huber ldquoOriginand differentiation of microgliardquo Frontiers in Cellular Neuro-science vol 7 article 45 2013
[3] E Gomez Perdiguero C Schulz and F Geissmann ldquoDevelop-ment and homeostasis of ldquoresidentrdquomyeloid cells the case of themicrogliardquo GLIA vol 61 no 1 pp 112ndash120 2013
[4] H Kettenmann F Kirchhoff and A Verkhratsky ldquoMicroglianew roles for the synaptic stripperrdquo Neuron vol 77 no 1 pp10ndash18 2013
[5] A Aguzzi B A Barres and M L Bennett ldquoMicroglia scape-goat saboteur or something elserdquo Science vol 339 no 6116 pp156ndash161 2013
[6] K Helmut U K Hanisch M Noda and A VerkhratskyldquoPhysiology of microgliardquo Physiological Reviews vol 91 no 2pp 461ndash553 2011
[7] M E Tremblay B Stevens A Sierra H Wake A Bessis andA Nimmerjahn ldquoThe role of microglia in the healthy brainrdquoJournal of Neuroscience vol 31 no 45 pp 16064ndash16069 2011
[8] A Miyamoto H Wake A J Moorhouse and J NabekuraldquoMicroglia and synapse interactions fine tuaning neural circuitsand candidate moleculesrdquo Frontiers in Cellular Neurosciencevol 7 article 70 2013
[9] C Bechade Y Cantaut-Belarif and A Bessis ldquoMicroglialcontrol of neuronal activityrdquo Frontiers in Cellular Neurosciencevol 7 article 32 2013
[10] A Sierra O Abiega A Shahraz and H Neumann ldquoJanus-faced microglia beneficial and detrimental consequences ofmicroglial phagocytosisrdquo Frontiers in Cellular Neuroscience vol7 article 6 2013
[11] G Kempermann S Jessberger B Steiner and G KronenbergldquoMilestones of neuronal development in the adult hippocam-pusrdquo Trends in Neurosciences vol 27 no 8 pp 447ndash452 2004
[12] J M Encinas T V Michurina N Peunova et al ldquoDivision-coupled astrocytic differentiation and age-related depletion ofneural stem cells in the adult hippocampusrdquo Cell Stem Cell vol8 no 5 pp 566ndash579 2011
[13] M A Bonaguidi M A Wheeler J S Shapiro et al ldquoIn vivoclonal analysis reveals self-renewing and multipotent adultneural stem cell characteristicsrdquo Cell vol 145 no 7 pp 1142ndash1155 2011
[14] J J Breunig J I Arellano J D Macklis and P RakicldquoEverything that glitters isnrsquot gold a critical review of postnatalneural precursor analysesrdquo Cell Stem Cell vol 1 no 6 pp 612ndash627 2007
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[19] M Krampert S R Chirasani F P Wachs et al ldquoSmad7regulates the adult neural stemprogenitor cell pool in a trans-forming growth factor 120573- and bone morphogenetic protein-independent mannerrdquo Molecular and Cellular Biology vol 30no 14 pp 3685ndash3694 2010
[20] K I Mosher R H Andres T Fukuhara et al ldquoNeural pro-genitor cells regulate microglia functions and activityrdquo NatureNeuroscience vol 15 no 11 pp 1485ndash1487 2012
[21] V Tropepe M Sibilia B G Ciruna J Rossant E F Wagnerand D van der Kooy ldquoDistinct neural stem cells proliferatein response to EGF and FGF in the developing mouse telen-cephalonrdquo Developmental Biology vol 208 no 1 pp 166ndash1881999
[22] S U Kim and J De Vellis ldquoMicroglia in health and diseaserdquoJournal of Neuroscience Research vol 81 no 3 pp 302ndash3132005
[23] B A Reynolds and R L Rietze ldquoNeural stem cells andneurospheresmdashre-evaluating the relationshiprdquoNatureMethodsvol 2 no 5 pp 333ndash336 2005
[24] K Satake Y Matsuyama M Kamiya et al ldquoUp-regulation ofglial cell line-derived neurotrophic factor (GDNF) followingtraumatic spinal cord injuryrdquo NeuroReport vol 11 no 17 pp3877ndash3881 2000
[25] Y M Yoo C J Lee and Y J Kim ldquoExogenous GDNF increasesthe migration of the neural stem cells with no protectionagainst kainic acid-induced excitotoxic cell death in ratsrdquo BrainResearch vol 1486 pp 27ndash38 2012
[26] J L Trejo E Carro and I Torres-Aleman ldquoCirculating insulin-like growth factor I mediates exercise-induced increases in thenumber of new neurons in the adult hippocampusrdquo Journal ofNeuroscience vol 21 no 5 pp 1628ndash1634 2001
Neural Plasticity 11
[27] K Striedinger and E Scemes ldquoInterleukin-1120573 affects calciumsignaling and in vitro cell migration of astrocyte progenitorsrdquoJournal of Neuroimmunology vol 196 no 1-2 pp 116ndash123 2008
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[29] G Kempermann and H Neumann ldquoMicroglia the enemywithinrdquo Science vol 302 no 5651 pp 1689ndash1690 2003
[30] M F Mehler R Rozental M Dougherty D C Spray and JA Kessler ldquoCytokine regulation of neuronal differentiation ofhippocampal progenitor cellsrdquo Nature vol 362 no 6415 pp62ndash65 1993
[31] U Gurok C Steinhoff B Lipkowitz H H Ropers C Scharffand U A Nuber ldquoGene expression changes in the course ofneural progenitor cell differentiationrdquo Journal of Neurosciencevol 24 no 26 pp 5982ndash6002 2004
[32] J B Demoulin M Enarsson J Larsson A Essaghir C HHeldin and K Forsberg-Nilsson ldquoThe gene expression profileof PDGF-treated neural stem cells corresponds to partiallydifferentiated neurons and gliardquo Growth Factors vol 24 no 3pp 184ndash196 2006
[33] F C Mansergh M A Wride and D E Rancourt ldquoNeuronsfrom stem cells implications for understanding nervous systemdevelopment and repairrdquo Biochemistry and Cell Biology vol 78no 5 pp 613ndash628 2000
[34] F C Alcantara Gomes V De Oliveira Sousa and L RomaoldquoEmerging roles for TGF-1205731 in nervous system developmentrdquoInternational Journal of Developmental Neuroscience vol 23 no5 pp 413ndash424 2005
[35] S Elkabes E M DiCicco-Bloom and I B Black ldquoBrainmicrogliamacrophages express neurotrophins that selectivelyregulate microglial proliferation and functionrdquo Journal of Neu-roscience vol 16 no 8 pp 2508ndash2521 1996
[36] U K Hanisch and H Kettenmann ldquoMicroglia active sensorand versatile effector cells in the normal and pathologic brainrdquoNature Neuroscience vol 10 no 11 pp 1387ndash1394 2007
[37] H J Klassen T F Ng Y Kurimoto et al ldquoMultipotent retinalprogenitors express developmental markers differentiate intoretinal neurons and preserve light-mediated behaviorrdquo Inves-tigative Ophthalmology and Visual Science vol 45 no 11 pp4167ndash4173 2004
[38] W J Streit S D Hurley T S McGraw and S L Semple-Rowland ldquoComparative evaluation of cytokine profiles andreactive gliosis supports a critical role for interleukin-6 inneuron-glia signaling during regenerationrdquo Journal of Neuro-science Research vol 61 no 1 pp 10ndash20 2000
[39] A Suzumura M Sawada H Yamamoto and T MarunouchildquoEffects of colony stimulating factors on isolated microglia invitrordquo Journal of Neuroimmunology vol 30 no 2-3 pp 111ndash1201990
[40] Z Lu M R Elliott Y Chen et al ldquoPhagocytic activity ofneuronal progenitors regulates adult neurogenesisrdquoNature CellBiology vol 13 no 9 pp 1076ndash1084 2011
[41] K Nakajima Y Kikuchi E Ikoma et al ldquoNeurotrophinsregulate the function of cultured microgliardquo GLIA vol 24 no3 pp 272ndash289 1998
[42] P A Lodge and S Sriram ldquoRegulation of microglial activationby TGF-120573 IL-10 and CSF-1rdquo Journal of Leukocyte Biology vol60 no 4 pp 502ndash508 1996
[43] W S Sheng S Hu F H Kravitz P K Peterson and C C ChaoldquoTumor necrosis factor alpha upregulates humanmicroglial cell
production of interleukin-10 in vitrordquo Clinical and DiagnosticLaboratory Immunology vol 2 no 5 pp 604ndash608 1995
[44] G LMing andH Song ldquoAdult neurogenesis in themammalianbrain significant answers and significant questionsrdquo Neuronvol 70 no 4 pp 687ndash702 2011
[45] E Bruel-Jungerman S Davis C Rampon and S LarocheldquoLong-term potentiation enhances neurogenesis in the adultdentate gyrusrdquo Journal of Neuroscience vol 26 no 22 pp 5888ndash5893 2006
[46] E Drapeau M F Montaron S Aguerre and D N AbrousldquoLearning-induced survival of new neurons depends on thecognitive status of aged ratsrdquo Journal of Neuroscience vol 27no 22 pp 6037ndash6044 2007
[47] A Mouret G Gheusi M M Gabellec F De Chaumont J COlivo-Marin and P M Lledo ldquoLearning and survival of newlygenerated neurons when timemattersrdquo Journal of Neurosciencevol 28 no 45 pp 11511ndash11516 2008
[48] N Kee C M Teixeira A H Wang and P W FranklandldquoPreferential incorporation of adult-generated granule cellsinto spatial memory networks in the dentate gyrusrdquo NatureNeuroscience vol 10 no 3 pp 355ndash362 2007
[49] F Massa M Koelh T Wiesner et al ldquoConditional reduction ofadult neurogenesis impairs bidirectional hippocampal synapticplasticityrdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 108 no 16 pp 6644ndash6649 2011
[50] T J Shors G Miesegaes A Beylin M Zhao T Rydel and EGould ldquoNeurogenesis in the adult is involved in the formationof tracememoriesrdquoNature vol 410 no 6826 pp 372ndash376 2001
[51] W Deng M D Saxe I S Gallina and F H Gage ldquoAdult-born hippocampal dentate granule cells undergoingmaturationmodulate learning and memory in the brainrdquo Journal of Neuro-science vol 29 no 43 pp 13532ndash13542 2009
[52] M Arruda-Carvalho M Sakaguchi K G Akers S A Josselynand P W Frankland ldquoPosttraining ablation of adult-generatedneurons degrades previously acquired memoriesrdquo Journal ofNeuroscience vol 31 no 42 pp 15113ndash15127 2011
[53] A Sahay K N Scobie A S Hill et al ldquoIncreasing adulthippocampal neurogenesis is sufficient to improve patternseparationrdquo Nature vol 472 no 7344 pp 466ndash470 2011
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[56] H K Jeong K Ji K Min and E H Joe ldquoBrain inflammationand microglia facts and misconceptionsrdquo Experimental Neuro-biology vol 22 no 2 pp 59ndash67 2013
[57] D Stellwagen and R CMalenka ldquoSynaptic scalingmediated byglial TNF-120572rdquo Nature vol 440 no 7087 pp 1054ndash1059 2006
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12 Neural Plasticity
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[76] S Nadeau and S Rivest ldquoEndotoxemia prevents the cerebralinflammatory wave induced by intraparenchymal lipopolysac-charide injection role of glucocorticoids and CD14rdquo Journal ofImmunology vol 169 no 6 pp 3370ndash3381 2002
[77] A Sierra A Gottfried-Blackmore T A Milner B S McEwenand K Bulloch ldquoSteroid hormone receptor expression andfunction in microgliardquo GLIA vol 56 no 6 pp 659ndash674 2008
[78] C Liston andW B Gan ldquoGlucocorticoids are critical regulatorsof dendritic spine development and plasticity in vivordquo Proceed-ings of the National Academy of Sciences of the United States ofAmerica vol 108 no 38 pp 16074ndash16079 2011
[79] C Liston J M Cichon F Jeanneteau Z Jia M V Chaoand W B Gan ldquoCircadian glucocorticoid oscillations pro-mote learning-dependent synapse formation andmaintenancerdquoNature Neuroscience vol 16 no 6 pp 698ndash705 2013
[80] M A Carrillo-de Sauvage L Maatouk I Arnoux et al ldquoPotentand multiple regulatory actions of microglial glucocorticoidreceptors during CNS inflammationrdquo Cell Death amp Differenti-ation vol 20 no 11 pp 1546ndash1557 2013
[81] S F Sorrells J R Caso C DMunhoz and RM Sapolsky ldquoThestressed CNS when glucocorticoids aggravate inflammationrdquoNeuron vol 64 no 1 pp 33ndash39 2009
[82] M A Bellavance and S Rivest ldquoThe neuroendocrine controlof the innate immune system in health and brain diseasesrdquoImmunological Reviews vol 248 no 1 pp 36ndash55 2012
[83] R J Tynan S Naicker M Hinwood et al ldquoChronic stress altersthe density and morphology of microglia in a subset of stress-responsive brain regionsrdquo Brain Behavior and Immunity vol24 no 7 pp 1058ndash1068 2010
[84] E S Wohleb N D Powell J P Godbout and J F SheridanldquoStress-induced recruitment of bone marrow-derived mono-cytes to the brain promotes anxiety-like behaviorrdquo The Journalof Neuroscience vol 33 no 34 pp 13820ndash13833 2013
[85] Y Diz-Chaves M Astiz M J Bellini and L M Garcia-SeguraldquoPrenatal stress increases the expression of proinflammatorycytokines and exacerbates the inflammatory response to LPS inthe hippocampal formation of adultmalemicerdquoBrain Behaviorand Immunity vol 28 pp 196ndash206 2013
[86] E S Wohleb A M Fenn A M Pacenta N D Powell J FSheridan and J P Godbout ldquoPeripheral innate immune chal-lenge exaggerated microglia activation increased the numberof inflammatory CNSmacrophages and prolonged social with-drawal in socially defeated micerdquo Psychoneuroendocrinologyvol 37 no 9 pp 1491ndash1505 2012
[87] C Mirescu and E Gould ldquoStress and adult neurogenesisrdquoHippocampus vol 16 no 3 pp 233ndash238 2006
[88] J LWarner-Schmidt andR SDuman ldquoHippocampal neuroge-nesis opposing effects of stress and antidepressant treatmentrdquoHippocampus vol 16 no 3 pp 239ndash249 2006
[89] N D Hanson M J Owens K A Boss-Williams J M Weissand C B Nemeroff ldquoSeveral stressors fail to reduce adulthippocampal neurogenesisrdquo Psychoneuroendocrinology vol 36no 10 pp 1520ndash1529 2011
[90] E Gould B S McEwen P Tanapat L A M Galea and EFuchs ldquoNeurogenesis in the dentate gyrus of the adult treeshrew is regulated by psychosocial stress and NMDA receptoractivationrdquo Journal of Neuroscience vol 17 no 7 pp 2492ndash24981997
[91] JW Koo andR S Duman ldquoIL-1120573 is an essentialmediator of theantineurogenic and anhedonic effects of stressrdquo Proceedings ofthe National Academy of Sciences of the United States of Americavol 105 no 2 pp 751ndash756 2008
[92] D C Lagace M H Donovan N A Decarolis et al ldquoAdulthippocampal neurogenesis is functionally important for stress-induced social avoidancerdquo Proceedings of the National Academy
Neural Plasticity 13
of Sciences of the United States of America vol 107 no 9 pp4436ndash4441 2010
[93] G Kronenberg I Kirste D Inta et al ldquoReduced hippocampalneurogenesis in the GR+- genetic mousemodel of depressionrdquoEuropean Archives of Psychiatry and Clinical Neuroscience vol259 no 8 pp 499ndash504 2009
[94] M B Howren D M Lamkin and J Suls ldquoAssociations ofdepression with c-reactive protein IL-1 and IL-6 a meta-analysisrdquo Psychosomatic Medicine vol 71 no 2 pp 171ndash1862009
[95] J W Koo S J Russo D Ferguson E J Nestler and R SDuman ldquoNuclear factor-120581B is a critical mediator of stress-impaired neurogenesis and depressive behaviorrdquo Proceedings ofthe National Academy of Sciences of the United States of Americavol 107 no 6 pp 2669ndash2674 2010
[96] I Goshen T Kreisel O Ben-Menachem-Zidon et al ldquoBraininterleukin-1 mediates chronic stress-induced depression inmice via adrenocortical activation and hippocampal neuroge-nesis suppressionrdquo Molecular Psychiatry vol 13 no 7 pp 717ndash728 2008
[97] C D Munhoz L B Lepsch E M Kawamoto et al ldquoChronicunpredictable stress exacerbates lipopolysaccharide-inducedactivation of nuclear factor-120581B in the frontal cortex andhippocampus via glucocorticoid secretionrdquo Journal of Neuro-science vol 26 no 14 pp 3813ndash3820 2006
[98] S J Sukoff Rizzo S J Neal Z A Hughes et al ldquoEvidence forsustained elevation of IL-6 in the CNS as a key contributorof depressive-like phenotypesrdquo Translational Psychiatry vol 2article e199 2012
[99] A Garcia B Steiner G Kronenberg A Bick-Sander and GKempermann ldquoAge-dependent expression of glucocorticoid-andmineralocorticoid receptors on neural precursor cell popu-lations in the adult murine hippocampusrdquoAging Cell vol 3 no6 pp 363ndash371 2004
[100] M G Frank B M Thompson L R Watkins and S F MaierldquoGlucocorticoids mediate stress-induced priming of microglialpro-inflammatory responsesrdquo Brain Behavior and Immunityvol 26 no 2 pp 337ndash345 2012
[101] S Sugama M Fujita M Hashimoto and B Conti ldquoStressinduced morphological microglial activation in the rodentbrain involvement of interleukin-18rdquoNeuroscience vol 146 no3 pp 1388ndash1399 2007
[102] A Sierra J M Encinas and M Maletic-Savatic ldquoAdult humanneurogenesis from microscopy to magnetic resonance imag-ingrdquo Frontiers in Neuroscience vol 5 article 47 2011
[103] H G Kuhn H Dickinson-Anson and F H Gage ldquoNeurogen-esis in the dentate gyrus of the adult rat age-related decrease ofneuronal progenitor proliferationrdquo Journal of Neuroscience vol16 no 6 pp 2027ndash2033 1996
[104] L N Manganas X Zhang Y Li et al ldquoMagnetic resonancespectroscopy identifies neural progenitor cells in the live humanbrainrdquo Science vol 318 no 5852 pp 980ndash985 2007
[105] K L Spalding O Bergmann K Alkass et al ldquoDynamics ofhippocampal neurogenesis in adult humansrdquo Cell vol 153 no6 pp 1219ndash1227 2013
[106] J M Encinas and A Sierra ldquoNeural stem cell deforestationas the main force driving the age-related decline in adulthippocampal neurogenesisrdquo Behavioural Brain Research vol227 no 2 pp 433ndash439 2012
[107] K S Krabbe M Pedersen andH Bruunsgaard ldquoInflammatorymediators in the elderlyrdquo Experimental Gerontology vol 39 no5 pp 687ndash699 2004
[108] B S Diniz A L Teixeira L Talib W F Gattaz andO V Forlenza ldquoInterleukin-1120573 serum levels is increased inantidepressant-free elderly depressed patientsrdquo American Jour-nal of Geriatric Psychiatry vol 18 no 2 pp 172ndash176 2010
[109] A Sierra A C Gottfried-Blackmore B S Mcewen and KBulloch ldquoMicroglia derived from aging mice exhibit an alteredinflammatory profilerdquo GLIA vol 55 no 4 pp 412ndash424 2007
[110] C FranceschiM Bonafe S Valensin et al ldquoInflamm-aging Anevolutionary perspective on immunosenescencerdquo Annals of theNew York Academy of Sciences vol 908 pp 244ndash254 2000
[111] R Sano and J C Reed ldquoER stress-induced cell death mecha-nismsrdquoBiochimica et BiophysicaActa vol 1833 no 12 pp 3460ndash3470 2013
[112] S Z Hasnain R Lourie I Das A C H Chen and MA McGuckin ldquoThe interplay between endoplasmic reticulumstress and inflammationrdquo Immunology and Cell Biology vol 90no 3 pp 260ndash270 2012
[113] S Matus L H Glimcher and C Hetz ldquoProtein folding stressin neurodegenerative diseases a glimpse into the ERrdquo CurrentOpinion in Cell Biology vol 23 no 2 pp 239ndash252 2011
[114] Y Ito M Yamada H Tanaka et al ldquoInvolvement of CHOP anER-stress apoptotic mediator in both human sporadic ALS andALS model micerdquo Neurobiology of Disease vol 36 no 3 pp470ndash476 2009
[115] D Papadimitriou V Le Verche A Jacquier B Ikiz S Przed-borski and D B Re ldquoInflammation in ALS and SMA sortingout the good from the evilrdquo Neurobiology of Disease vol 37 no3 pp 493ndash502 2010
[116] A R Johnson J J Milner and LMakowski ldquoThe inflammationhighway metabolism accelerates inflammatory traffic in obe-sityrdquo Immunological Reviews vol 249 no 1 pp 218ndash238 2012
[117] S Buch H Yao M Guo et al ldquoCocaine and HIV-1 interplayin CNS cellular and molecular mechanismsrdquo Current HIVResearch vol 10 no 5 pp 425ndash428 2012
[118] M K Brown and N Naidoo ldquoThe endoplasmic reticulumstress response in aging and age-related diseasesrdquo Frontiers inPhysiology vol 3 article 263 2012
[119] G Castro C Areias MF L Weissmann et al ldquoDiet-inducedobesity induces endoplasmic reticulum stress and insulin resis-tance in the amygdala of ratsrdquo FEBS Open Bio vol 3 pp 443ndash449 2013
[120] A A Pavlovsky D Boehning D Li Y Zhang X Fan andT A Green ldquoPsychological stress cocaine and natural rewardeach induce endoplasmic reticulum stress genes in rat brainrdquoNeuroscience vol 246 pp 160ndash169 2013
[121] G GargiuloM CesaroniM Serresi et al ldquoIn vivo RNAi screenfor BMI1 targets identifies TGF-betaBMP-ER stress pathwaysas key regulators of neural- and malignant glioma-stem cellhomeostasisrdquo Cancer Cell vol 23 no 5 pp 660ndash676 2013
[122] A Salminen K Kaarniranta and A Kauppinen ldquoInflammag-ing disturbed interplay between autophagy and inflamma-somesrdquo Aging vol 4 no 3 pp 166ndash175 2012
[123] E Latz T S Xiao andA Stutz ldquoActivation and regulation of theinflammasomesrdquoNature Reviews Immunology vol 13 no 6 pp397ndash411 2013
[124] C Gemma A D Bachstetter M J Cole M Fister C Hudsonand P C Bickford ldquoBlockade of caspase-1 increases neurogene-sis in the aged hippocampusrdquo European Journal of Neurosciencevol 26 no 10 pp 2795ndash2803 2007
[125] M D Wu A M Hein M J Moravan S S Shaftel J AOlschowka and M K OrsquoBanion ldquoAdult murine hippocampal
14 Neural Plasticity
neurogenesis is inhibited by sustained IL-1120573 and not rescued byvoluntary runningrdquo Brain Behavior and Immunity vol 26 no2 pp 292ndash300 2012
[126] Y Wolf S Yona K W Kim and S Jung ldquoMicroglia seen fromthe CX3CR1 anglerdquo Frontiers in Cellular Neuroscience vol 7article 26 2013
[127] A E Cardona E P Pioro M E Sasse et al ldquoControl ofmicroglial neurotoxicity by the fractalkine receptorrdquo NatureNeuroscience vol 9 no 7 pp 917ndash924 2006
[128] K Bhaskar M Konerth O N Kokiko-Cochran A Cardona RM Ransohoff and B T Lamb ldquoRegulation of tau pathology bythe microglial fractalkine receptorrdquo Neuron vol 68 no 1 pp19ndash31 2010
[129] A D Bachstetter J M Morganti J Jernberg et al ldquoFractalkineand CX3CR1 regulate hippocampal neurogenesis in adult andaged ratsrdquo Neurobiology of Aging vol 32 no 11 pp 2030ndash20442011
[130] S Jung J Aliberti P Graemmel et al ldquoAnalysis of fractalkinereceptor CX3CR1 function by targeted deletion and greenfluorescent protein reporter gene insertionrdquo Molecular andCellular Biology vol 20 no 11 pp 4106ndash4114 2000
[131] J T Rogers J M Morganti A D Bachstetter et al ldquoCX3CR1deficiency leads to impairment of hippocampal cognitive func-tion and synaptic plasticityrdquo Journal of Neuroscience vol 31 no45 pp 16241ndash16250 2011
[132] W S T Griffin L C Stanley C Ling et al ldquoBrain interleukin1 and S-100 immunoreactivity are elevated in Down syndromeand Alzheimer diseaserdquo Proceedings of the National Academy ofSciences of the United States of America vol 86 no 19 pp 7611ndash7615 1989
[133] W C Benzing J RWujek E KWard et al ldquoEvidence for glial-mediated inflammation in aged APP(SW) transgenic micerdquoNeurobiology of Aging vol 20 no 6 pp 581ndash589 1999
[134] T J Seabrook L Jiang M Maier and C A Lemere ldquoMinocy-cline affects microglia activation A120573 deposition and behaviorin APP-tg micerdquo GLIA vol 53 no 7 pp 776ndash782 2006
[135] B Biscaro O Lindvall G Tesco C T Ekdahl and RM NitschldquoInhibition of microglial activation protects hippocampal neu-rogenesis and improves cognitive deficits in a transgenic mousemodel for Alzheimerrsquos diseaserdquoNeurodegenerative Diseases vol9 no 4 pp 187ndash198 2012
[136] P A Zunszain C Anacker A Cattaneo et al ldquoInterleukin-1120573a new regulator of the kynurenine pathway affecting humanhippocampal neurogenesisrdquo Neuropsychopharmacology vol 37no 4 pp 939ndash949 2012
[137] R De Simone M Antonietta Ajmone-Cat P Tirassa and LMinghetti ldquoApoptotic PC12 cells exposing phosphatidylserinepromote the production of anti-inflammatory and neuropro-tective molecules bymicroglial cellsrdquo Journal of Neuropathologyand Experimental Neurology vol 62 no 2 pp 208ndash216 2003
[138] M S Buckwalter M Yamane B S Coleman et al ldquoChroni-cally increased transforming growth factor-1205731 strongly inhibitshippocampal neurogenesis in aged micerdquo American Journal ofPathology vol 169 no 1 pp 154ndash164 2006
[139] O Butovsky Y Ziv A Schwartz et al ldquoMicroglia activatedby IL-4 or IFN-120574 differentially induce neurogenesis and oligo-dendrogenesis from adult stemprogenitor cellsrdquoMolecular andCellular Neuroscience vol 31 no 1 pp 149ndash160 2006
[140] C T Ekdahl ldquoMicroglial activationmdashtuning and pruning adultneurogenesisrdquo Frontiers in Pharmacology vol 3 article 41 2012
[141] HWakeA JMoorhouse S Jinno S Kohsaka and JNabekuraldquoResting microglia directly monitor the functional state ofsynapses in vivo and determine the fate of ischemic terminalsrdquoJournal of Neuroscience vol 29 no 13 pp 3974ndash3980 2009
[142] M E Tremblay R L Lowery and A K Majewska ldquoMicroglialinteractions with synapses are modulated by visual experiencerdquoPLoS Biology vol 8 no 11 Article ID e1000527 2010
[143] M E Tremblay M L Zettel J R Ison P D Allen and A KMajewska ldquoEffects of aging and sensory loss on glial cells inmouse visual and auditory corticesrdquo GLIA vol 60 no 4 pp541ndash558 2012
[144] D P Schafer E K Lehrman A G Kautzman et al ldquoMicrogliasculpt postnatal neural circuits in an activity and complement-dependent mannerrdquo Neuron vol 74 no 4 pp 691ndash705 2012
[145] H Nakanishi ldquoMicroglial functions and proteasesrdquo MolecularNeurobiology vol 27 no 2 pp 163ndash176 2003
[146] M E Tremblay and A K Majewska ldquoA role for microglia insynaptic plasticityrdquoCommunicative and Integrative Biology vol4 no 2 pp 220ndash222 2011
[147] R C Paolicelli G Bolasco F Pagani et al ldquoSynaptic pruning bymicroglia is necessary for normal brain developmentrdquo Sciencevol 333 no 6048 pp 1456ndash1458 2011
[148] GKempermannHGKuhn and FHGage ldquoMore hippocam-pal neurons in adult mice living in an enriched environmentrdquoNature vol 386 no 6624 pp 493ndash495 1997
[149] M Nilsson E Perfilieva U Johansson O Orwar and P SEriksson ldquoEnriched environment increases neurogenesis in theadult rat dentate gyrus and improves spatial memoryrdquo Journalof Neurobiology vol 39 no 4 pp 569ndash578 1999
[150] H van Praag G Kempermann and F H Gage ldquoRunningincreases cell proliferation and neurogenesis in the adult mousedentate gyrusrdquo Nature Neuroscience vol 2 no 3 pp 266ndash2701999
[151] D Young P A Lawlor P Leone M Dragunow and MJ During ldquoEnvironmental enrichment inhibits spontaneousapoptosis prevents seizures and is neuroprotectiverdquo NatureMedicine vol 5 no 4 pp 448ndash453 1999
[152] L L Williamson A Chao and S D Bilbo ldquoEnvironmentalenrichment alters glial antigen expression and neuroimmunefunction in the adult rat hippocampusrdquo Brain Behavior andImmunity vol 26 no 3 pp 500ndash510 2012
[153] L Maggi M Scianni I Branchi I DrsquoAndrea C Lauro and CLimatola ldquoCX(3)CR1 deficiency alters hippocampal-dependentplasticity phenomena blunting the effects of enriched environ-mentrdquo Frontiers in Cellular Neuroscience vol 5 article 22 2011
[154] I Goshen A Avital T Kreisel T Licht M Segal and RYirmiya ldquoEnvironmental enrichment restores memory func-tioning in mice with impaired IL-1 signaling via reinstatementof long-term potentiation and spine size enlargementrdquo Journalof Neuroscience vol 29 no 11 pp 3395ndash3403 2009
[155] Y Ziv N Ron O Butovsky et al ldquoImmune cells contribute tothe maintenance of neurogenesis and spatial learning abilitiesin adulthoodrdquo Nature Neuroscience vol 9 no 2 pp 268ndash2752006
[156] J Kipnis H Cohen M Cardon Y Ziv and M Schwartz ldquoTcell deficiency leads to cognitive dysfunction implications fortherapeutic vaccination for schizophrenia and other psychiatricconditionsrdquo Proceedings of the National Academy of Sciences ofthe United States of America vol 101 no 21 pp 8180ndash8185 2004
[157] S A Wolf B Steiner A Akpinarli et al ldquoCD4-positive Tlymphocytes provide a neuroimmunological link in the control
Neural Plasticity 15
of adult hippocampal neurogenesisrdquo Journal of Immunologyvol 182 no 7 pp 3979ndash3984 2009
[158] G J Huang A L Smith D H D Gray et al ldquoA genetic andfunctional relationship between T cells and cellular prolifera-tion in the adult hippocampusrdquo PLOS Biology vol 8 no 12Article ID e1000561 2010
[159] R M Ransohoff and B Engelhardt ldquoThe anatomical andcellular basis of immune surveillance in the central nervoussystemrdquoNature Reviews Immunology vol 12 no 9 pp 623ndash6352012
[160] M Olah G Ping A H De Haas et al ldquoEnhanced hippocampalneurogenesis in the absence of microglia T cell interactionand microglia activation in the murine running wheel modelrdquoGLIA vol 57 no 10 pp 1046ndash1061 2009
[161] E Gebara S Sultan J Kocher-Braissant and N Toni ldquoAdulthippocampal neurogenesis inversely correlates with microgliain conditions of voluntary running and agingrdquo Frontiers inNeuroscience vol 7 article 145 2013
[162] R Aharoni B Kayhan R Eilam M Sela and R ArnonldquoGlatiramer acetate-specific T cells in the brain express T helper23 cytokines and brain-derived neurotrophic factor in siturdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 100 no 2 pp 14157ndash14162 2003
[163] C Rossi A Angelucci L Costantin et al ldquoBrain-derivedneurotrophic factor (BDNF) is required for the enhancementof hippocampal neurogenesis following environmental enrich-mentrdquo European Journal of Neuroscience vol 24 no 7 pp 1850ndash1856 2006
Neural Plasticity 9
neurogenesis [161] Even though EE is clearly a more com-plex environmental factor than voluntary running furtherresearch is necessary to disregard nonspecific or indirecteffects of genetic or antibody-based T cells depletion onmicroglia and other brain cell populations including rNSCsFor instance adoptive transfer of T helper cells treated withglatiramer acetate a synthetic analog of myelin basic protein(MBP) approved for the treatment of multiple sclerosis pro-duces a bystander effect on resident astrocytes and microgliaby increasing their expression of anti-inflammatory cytokinessuch as TGF120573 [162] Alternatively it has been suggested thatT cells may mediate an indirect effect on adult hippocampalneurogenesis by increasing the production of brain-derivedneurotrophic factor (BDNF) [157] which is involved in theproneurogenic actions of EE [163] Whether BDNF cancounteract the detrimental effects of T cell depletion on neu-rogenesis remains unknownOverall the roles ofmicroglia inEE and running-induced neurogenesis are unclear and haveto be addressed with more precise experimental designs Insummary surveillant microglia are part of the physical nichesurrounding the neural stem cells and newborn neurons ofthe mature hippocampus where they continuously phagocy-tose the excess of newborn cellsMicroglia were also linked tothe proneurogenic and anti-inflammatory effects of voluntaryrunning and EE but direct evidence is missing The overallcontribution of microglia to neurogenesis and learning andmemory in normal physiological conditions remains largelyunexplored at this early stage in the field
7 Conclusion
In light of these observations microglia are now emergingas important effector cells during normal brain developmentand functions including adult hippocampal neurogenesisMicroglia can exert a positive or negative influence onthe proliferation survival or differentiation of newborncells depending on the inflammatory context For instancemicroglia can compromise the neurogenic cascade duringchronic stress aging and neurodegenerative diseases bytheir release of proinflammatory cytokines such as IL-1120573IL-6 and TNF120572 A reduced fractalkine signalling betweenneurons and microglia could also be involved during normalaging However microglia are not necessarily the only celltype implicated because astrocytes endothelial cells mastcells perivascular and meningeal macrophages and to alesser extent neurons and invading peripheral immune cellscould further contribute by releasing proinflammatorymedi-ators
Additionally microglia were shown to phagocytose theexcess of newborn neurons undergoing apoptosis in thehippocampal neurogenic niche during normal physiologicalconditions while a similar role in the synaptic integrationof newborn cells was also proposed in light of their capacityto phagocytose synaptic elements Lastly microglial interac-tions with T cells leading to the release of anti-inflammatorycytokines neurotrophic factors and other proneurogenicmediators (notably during EE and voluntary running) couldcounteract the detrimental effects of inflammation on adult
hippocampal neurogenesis and their functional implicationsfor learning and memory
However further research is necessary to assess the rela-tive contribution of microglia versus other types of residentand infiltrating inflammatory cells and to determine thenature of the effector cytokines and other inflammatorymediators involved as well as their cellular andmolecular tar-gets in the neurogenic cascade Such research will undoubt-edly help to develop novel strategies aiming at protecting theneurogenic potential and ultimately its essential contributionto learning and memory
The authors declare that there is no conflict of interestsregarding the publication of this paper
Acknowledgments
This work was supported by grants from the Spanish Min-istry of Economy and Competitiveness to Amanda Sierra(BFU2012-32089) and Juan M Encinas (SAF2012-40085)from Basque Government (Saiotek S-PC 12UN014) and Iker-basque start-up funds to JuanM Encinas andAmanda Sierraand fromTheBanting Research Foundation the Scottish RiteCharitable Foundation of Canada and start-up funds fromUniversite Laval andCentre de recherche duCHUdeQuebecto Marie-Eve Tremblay
References
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production of interleukin-10 in vitrordquo Clinical and DiagnosticLaboratory Immunology vol 2 no 5 pp 604ndash608 1995
[44] G LMing andH Song ldquoAdult neurogenesis in themammalianbrain significant answers and significant questionsrdquo Neuronvol 70 no 4 pp 687ndash702 2011
[45] E Bruel-Jungerman S Davis C Rampon and S LarocheldquoLong-term potentiation enhances neurogenesis in the adultdentate gyrusrdquo Journal of Neuroscience vol 26 no 22 pp 5888ndash5893 2006
[46] E Drapeau M F Montaron S Aguerre and D N AbrousldquoLearning-induced survival of new neurons depends on thecognitive status of aged ratsrdquo Journal of Neuroscience vol 27no 22 pp 6037ndash6044 2007
[47] A Mouret G Gheusi M M Gabellec F De Chaumont J COlivo-Marin and P M Lledo ldquoLearning and survival of newlygenerated neurons when timemattersrdquo Journal of Neurosciencevol 28 no 45 pp 11511ndash11516 2008
[48] N Kee C M Teixeira A H Wang and P W FranklandldquoPreferential incorporation of adult-generated granule cellsinto spatial memory networks in the dentate gyrusrdquo NatureNeuroscience vol 10 no 3 pp 355ndash362 2007
[49] F Massa M Koelh T Wiesner et al ldquoConditional reduction ofadult neurogenesis impairs bidirectional hippocampal synapticplasticityrdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 108 no 16 pp 6644ndash6649 2011
[50] T J Shors G Miesegaes A Beylin M Zhao T Rydel and EGould ldquoNeurogenesis in the adult is involved in the formationof tracememoriesrdquoNature vol 410 no 6826 pp 372ndash376 2001
[51] W Deng M D Saxe I S Gallina and F H Gage ldquoAdult-born hippocampal dentate granule cells undergoingmaturationmodulate learning and memory in the brainrdquo Journal of Neuro-science vol 29 no 43 pp 13532ndash13542 2009
[52] M Arruda-Carvalho M Sakaguchi K G Akers S A Josselynand P W Frankland ldquoPosttraining ablation of adult-generatedneurons degrades previously acquired memoriesrdquo Journal ofNeuroscience vol 31 no 42 pp 15113ndash15127 2011
[53] A Sahay K N Scobie A S Hill et al ldquoIncreasing adulthippocampal neurogenesis is sufficient to improve patternseparationrdquo Nature vol 472 no 7344 pp 466ndash470 2011
[54] G LMing andH Song ldquoAdult neurogenesis in themammaliancentral nervous systemrdquoAnnual Review of Neuroscience vol 28pp 223ndash250 2005
[55] K Newton and V M Dixit ldquoSignaling in innate immunity andinflammationrdquo Cold Spring Harbor Perspectives in Biology vol4 no 3 2012
[56] H K Jeong K Ji K Min and E H Joe ldquoBrain inflammationand microglia facts and misconceptionsrdquo Experimental Neuro-biology vol 22 no 2 pp 59ndash67 2013
[57] D Stellwagen and R CMalenka ldquoSynaptic scalingmediated byglial TNF-120572rdquo Nature vol 440 no 7087 pp 1054ndash1059 2006
[58] M Pickering D Cumiskey and J J OrsquoConnor ldquoActions of TNF-120572 on glutamatergic synaptic transmission in the central nervoussystemrdquo Experimental Physiology vol 90 no 5 pp 663ndash6702005
[59] K Belarbi T Jopson D Tweedie et al ldquoTNF-120572 protein synthe-sis inhibitor restores neuronal function and reverses cognitivedeficits induced by chronic neuroinflammationrdquo Journal ofNeuroinflammation vol 9 article 23 2012
[60] C T Ekdahl J H Claasen S Bonde Z Kokaia andO LindvallldquoInflammation is detrimental for neurogenesis in adult brainrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 100 no 23 pp 13632ndash13637 2003
12 Neural Plasticity
[61] M L Monje H Toda and T D Palmer ldquoInflammatoryblockade restores adult hippocampal neurogenesisrdquo Sciencevol 302 no 5651 pp 1760ndash1765 2003
[62] A Sierra J M Encinas J J P Deudero et al ldquoMicroglia shapeadult hippocampal neurogenesis through apoptosis-coupledphagocytosisrdquo Cell Stem Cell vol 7 no 4 pp 483ndash495 2010
[63] D Chugh P Nilsson S A Afjei A Bakochi and C T EkdahlldquoBrain inflammation induces post-synaptic changes duringearly synapse formation in adult-born hippocampal neuronsrdquoExperimental Neurobiology vol 250 pp 176ndash188 2013
[64] K Belarbi C Arellano R Ferguson T Jopson and S RosildquoChronic neuroinflammation impacts the recruitment of adult-born neurons into behaviorally relevant hippocampal net-worksrdquo Brain Behavior and Immunity vol 26 no 1 pp 18ndash232012
[65] S Johann E Kampmann B Denecke et al ldquoExpression ofenzymes involved in the prostanoid metabolism by corticalastrocytes after LPS-induced inflammationrdquo Journal of Molec-ular Neuroscience vol 34 no 2 pp 177ndash185 2008
[66] P V B Reddy K V Rama Rao and M D NorenbergldquoInhibitors of the mitochondrial permeability transition reduceammonia-induced cell swelling in cultured astrocytesrdquo Journalof Neuroscience Research vol 87 no 12 pp 2677ndash2685 2009
[67] H Nie H Zhang and H R Weng ldquoMinocycline preventsimpaired glial glutamate uptake in the spinal sensory synapsesof neuropathic ratsrdquo Neuroscience vol 170 no 3 pp 901ndash9122010
[68] F Cerbai D Lana D Nosi et al ldquoThe neuron-astrocyte-microglia triad in normal brain ageing and in a model ofneuroinflammation in the rat hippocampusrdquo PLoS ONE vol 7no 9 Article ID e45250 2012
[69] W J Jin S W Feng Z Feng S M Lu T Qi and Y N QianldquoMinocycline improves postoperative cognitive impairment inaged mice by inhibiting astrocytic activationrdquo NeuroReport2013
[70] K A Ji M S Yang H K Jeong et al ldquoResident microgliadie and infiltrated neutrophils and monocytes become majorinflammatory cells in lipopolysaccharide-injected brainrdquoGLIAvol 55 no 15 pp 1577ndash1588 2007
[71] N J van Wagoner J W Oh P Repovic and E N BenvenisteldquoInterleukin-6 (IL-6) production by astrocytes autocrine reg-ulation by IL-6 and the soluble IL-6 receptorrdquo Journal ofNeuroscience vol 19 no 13 pp 5236ndash5244 1999
[72] L Vallieres I L Campbell F H Gage and P E SawchenkoldquoReduced hippocampal neurogenesis in adult transgenic micewith chronic astrocytic production of interleukin-6rdquo Journal ofNeuroscience vol 22 no 2 pp 486ndash492 2002
[73] B S McEwen ldquoPhysiology and neurobiology of stress andadaptation central role of the brainrdquo Physiological Reviews vol87 no 3 pp 873ndash904 2007
[74] V LuineMVillegas CMartinez and B SMcEwen ldquoRepeatedstress causes reversible impairments of spatial memory perfor-mancerdquo Brain Research vol 639 no 1 pp 167ndash170 1994
[75] S Rivest ldquoMolecular insights on the cerebral innate immunesystemrdquo Brain Behavior and Immunity vol 17 no 1 pp 13ndash192003
[76] S Nadeau and S Rivest ldquoEndotoxemia prevents the cerebralinflammatory wave induced by intraparenchymal lipopolysac-charide injection role of glucocorticoids and CD14rdquo Journal ofImmunology vol 169 no 6 pp 3370ndash3381 2002
[77] A Sierra A Gottfried-Blackmore T A Milner B S McEwenand K Bulloch ldquoSteroid hormone receptor expression andfunction in microgliardquo GLIA vol 56 no 6 pp 659ndash674 2008
[78] C Liston andW B Gan ldquoGlucocorticoids are critical regulatorsof dendritic spine development and plasticity in vivordquo Proceed-ings of the National Academy of Sciences of the United States ofAmerica vol 108 no 38 pp 16074ndash16079 2011
[79] C Liston J M Cichon F Jeanneteau Z Jia M V Chaoand W B Gan ldquoCircadian glucocorticoid oscillations pro-mote learning-dependent synapse formation andmaintenancerdquoNature Neuroscience vol 16 no 6 pp 698ndash705 2013
[80] M A Carrillo-de Sauvage L Maatouk I Arnoux et al ldquoPotentand multiple regulatory actions of microglial glucocorticoidreceptors during CNS inflammationrdquo Cell Death amp Differenti-ation vol 20 no 11 pp 1546ndash1557 2013
[81] S F Sorrells J R Caso C DMunhoz and RM Sapolsky ldquoThestressed CNS when glucocorticoids aggravate inflammationrdquoNeuron vol 64 no 1 pp 33ndash39 2009
[82] M A Bellavance and S Rivest ldquoThe neuroendocrine controlof the innate immune system in health and brain diseasesrdquoImmunological Reviews vol 248 no 1 pp 36ndash55 2012
[83] R J Tynan S Naicker M Hinwood et al ldquoChronic stress altersthe density and morphology of microglia in a subset of stress-responsive brain regionsrdquo Brain Behavior and Immunity vol24 no 7 pp 1058ndash1068 2010
[84] E S Wohleb N D Powell J P Godbout and J F SheridanldquoStress-induced recruitment of bone marrow-derived mono-cytes to the brain promotes anxiety-like behaviorrdquo The Journalof Neuroscience vol 33 no 34 pp 13820ndash13833 2013
[85] Y Diz-Chaves M Astiz M J Bellini and L M Garcia-SeguraldquoPrenatal stress increases the expression of proinflammatorycytokines and exacerbates the inflammatory response to LPS inthe hippocampal formation of adultmalemicerdquoBrain Behaviorand Immunity vol 28 pp 196ndash206 2013
[86] E S Wohleb A M Fenn A M Pacenta N D Powell J FSheridan and J P Godbout ldquoPeripheral innate immune chal-lenge exaggerated microglia activation increased the numberof inflammatory CNSmacrophages and prolonged social with-drawal in socially defeated micerdquo Psychoneuroendocrinologyvol 37 no 9 pp 1491ndash1505 2012
[87] C Mirescu and E Gould ldquoStress and adult neurogenesisrdquoHippocampus vol 16 no 3 pp 233ndash238 2006
[88] J LWarner-Schmidt andR SDuman ldquoHippocampal neuroge-nesis opposing effects of stress and antidepressant treatmentrdquoHippocampus vol 16 no 3 pp 239ndash249 2006
[89] N D Hanson M J Owens K A Boss-Williams J M Weissand C B Nemeroff ldquoSeveral stressors fail to reduce adulthippocampal neurogenesisrdquo Psychoneuroendocrinology vol 36no 10 pp 1520ndash1529 2011
[90] E Gould B S McEwen P Tanapat L A M Galea and EFuchs ldquoNeurogenesis in the dentate gyrus of the adult treeshrew is regulated by psychosocial stress and NMDA receptoractivationrdquo Journal of Neuroscience vol 17 no 7 pp 2492ndash24981997
[91] JW Koo andR S Duman ldquoIL-1120573 is an essentialmediator of theantineurogenic and anhedonic effects of stressrdquo Proceedings ofthe National Academy of Sciences of the United States of Americavol 105 no 2 pp 751ndash756 2008
[92] D C Lagace M H Donovan N A Decarolis et al ldquoAdulthippocampal neurogenesis is functionally important for stress-induced social avoidancerdquo Proceedings of the National Academy
Neural Plasticity 13
of Sciences of the United States of America vol 107 no 9 pp4436ndash4441 2010
[93] G Kronenberg I Kirste D Inta et al ldquoReduced hippocampalneurogenesis in the GR+- genetic mousemodel of depressionrdquoEuropean Archives of Psychiatry and Clinical Neuroscience vol259 no 8 pp 499ndash504 2009
[94] M B Howren D M Lamkin and J Suls ldquoAssociations ofdepression with c-reactive protein IL-1 and IL-6 a meta-analysisrdquo Psychosomatic Medicine vol 71 no 2 pp 171ndash1862009
[95] J W Koo S J Russo D Ferguson E J Nestler and R SDuman ldquoNuclear factor-120581B is a critical mediator of stress-impaired neurogenesis and depressive behaviorrdquo Proceedings ofthe National Academy of Sciences of the United States of Americavol 107 no 6 pp 2669ndash2674 2010
[96] I Goshen T Kreisel O Ben-Menachem-Zidon et al ldquoBraininterleukin-1 mediates chronic stress-induced depression inmice via adrenocortical activation and hippocampal neuroge-nesis suppressionrdquo Molecular Psychiatry vol 13 no 7 pp 717ndash728 2008
[97] C D Munhoz L B Lepsch E M Kawamoto et al ldquoChronicunpredictable stress exacerbates lipopolysaccharide-inducedactivation of nuclear factor-120581B in the frontal cortex andhippocampus via glucocorticoid secretionrdquo Journal of Neuro-science vol 26 no 14 pp 3813ndash3820 2006
[98] S J Sukoff Rizzo S J Neal Z A Hughes et al ldquoEvidence forsustained elevation of IL-6 in the CNS as a key contributorof depressive-like phenotypesrdquo Translational Psychiatry vol 2article e199 2012
[99] A Garcia B Steiner G Kronenberg A Bick-Sander and GKempermann ldquoAge-dependent expression of glucocorticoid-andmineralocorticoid receptors on neural precursor cell popu-lations in the adult murine hippocampusrdquoAging Cell vol 3 no6 pp 363ndash371 2004
[100] M G Frank B M Thompson L R Watkins and S F MaierldquoGlucocorticoids mediate stress-induced priming of microglialpro-inflammatory responsesrdquo Brain Behavior and Immunityvol 26 no 2 pp 337ndash345 2012
[101] S Sugama M Fujita M Hashimoto and B Conti ldquoStressinduced morphological microglial activation in the rodentbrain involvement of interleukin-18rdquoNeuroscience vol 146 no3 pp 1388ndash1399 2007
[102] A Sierra J M Encinas and M Maletic-Savatic ldquoAdult humanneurogenesis from microscopy to magnetic resonance imag-ingrdquo Frontiers in Neuroscience vol 5 article 47 2011
[103] H G Kuhn H Dickinson-Anson and F H Gage ldquoNeurogen-esis in the dentate gyrus of the adult rat age-related decrease ofneuronal progenitor proliferationrdquo Journal of Neuroscience vol16 no 6 pp 2027ndash2033 1996
[104] L N Manganas X Zhang Y Li et al ldquoMagnetic resonancespectroscopy identifies neural progenitor cells in the live humanbrainrdquo Science vol 318 no 5852 pp 980ndash985 2007
[105] K L Spalding O Bergmann K Alkass et al ldquoDynamics ofhippocampal neurogenesis in adult humansrdquo Cell vol 153 no6 pp 1219ndash1227 2013
[106] J M Encinas and A Sierra ldquoNeural stem cell deforestationas the main force driving the age-related decline in adulthippocampal neurogenesisrdquo Behavioural Brain Research vol227 no 2 pp 433ndash439 2012
[107] K S Krabbe M Pedersen andH Bruunsgaard ldquoInflammatorymediators in the elderlyrdquo Experimental Gerontology vol 39 no5 pp 687ndash699 2004
[108] B S Diniz A L Teixeira L Talib W F Gattaz andO V Forlenza ldquoInterleukin-1120573 serum levels is increased inantidepressant-free elderly depressed patientsrdquo American Jour-nal of Geriatric Psychiatry vol 18 no 2 pp 172ndash176 2010
[109] A Sierra A C Gottfried-Blackmore B S Mcewen and KBulloch ldquoMicroglia derived from aging mice exhibit an alteredinflammatory profilerdquo GLIA vol 55 no 4 pp 412ndash424 2007
[110] C FranceschiM Bonafe S Valensin et al ldquoInflamm-aging Anevolutionary perspective on immunosenescencerdquo Annals of theNew York Academy of Sciences vol 908 pp 244ndash254 2000
[111] R Sano and J C Reed ldquoER stress-induced cell death mecha-nismsrdquoBiochimica et BiophysicaActa vol 1833 no 12 pp 3460ndash3470 2013
[112] S Z Hasnain R Lourie I Das A C H Chen and MA McGuckin ldquoThe interplay between endoplasmic reticulumstress and inflammationrdquo Immunology and Cell Biology vol 90no 3 pp 260ndash270 2012
[113] S Matus L H Glimcher and C Hetz ldquoProtein folding stressin neurodegenerative diseases a glimpse into the ERrdquo CurrentOpinion in Cell Biology vol 23 no 2 pp 239ndash252 2011
[114] Y Ito M Yamada H Tanaka et al ldquoInvolvement of CHOP anER-stress apoptotic mediator in both human sporadic ALS andALS model micerdquo Neurobiology of Disease vol 36 no 3 pp470ndash476 2009
[115] D Papadimitriou V Le Verche A Jacquier B Ikiz S Przed-borski and D B Re ldquoInflammation in ALS and SMA sortingout the good from the evilrdquo Neurobiology of Disease vol 37 no3 pp 493ndash502 2010
[116] A R Johnson J J Milner and LMakowski ldquoThe inflammationhighway metabolism accelerates inflammatory traffic in obe-sityrdquo Immunological Reviews vol 249 no 1 pp 218ndash238 2012
[117] S Buch H Yao M Guo et al ldquoCocaine and HIV-1 interplayin CNS cellular and molecular mechanismsrdquo Current HIVResearch vol 10 no 5 pp 425ndash428 2012
[118] M K Brown and N Naidoo ldquoThe endoplasmic reticulumstress response in aging and age-related diseasesrdquo Frontiers inPhysiology vol 3 article 263 2012
[119] G Castro C Areias MF L Weissmann et al ldquoDiet-inducedobesity induces endoplasmic reticulum stress and insulin resis-tance in the amygdala of ratsrdquo FEBS Open Bio vol 3 pp 443ndash449 2013
[120] A A Pavlovsky D Boehning D Li Y Zhang X Fan andT A Green ldquoPsychological stress cocaine and natural rewardeach induce endoplasmic reticulum stress genes in rat brainrdquoNeuroscience vol 246 pp 160ndash169 2013
[121] G GargiuloM CesaroniM Serresi et al ldquoIn vivo RNAi screenfor BMI1 targets identifies TGF-betaBMP-ER stress pathwaysas key regulators of neural- and malignant glioma-stem cellhomeostasisrdquo Cancer Cell vol 23 no 5 pp 660ndash676 2013
[122] A Salminen K Kaarniranta and A Kauppinen ldquoInflammag-ing disturbed interplay between autophagy and inflamma-somesrdquo Aging vol 4 no 3 pp 166ndash175 2012
[123] E Latz T S Xiao andA Stutz ldquoActivation and regulation of theinflammasomesrdquoNature Reviews Immunology vol 13 no 6 pp397ndash411 2013
[124] C Gemma A D Bachstetter M J Cole M Fister C Hudsonand P C Bickford ldquoBlockade of caspase-1 increases neurogene-sis in the aged hippocampusrdquo European Journal of Neurosciencevol 26 no 10 pp 2795ndash2803 2007
[125] M D Wu A M Hein M J Moravan S S Shaftel J AOlschowka and M K OrsquoBanion ldquoAdult murine hippocampal
14 Neural Plasticity
neurogenesis is inhibited by sustained IL-1120573 and not rescued byvoluntary runningrdquo Brain Behavior and Immunity vol 26 no2 pp 292ndash300 2012
[126] Y Wolf S Yona K W Kim and S Jung ldquoMicroglia seen fromthe CX3CR1 anglerdquo Frontiers in Cellular Neuroscience vol 7article 26 2013
[127] A E Cardona E P Pioro M E Sasse et al ldquoControl ofmicroglial neurotoxicity by the fractalkine receptorrdquo NatureNeuroscience vol 9 no 7 pp 917ndash924 2006
[128] K Bhaskar M Konerth O N Kokiko-Cochran A Cardona RM Ransohoff and B T Lamb ldquoRegulation of tau pathology bythe microglial fractalkine receptorrdquo Neuron vol 68 no 1 pp19ndash31 2010
[129] A D Bachstetter J M Morganti J Jernberg et al ldquoFractalkineand CX3CR1 regulate hippocampal neurogenesis in adult andaged ratsrdquo Neurobiology of Aging vol 32 no 11 pp 2030ndash20442011
[130] S Jung J Aliberti P Graemmel et al ldquoAnalysis of fractalkinereceptor CX3CR1 function by targeted deletion and greenfluorescent protein reporter gene insertionrdquo Molecular andCellular Biology vol 20 no 11 pp 4106ndash4114 2000
[131] J T Rogers J M Morganti A D Bachstetter et al ldquoCX3CR1deficiency leads to impairment of hippocampal cognitive func-tion and synaptic plasticityrdquo Journal of Neuroscience vol 31 no45 pp 16241ndash16250 2011
[132] W S T Griffin L C Stanley C Ling et al ldquoBrain interleukin1 and S-100 immunoreactivity are elevated in Down syndromeand Alzheimer diseaserdquo Proceedings of the National Academy ofSciences of the United States of America vol 86 no 19 pp 7611ndash7615 1989
[133] W C Benzing J RWujek E KWard et al ldquoEvidence for glial-mediated inflammation in aged APP(SW) transgenic micerdquoNeurobiology of Aging vol 20 no 6 pp 581ndash589 1999
[134] T J Seabrook L Jiang M Maier and C A Lemere ldquoMinocy-cline affects microglia activation A120573 deposition and behaviorin APP-tg micerdquo GLIA vol 53 no 7 pp 776ndash782 2006
[135] B Biscaro O Lindvall G Tesco C T Ekdahl and RM NitschldquoInhibition of microglial activation protects hippocampal neu-rogenesis and improves cognitive deficits in a transgenic mousemodel for Alzheimerrsquos diseaserdquoNeurodegenerative Diseases vol9 no 4 pp 187ndash198 2012
[136] P A Zunszain C Anacker A Cattaneo et al ldquoInterleukin-1120573a new regulator of the kynurenine pathway affecting humanhippocampal neurogenesisrdquo Neuropsychopharmacology vol 37no 4 pp 939ndash949 2012
[137] R De Simone M Antonietta Ajmone-Cat P Tirassa and LMinghetti ldquoApoptotic PC12 cells exposing phosphatidylserinepromote the production of anti-inflammatory and neuropro-tective molecules bymicroglial cellsrdquo Journal of Neuropathologyand Experimental Neurology vol 62 no 2 pp 208ndash216 2003
[138] M S Buckwalter M Yamane B S Coleman et al ldquoChroni-cally increased transforming growth factor-1205731 strongly inhibitshippocampal neurogenesis in aged micerdquo American Journal ofPathology vol 169 no 1 pp 154ndash164 2006
[139] O Butovsky Y Ziv A Schwartz et al ldquoMicroglia activatedby IL-4 or IFN-120574 differentially induce neurogenesis and oligo-dendrogenesis from adult stemprogenitor cellsrdquoMolecular andCellular Neuroscience vol 31 no 1 pp 149ndash160 2006
[140] C T Ekdahl ldquoMicroglial activationmdashtuning and pruning adultneurogenesisrdquo Frontiers in Pharmacology vol 3 article 41 2012
[141] HWakeA JMoorhouse S Jinno S Kohsaka and JNabekuraldquoResting microglia directly monitor the functional state ofsynapses in vivo and determine the fate of ischemic terminalsrdquoJournal of Neuroscience vol 29 no 13 pp 3974ndash3980 2009
[142] M E Tremblay R L Lowery and A K Majewska ldquoMicroglialinteractions with synapses are modulated by visual experiencerdquoPLoS Biology vol 8 no 11 Article ID e1000527 2010
[143] M E Tremblay M L Zettel J R Ison P D Allen and A KMajewska ldquoEffects of aging and sensory loss on glial cells inmouse visual and auditory corticesrdquo GLIA vol 60 no 4 pp541ndash558 2012
[144] D P Schafer E K Lehrman A G Kautzman et al ldquoMicrogliasculpt postnatal neural circuits in an activity and complement-dependent mannerrdquo Neuron vol 74 no 4 pp 691ndash705 2012
[145] H Nakanishi ldquoMicroglial functions and proteasesrdquo MolecularNeurobiology vol 27 no 2 pp 163ndash176 2003
[146] M E Tremblay and A K Majewska ldquoA role for microglia insynaptic plasticityrdquoCommunicative and Integrative Biology vol4 no 2 pp 220ndash222 2011
[147] R C Paolicelli G Bolasco F Pagani et al ldquoSynaptic pruning bymicroglia is necessary for normal brain developmentrdquo Sciencevol 333 no 6048 pp 1456ndash1458 2011
[148] GKempermannHGKuhn and FHGage ldquoMore hippocam-pal neurons in adult mice living in an enriched environmentrdquoNature vol 386 no 6624 pp 493ndash495 1997
[149] M Nilsson E Perfilieva U Johansson O Orwar and P SEriksson ldquoEnriched environment increases neurogenesis in theadult rat dentate gyrus and improves spatial memoryrdquo Journalof Neurobiology vol 39 no 4 pp 569ndash578 1999
[150] H van Praag G Kempermann and F H Gage ldquoRunningincreases cell proliferation and neurogenesis in the adult mousedentate gyrusrdquo Nature Neuroscience vol 2 no 3 pp 266ndash2701999
[151] D Young P A Lawlor P Leone M Dragunow and MJ During ldquoEnvironmental enrichment inhibits spontaneousapoptosis prevents seizures and is neuroprotectiverdquo NatureMedicine vol 5 no 4 pp 448ndash453 1999
[152] L L Williamson A Chao and S D Bilbo ldquoEnvironmentalenrichment alters glial antigen expression and neuroimmunefunction in the adult rat hippocampusrdquo Brain Behavior andImmunity vol 26 no 3 pp 500ndash510 2012
[153] L Maggi M Scianni I Branchi I DrsquoAndrea C Lauro and CLimatola ldquoCX(3)CR1 deficiency alters hippocampal-dependentplasticity phenomena blunting the effects of enriched environ-mentrdquo Frontiers in Cellular Neuroscience vol 5 article 22 2011
[154] I Goshen A Avital T Kreisel T Licht M Segal and RYirmiya ldquoEnvironmental enrichment restores memory func-tioning in mice with impaired IL-1 signaling via reinstatementof long-term potentiation and spine size enlargementrdquo Journalof Neuroscience vol 29 no 11 pp 3395ndash3403 2009
[155] Y Ziv N Ron O Butovsky et al ldquoImmune cells contribute tothe maintenance of neurogenesis and spatial learning abilitiesin adulthoodrdquo Nature Neuroscience vol 9 no 2 pp 268ndash2752006
[156] J Kipnis H Cohen M Cardon Y Ziv and M Schwartz ldquoTcell deficiency leads to cognitive dysfunction implications fortherapeutic vaccination for schizophrenia and other psychiatricconditionsrdquo Proceedings of the National Academy of Sciences ofthe United States of America vol 101 no 21 pp 8180ndash8185 2004
[157] S A Wolf B Steiner A Akpinarli et al ldquoCD4-positive Tlymphocytes provide a neuroimmunological link in the control
Neural Plasticity 15
of adult hippocampal neurogenesisrdquo Journal of Immunologyvol 182 no 7 pp 3979ndash3984 2009
[158] G J Huang A L Smith D H D Gray et al ldquoA genetic andfunctional relationship between T cells and cellular prolifera-tion in the adult hippocampusrdquo PLOS Biology vol 8 no 12Article ID e1000561 2010
[159] R M Ransohoff and B Engelhardt ldquoThe anatomical andcellular basis of immune surveillance in the central nervoussystemrdquoNature Reviews Immunology vol 12 no 9 pp 623ndash6352012
[160] M Olah G Ping A H De Haas et al ldquoEnhanced hippocampalneurogenesis in the absence of microglia T cell interactionand microglia activation in the murine running wheel modelrdquoGLIA vol 57 no 10 pp 1046ndash1061 2009
[161] E Gebara S Sultan J Kocher-Braissant and N Toni ldquoAdulthippocampal neurogenesis inversely correlates with microgliain conditions of voluntary running and agingrdquo Frontiers inNeuroscience vol 7 article 145 2013
[162] R Aharoni B Kayhan R Eilam M Sela and R ArnonldquoGlatiramer acetate-specific T cells in the brain express T helper23 cytokines and brain-derived neurotrophic factor in siturdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 100 no 2 pp 14157ndash14162 2003
[163] C Rossi A Angelucci L Costantin et al ldquoBrain-derivedneurotrophic factor (BDNF) is required for the enhancementof hippocampal neurogenesis following environmental enrich-mentrdquo European Journal of Neuroscience vol 24 no 7 pp 1850ndash1856 2006
The authors declare that there is no conflict of interestsregarding the publication of this paper
Acknowledgments
This work was supported by grants from the Spanish Min-istry of Economy and Competitiveness to Amanda Sierra(BFU2012-32089) and Juan M Encinas (SAF2012-40085)from Basque Government (Saiotek S-PC 12UN014) and Iker-basque start-up funds to JuanM Encinas andAmanda Sierraand fromTheBanting Research Foundation the Scottish RiteCharitable Foundation of Canada and start-up funds fromUniversite Laval andCentre de recherche duCHUdeQuebecto Marie-Eve Tremblay
References
[1] P Rezaie and D Male ldquoMesoglia and microgliamdasha historicalreview of the concept of mononuclear phagocytes within thecentral nervous systemrdquo Journal of the History of the Neuro-sciences vol 11 no 4 pp 325ndash374 2002
[2] F Ginhoux S Lim G Hoeffel D Low and T Huber ldquoOriginand differentiation of microgliardquo Frontiers in Cellular Neuro-science vol 7 article 45 2013
[3] E Gomez Perdiguero C Schulz and F Geissmann ldquoDevelop-ment and homeostasis of ldquoresidentrdquomyeloid cells the case of themicrogliardquo GLIA vol 61 no 1 pp 112ndash120 2013
[4] H Kettenmann F Kirchhoff and A Verkhratsky ldquoMicroglianew roles for the synaptic stripperrdquo Neuron vol 77 no 1 pp10ndash18 2013
[5] A Aguzzi B A Barres and M L Bennett ldquoMicroglia scape-goat saboteur or something elserdquo Science vol 339 no 6116 pp156ndash161 2013
[6] K Helmut U K Hanisch M Noda and A VerkhratskyldquoPhysiology of microgliardquo Physiological Reviews vol 91 no 2pp 461ndash553 2011
[7] M E Tremblay B Stevens A Sierra H Wake A Bessis andA Nimmerjahn ldquoThe role of microglia in the healthy brainrdquoJournal of Neuroscience vol 31 no 45 pp 16064ndash16069 2011
[8] A Miyamoto H Wake A J Moorhouse and J NabekuraldquoMicroglia and synapse interactions fine tuaning neural circuitsand candidate moleculesrdquo Frontiers in Cellular Neurosciencevol 7 article 70 2013
[9] C Bechade Y Cantaut-Belarif and A Bessis ldquoMicroglialcontrol of neuronal activityrdquo Frontiers in Cellular Neurosciencevol 7 article 32 2013
[10] A Sierra O Abiega A Shahraz and H Neumann ldquoJanus-faced microglia beneficial and detrimental consequences ofmicroglial phagocytosisrdquo Frontiers in Cellular Neuroscience vol7 article 6 2013
[11] G Kempermann S Jessberger B Steiner and G KronenbergldquoMilestones of neuronal development in the adult hippocam-pusrdquo Trends in Neurosciences vol 27 no 8 pp 447ndash452 2004
[12] J M Encinas T V Michurina N Peunova et al ldquoDivision-coupled astrocytic differentiation and age-related depletion ofneural stem cells in the adult hippocampusrdquo Cell Stem Cell vol8 no 5 pp 566ndash579 2011
[13] M A Bonaguidi M A Wheeler J S Shapiro et al ldquoIn vivoclonal analysis reveals self-renewing and multipotent adultneural stem cell characteristicsrdquo Cell vol 145 no 7 pp 1142ndash1155 2011
[14] J J Breunig J I Arellano J D Macklis and P RakicldquoEverything that glitters isnrsquot gold a critical review of postnatalneural precursor analysesrdquo Cell Stem Cell vol 1 no 6 pp 612ndash627 2007
[15] L S Overstreet-Wadiche and G L Westbrook ldquoFunctionalmaturation of adult-generated granule cellsrdquoHippocampus vol16 no 3 pp 208ndash215 2006
[16] S Ge C H Yang K S Hsu G L Ming andH Song ldquoA criticalperiod for enhanced synaptic plasticity in newly generatedneurons of the adult brainrdquo Neuron vol 54 no 4 pp 559ndash5662007
[17] E Bruel-Jungerman C Rampon and S Laroche ldquoAdult hip-pocampal neurogenesis synaptic plasticity and memory factsand hypothesesrdquo Reviews in the Neurosciences vol 18 no 2 pp93ndash114 2007
[18] K Nakajima S Honda Y Tohyama Y Imai S Kohsaka andT Kurihara ldquoNeurotrophin secretion from cultured microgliardquoJournal of Neuroscience Research vol 65 no 4 pp 322ndash3312001
[19] M Krampert S R Chirasani F P Wachs et al ldquoSmad7regulates the adult neural stemprogenitor cell pool in a trans-forming growth factor 120573- and bone morphogenetic protein-independent mannerrdquo Molecular and Cellular Biology vol 30no 14 pp 3685ndash3694 2010
[20] K I Mosher R H Andres T Fukuhara et al ldquoNeural pro-genitor cells regulate microglia functions and activityrdquo NatureNeuroscience vol 15 no 11 pp 1485ndash1487 2012
[21] V Tropepe M Sibilia B G Ciruna J Rossant E F Wagnerand D van der Kooy ldquoDistinct neural stem cells proliferatein response to EGF and FGF in the developing mouse telen-cephalonrdquo Developmental Biology vol 208 no 1 pp 166ndash1881999
[22] S U Kim and J De Vellis ldquoMicroglia in health and diseaserdquoJournal of Neuroscience Research vol 81 no 3 pp 302ndash3132005
[23] B A Reynolds and R L Rietze ldquoNeural stem cells andneurospheresmdashre-evaluating the relationshiprdquoNatureMethodsvol 2 no 5 pp 333ndash336 2005
[24] K Satake Y Matsuyama M Kamiya et al ldquoUp-regulation ofglial cell line-derived neurotrophic factor (GDNF) followingtraumatic spinal cord injuryrdquo NeuroReport vol 11 no 17 pp3877ndash3881 2000
[25] Y M Yoo C J Lee and Y J Kim ldquoExogenous GDNF increasesthe migration of the neural stem cells with no protectionagainst kainic acid-induced excitotoxic cell death in ratsrdquo BrainResearch vol 1486 pp 27ndash38 2012
[26] J L Trejo E Carro and I Torres-Aleman ldquoCirculating insulin-like growth factor I mediates exercise-induced increases in thenumber of new neurons in the adult hippocampusrdquo Journal ofNeuroscience vol 21 no 5 pp 1628ndash1634 2001
Neural Plasticity 11
[27] K Striedinger and E Scemes ldquoInterleukin-1120573 affects calciumsignaling and in vitro cell migration of astrocyte progenitorsrdquoJournal of Neuroimmunology vol 196 no 1-2 pp 116ndash123 2008
[28] Y B Lee A Nagai and S U Kim ldquoCytokines chemokines andcytokine receptors in humanmicrogliardquo Journal of NeuroscienceResearch vol 69 no 1 pp 94ndash103 2002
[29] G Kempermann and H Neumann ldquoMicroglia the enemywithinrdquo Science vol 302 no 5651 pp 1689ndash1690 2003
[30] M F Mehler R Rozental M Dougherty D C Spray and JA Kessler ldquoCytokine regulation of neuronal differentiation ofhippocampal progenitor cellsrdquo Nature vol 362 no 6415 pp62ndash65 1993
[31] U Gurok C Steinhoff B Lipkowitz H H Ropers C Scharffand U A Nuber ldquoGene expression changes in the course ofneural progenitor cell differentiationrdquo Journal of Neurosciencevol 24 no 26 pp 5982ndash6002 2004
[32] J B Demoulin M Enarsson J Larsson A Essaghir C HHeldin and K Forsberg-Nilsson ldquoThe gene expression profileof PDGF-treated neural stem cells corresponds to partiallydifferentiated neurons and gliardquo Growth Factors vol 24 no 3pp 184ndash196 2006
[33] F C Mansergh M A Wride and D E Rancourt ldquoNeuronsfrom stem cells implications for understanding nervous systemdevelopment and repairrdquo Biochemistry and Cell Biology vol 78no 5 pp 613ndash628 2000
[34] F C Alcantara Gomes V De Oliveira Sousa and L RomaoldquoEmerging roles for TGF-1205731 in nervous system developmentrdquoInternational Journal of Developmental Neuroscience vol 23 no5 pp 413ndash424 2005
[35] S Elkabes E M DiCicco-Bloom and I B Black ldquoBrainmicrogliamacrophages express neurotrophins that selectivelyregulate microglial proliferation and functionrdquo Journal of Neu-roscience vol 16 no 8 pp 2508ndash2521 1996
[36] U K Hanisch and H Kettenmann ldquoMicroglia active sensorand versatile effector cells in the normal and pathologic brainrdquoNature Neuroscience vol 10 no 11 pp 1387ndash1394 2007
[37] H J Klassen T F Ng Y Kurimoto et al ldquoMultipotent retinalprogenitors express developmental markers differentiate intoretinal neurons and preserve light-mediated behaviorrdquo Inves-tigative Ophthalmology and Visual Science vol 45 no 11 pp4167ndash4173 2004
[38] W J Streit S D Hurley T S McGraw and S L Semple-Rowland ldquoComparative evaluation of cytokine profiles andreactive gliosis supports a critical role for interleukin-6 inneuron-glia signaling during regenerationrdquo Journal of Neuro-science Research vol 61 no 1 pp 10ndash20 2000
[39] A Suzumura M Sawada H Yamamoto and T MarunouchildquoEffects of colony stimulating factors on isolated microglia invitrordquo Journal of Neuroimmunology vol 30 no 2-3 pp 111ndash1201990
[40] Z Lu M R Elliott Y Chen et al ldquoPhagocytic activity ofneuronal progenitors regulates adult neurogenesisrdquoNature CellBiology vol 13 no 9 pp 1076ndash1084 2011
[41] K Nakajima Y Kikuchi E Ikoma et al ldquoNeurotrophinsregulate the function of cultured microgliardquo GLIA vol 24 no3 pp 272ndash289 1998
[42] P A Lodge and S Sriram ldquoRegulation of microglial activationby TGF-120573 IL-10 and CSF-1rdquo Journal of Leukocyte Biology vol60 no 4 pp 502ndash508 1996
[43] W S Sheng S Hu F H Kravitz P K Peterson and C C ChaoldquoTumor necrosis factor alpha upregulates humanmicroglial cell
production of interleukin-10 in vitrordquo Clinical and DiagnosticLaboratory Immunology vol 2 no 5 pp 604ndash608 1995
[44] G LMing andH Song ldquoAdult neurogenesis in themammalianbrain significant answers and significant questionsrdquo Neuronvol 70 no 4 pp 687ndash702 2011
[45] E Bruel-Jungerman S Davis C Rampon and S LarocheldquoLong-term potentiation enhances neurogenesis in the adultdentate gyrusrdquo Journal of Neuroscience vol 26 no 22 pp 5888ndash5893 2006
[46] E Drapeau M F Montaron S Aguerre and D N AbrousldquoLearning-induced survival of new neurons depends on thecognitive status of aged ratsrdquo Journal of Neuroscience vol 27no 22 pp 6037ndash6044 2007
[47] A Mouret G Gheusi M M Gabellec F De Chaumont J COlivo-Marin and P M Lledo ldquoLearning and survival of newlygenerated neurons when timemattersrdquo Journal of Neurosciencevol 28 no 45 pp 11511ndash11516 2008
[48] N Kee C M Teixeira A H Wang and P W FranklandldquoPreferential incorporation of adult-generated granule cellsinto spatial memory networks in the dentate gyrusrdquo NatureNeuroscience vol 10 no 3 pp 355ndash362 2007
[49] F Massa M Koelh T Wiesner et al ldquoConditional reduction ofadult neurogenesis impairs bidirectional hippocampal synapticplasticityrdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 108 no 16 pp 6644ndash6649 2011
[50] T J Shors G Miesegaes A Beylin M Zhao T Rydel and EGould ldquoNeurogenesis in the adult is involved in the formationof tracememoriesrdquoNature vol 410 no 6826 pp 372ndash376 2001
[51] W Deng M D Saxe I S Gallina and F H Gage ldquoAdult-born hippocampal dentate granule cells undergoingmaturationmodulate learning and memory in the brainrdquo Journal of Neuro-science vol 29 no 43 pp 13532ndash13542 2009
[52] M Arruda-Carvalho M Sakaguchi K G Akers S A Josselynand P W Frankland ldquoPosttraining ablation of adult-generatedneurons degrades previously acquired memoriesrdquo Journal ofNeuroscience vol 31 no 42 pp 15113ndash15127 2011
[53] A Sahay K N Scobie A S Hill et al ldquoIncreasing adulthippocampal neurogenesis is sufficient to improve patternseparationrdquo Nature vol 472 no 7344 pp 466ndash470 2011
[54] G LMing andH Song ldquoAdult neurogenesis in themammaliancentral nervous systemrdquoAnnual Review of Neuroscience vol 28pp 223ndash250 2005
[55] K Newton and V M Dixit ldquoSignaling in innate immunity andinflammationrdquo Cold Spring Harbor Perspectives in Biology vol4 no 3 2012
[56] H K Jeong K Ji K Min and E H Joe ldquoBrain inflammationand microglia facts and misconceptionsrdquo Experimental Neuro-biology vol 22 no 2 pp 59ndash67 2013
[57] D Stellwagen and R CMalenka ldquoSynaptic scalingmediated byglial TNF-120572rdquo Nature vol 440 no 7087 pp 1054ndash1059 2006
[58] M Pickering D Cumiskey and J J OrsquoConnor ldquoActions of TNF-120572 on glutamatergic synaptic transmission in the central nervoussystemrdquo Experimental Physiology vol 90 no 5 pp 663ndash6702005
[59] K Belarbi T Jopson D Tweedie et al ldquoTNF-120572 protein synthe-sis inhibitor restores neuronal function and reverses cognitivedeficits induced by chronic neuroinflammationrdquo Journal ofNeuroinflammation vol 9 article 23 2012
[60] C T Ekdahl J H Claasen S Bonde Z Kokaia andO LindvallldquoInflammation is detrimental for neurogenesis in adult brainrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 100 no 23 pp 13632ndash13637 2003
12 Neural Plasticity
[61] M L Monje H Toda and T D Palmer ldquoInflammatoryblockade restores adult hippocampal neurogenesisrdquo Sciencevol 302 no 5651 pp 1760ndash1765 2003
[62] A Sierra J M Encinas J J P Deudero et al ldquoMicroglia shapeadult hippocampal neurogenesis through apoptosis-coupledphagocytosisrdquo Cell Stem Cell vol 7 no 4 pp 483ndash495 2010
[63] D Chugh P Nilsson S A Afjei A Bakochi and C T EkdahlldquoBrain inflammation induces post-synaptic changes duringearly synapse formation in adult-born hippocampal neuronsrdquoExperimental Neurobiology vol 250 pp 176ndash188 2013
[64] K Belarbi C Arellano R Ferguson T Jopson and S RosildquoChronic neuroinflammation impacts the recruitment of adult-born neurons into behaviorally relevant hippocampal net-worksrdquo Brain Behavior and Immunity vol 26 no 1 pp 18ndash232012
[65] S Johann E Kampmann B Denecke et al ldquoExpression ofenzymes involved in the prostanoid metabolism by corticalastrocytes after LPS-induced inflammationrdquo Journal of Molec-ular Neuroscience vol 34 no 2 pp 177ndash185 2008
[66] P V B Reddy K V Rama Rao and M D NorenbergldquoInhibitors of the mitochondrial permeability transition reduceammonia-induced cell swelling in cultured astrocytesrdquo Journalof Neuroscience Research vol 87 no 12 pp 2677ndash2685 2009
[67] H Nie H Zhang and H R Weng ldquoMinocycline preventsimpaired glial glutamate uptake in the spinal sensory synapsesof neuropathic ratsrdquo Neuroscience vol 170 no 3 pp 901ndash9122010
[68] F Cerbai D Lana D Nosi et al ldquoThe neuron-astrocyte-microglia triad in normal brain ageing and in a model ofneuroinflammation in the rat hippocampusrdquo PLoS ONE vol 7no 9 Article ID e45250 2012
[69] W J Jin S W Feng Z Feng S M Lu T Qi and Y N QianldquoMinocycline improves postoperative cognitive impairment inaged mice by inhibiting astrocytic activationrdquo NeuroReport2013
[70] K A Ji M S Yang H K Jeong et al ldquoResident microgliadie and infiltrated neutrophils and monocytes become majorinflammatory cells in lipopolysaccharide-injected brainrdquoGLIAvol 55 no 15 pp 1577ndash1588 2007
[71] N J van Wagoner J W Oh P Repovic and E N BenvenisteldquoInterleukin-6 (IL-6) production by astrocytes autocrine reg-ulation by IL-6 and the soluble IL-6 receptorrdquo Journal ofNeuroscience vol 19 no 13 pp 5236ndash5244 1999
[72] L Vallieres I L Campbell F H Gage and P E SawchenkoldquoReduced hippocampal neurogenesis in adult transgenic micewith chronic astrocytic production of interleukin-6rdquo Journal ofNeuroscience vol 22 no 2 pp 486ndash492 2002
[73] B S McEwen ldquoPhysiology and neurobiology of stress andadaptation central role of the brainrdquo Physiological Reviews vol87 no 3 pp 873ndash904 2007
[74] V LuineMVillegas CMartinez and B SMcEwen ldquoRepeatedstress causes reversible impairments of spatial memory perfor-mancerdquo Brain Research vol 639 no 1 pp 167ndash170 1994
[75] S Rivest ldquoMolecular insights on the cerebral innate immunesystemrdquo Brain Behavior and Immunity vol 17 no 1 pp 13ndash192003
[76] S Nadeau and S Rivest ldquoEndotoxemia prevents the cerebralinflammatory wave induced by intraparenchymal lipopolysac-charide injection role of glucocorticoids and CD14rdquo Journal ofImmunology vol 169 no 6 pp 3370ndash3381 2002
[77] A Sierra A Gottfried-Blackmore T A Milner B S McEwenand K Bulloch ldquoSteroid hormone receptor expression andfunction in microgliardquo GLIA vol 56 no 6 pp 659ndash674 2008
[78] C Liston andW B Gan ldquoGlucocorticoids are critical regulatorsof dendritic spine development and plasticity in vivordquo Proceed-ings of the National Academy of Sciences of the United States ofAmerica vol 108 no 38 pp 16074ndash16079 2011
[79] C Liston J M Cichon F Jeanneteau Z Jia M V Chaoand W B Gan ldquoCircadian glucocorticoid oscillations pro-mote learning-dependent synapse formation andmaintenancerdquoNature Neuroscience vol 16 no 6 pp 698ndash705 2013
[80] M A Carrillo-de Sauvage L Maatouk I Arnoux et al ldquoPotentand multiple regulatory actions of microglial glucocorticoidreceptors during CNS inflammationrdquo Cell Death amp Differenti-ation vol 20 no 11 pp 1546ndash1557 2013
[81] S F Sorrells J R Caso C DMunhoz and RM Sapolsky ldquoThestressed CNS when glucocorticoids aggravate inflammationrdquoNeuron vol 64 no 1 pp 33ndash39 2009
[82] M A Bellavance and S Rivest ldquoThe neuroendocrine controlof the innate immune system in health and brain diseasesrdquoImmunological Reviews vol 248 no 1 pp 36ndash55 2012
[83] R J Tynan S Naicker M Hinwood et al ldquoChronic stress altersthe density and morphology of microglia in a subset of stress-responsive brain regionsrdquo Brain Behavior and Immunity vol24 no 7 pp 1058ndash1068 2010
[84] E S Wohleb N D Powell J P Godbout and J F SheridanldquoStress-induced recruitment of bone marrow-derived mono-cytes to the brain promotes anxiety-like behaviorrdquo The Journalof Neuroscience vol 33 no 34 pp 13820ndash13833 2013
[85] Y Diz-Chaves M Astiz M J Bellini and L M Garcia-SeguraldquoPrenatal stress increases the expression of proinflammatorycytokines and exacerbates the inflammatory response to LPS inthe hippocampal formation of adultmalemicerdquoBrain Behaviorand Immunity vol 28 pp 196ndash206 2013
[86] E S Wohleb A M Fenn A M Pacenta N D Powell J FSheridan and J P Godbout ldquoPeripheral innate immune chal-lenge exaggerated microglia activation increased the numberof inflammatory CNSmacrophages and prolonged social with-drawal in socially defeated micerdquo Psychoneuroendocrinologyvol 37 no 9 pp 1491ndash1505 2012
[87] C Mirescu and E Gould ldquoStress and adult neurogenesisrdquoHippocampus vol 16 no 3 pp 233ndash238 2006
[88] J LWarner-Schmidt andR SDuman ldquoHippocampal neuroge-nesis opposing effects of stress and antidepressant treatmentrdquoHippocampus vol 16 no 3 pp 239ndash249 2006
[89] N D Hanson M J Owens K A Boss-Williams J M Weissand C B Nemeroff ldquoSeveral stressors fail to reduce adulthippocampal neurogenesisrdquo Psychoneuroendocrinology vol 36no 10 pp 1520ndash1529 2011
[90] E Gould B S McEwen P Tanapat L A M Galea and EFuchs ldquoNeurogenesis in the dentate gyrus of the adult treeshrew is regulated by psychosocial stress and NMDA receptoractivationrdquo Journal of Neuroscience vol 17 no 7 pp 2492ndash24981997
[91] JW Koo andR S Duman ldquoIL-1120573 is an essentialmediator of theantineurogenic and anhedonic effects of stressrdquo Proceedings ofthe National Academy of Sciences of the United States of Americavol 105 no 2 pp 751ndash756 2008
[92] D C Lagace M H Donovan N A Decarolis et al ldquoAdulthippocampal neurogenesis is functionally important for stress-induced social avoidancerdquo Proceedings of the National Academy
Neural Plasticity 13
of Sciences of the United States of America vol 107 no 9 pp4436ndash4441 2010
[93] G Kronenberg I Kirste D Inta et al ldquoReduced hippocampalneurogenesis in the GR+- genetic mousemodel of depressionrdquoEuropean Archives of Psychiatry and Clinical Neuroscience vol259 no 8 pp 499ndash504 2009
[94] M B Howren D M Lamkin and J Suls ldquoAssociations ofdepression with c-reactive protein IL-1 and IL-6 a meta-analysisrdquo Psychosomatic Medicine vol 71 no 2 pp 171ndash1862009
[95] J W Koo S J Russo D Ferguson E J Nestler and R SDuman ldquoNuclear factor-120581B is a critical mediator of stress-impaired neurogenesis and depressive behaviorrdquo Proceedings ofthe National Academy of Sciences of the United States of Americavol 107 no 6 pp 2669ndash2674 2010
[96] I Goshen T Kreisel O Ben-Menachem-Zidon et al ldquoBraininterleukin-1 mediates chronic stress-induced depression inmice via adrenocortical activation and hippocampal neuroge-nesis suppressionrdquo Molecular Psychiatry vol 13 no 7 pp 717ndash728 2008
[97] C D Munhoz L B Lepsch E M Kawamoto et al ldquoChronicunpredictable stress exacerbates lipopolysaccharide-inducedactivation of nuclear factor-120581B in the frontal cortex andhippocampus via glucocorticoid secretionrdquo Journal of Neuro-science vol 26 no 14 pp 3813ndash3820 2006
[98] S J Sukoff Rizzo S J Neal Z A Hughes et al ldquoEvidence forsustained elevation of IL-6 in the CNS as a key contributorof depressive-like phenotypesrdquo Translational Psychiatry vol 2article e199 2012
[99] A Garcia B Steiner G Kronenberg A Bick-Sander and GKempermann ldquoAge-dependent expression of glucocorticoid-andmineralocorticoid receptors on neural precursor cell popu-lations in the adult murine hippocampusrdquoAging Cell vol 3 no6 pp 363ndash371 2004
[100] M G Frank B M Thompson L R Watkins and S F MaierldquoGlucocorticoids mediate stress-induced priming of microglialpro-inflammatory responsesrdquo Brain Behavior and Immunityvol 26 no 2 pp 337ndash345 2012
[101] S Sugama M Fujita M Hashimoto and B Conti ldquoStressinduced morphological microglial activation in the rodentbrain involvement of interleukin-18rdquoNeuroscience vol 146 no3 pp 1388ndash1399 2007
[102] A Sierra J M Encinas and M Maletic-Savatic ldquoAdult humanneurogenesis from microscopy to magnetic resonance imag-ingrdquo Frontiers in Neuroscience vol 5 article 47 2011
[103] H G Kuhn H Dickinson-Anson and F H Gage ldquoNeurogen-esis in the dentate gyrus of the adult rat age-related decrease ofneuronal progenitor proliferationrdquo Journal of Neuroscience vol16 no 6 pp 2027ndash2033 1996
[104] L N Manganas X Zhang Y Li et al ldquoMagnetic resonancespectroscopy identifies neural progenitor cells in the live humanbrainrdquo Science vol 318 no 5852 pp 980ndash985 2007
[105] K L Spalding O Bergmann K Alkass et al ldquoDynamics ofhippocampal neurogenesis in adult humansrdquo Cell vol 153 no6 pp 1219ndash1227 2013
[106] J M Encinas and A Sierra ldquoNeural stem cell deforestationas the main force driving the age-related decline in adulthippocampal neurogenesisrdquo Behavioural Brain Research vol227 no 2 pp 433ndash439 2012
[107] K S Krabbe M Pedersen andH Bruunsgaard ldquoInflammatorymediators in the elderlyrdquo Experimental Gerontology vol 39 no5 pp 687ndash699 2004
[108] B S Diniz A L Teixeira L Talib W F Gattaz andO V Forlenza ldquoInterleukin-1120573 serum levels is increased inantidepressant-free elderly depressed patientsrdquo American Jour-nal of Geriatric Psychiatry vol 18 no 2 pp 172ndash176 2010
[109] A Sierra A C Gottfried-Blackmore B S Mcewen and KBulloch ldquoMicroglia derived from aging mice exhibit an alteredinflammatory profilerdquo GLIA vol 55 no 4 pp 412ndash424 2007
[110] C FranceschiM Bonafe S Valensin et al ldquoInflamm-aging Anevolutionary perspective on immunosenescencerdquo Annals of theNew York Academy of Sciences vol 908 pp 244ndash254 2000
[111] R Sano and J C Reed ldquoER stress-induced cell death mecha-nismsrdquoBiochimica et BiophysicaActa vol 1833 no 12 pp 3460ndash3470 2013
[112] S Z Hasnain R Lourie I Das A C H Chen and MA McGuckin ldquoThe interplay between endoplasmic reticulumstress and inflammationrdquo Immunology and Cell Biology vol 90no 3 pp 260ndash270 2012
[113] S Matus L H Glimcher and C Hetz ldquoProtein folding stressin neurodegenerative diseases a glimpse into the ERrdquo CurrentOpinion in Cell Biology vol 23 no 2 pp 239ndash252 2011
[114] Y Ito M Yamada H Tanaka et al ldquoInvolvement of CHOP anER-stress apoptotic mediator in both human sporadic ALS andALS model micerdquo Neurobiology of Disease vol 36 no 3 pp470ndash476 2009
[115] D Papadimitriou V Le Verche A Jacquier B Ikiz S Przed-borski and D B Re ldquoInflammation in ALS and SMA sortingout the good from the evilrdquo Neurobiology of Disease vol 37 no3 pp 493ndash502 2010
[116] A R Johnson J J Milner and LMakowski ldquoThe inflammationhighway metabolism accelerates inflammatory traffic in obe-sityrdquo Immunological Reviews vol 249 no 1 pp 218ndash238 2012
[117] S Buch H Yao M Guo et al ldquoCocaine and HIV-1 interplayin CNS cellular and molecular mechanismsrdquo Current HIVResearch vol 10 no 5 pp 425ndash428 2012
[118] M K Brown and N Naidoo ldquoThe endoplasmic reticulumstress response in aging and age-related diseasesrdquo Frontiers inPhysiology vol 3 article 263 2012
[119] G Castro C Areias MF L Weissmann et al ldquoDiet-inducedobesity induces endoplasmic reticulum stress and insulin resis-tance in the amygdala of ratsrdquo FEBS Open Bio vol 3 pp 443ndash449 2013
[120] A A Pavlovsky D Boehning D Li Y Zhang X Fan andT A Green ldquoPsychological stress cocaine and natural rewardeach induce endoplasmic reticulum stress genes in rat brainrdquoNeuroscience vol 246 pp 160ndash169 2013
[121] G GargiuloM CesaroniM Serresi et al ldquoIn vivo RNAi screenfor BMI1 targets identifies TGF-betaBMP-ER stress pathwaysas key regulators of neural- and malignant glioma-stem cellhomeostasisrdquo Cancer Cell vol 23 no 5 pp 660ndash676 2013
[122] A Salminen K Kaarniranta and A Kauppinen ldquoInflammag-ing disturbed interplay between autophagy and inflamma-somesrdquo Aging vol 4 no 3 pp 166ndash175 2012
[123] E Latz T S Xiao andA Stutz ldquoActivation and regulation of theinflammasomesrdquoNature Reviews Immunology vol 13 no 6 pp397ndash411 2013
[124] C Gemma A D Bachstetter M J Cole M Fister C Hudsonand P C Bickford ldquoBlockade of caspase-1 increases neurogene-sis in the aged hippocampusrdquo European Journal of Neurosciencevol 26 no 10 pp 2795ndash2803 2007
[125] M D Wu A M Hein M J Moravan S S Shaftel J AOlschowka and M K OrsquoBanion ldquoAdult murine hippocampal
14 Neural Plasticity
neurogenesis is inhibited by sustained IL-1120573 and not rescued byvoluntary runningrdquo Brain Behavior and Immunity vol 26 no2 pp 292ndash300 2012
[126] Y Wolf S Yona K W Kim and S Jung ldquoMicroglia seen fromthe CX3CR1 anglerdquo Frontiers in Cellular Neuroscience vol 7article 26 2013
[127] A E Cardona E P Pioro M E Sasse et al ldquoControl ofmicroglial neurotoxicity by the fractalkine receptorrdquo NatureNeuroscience vol 9 no 7 pp 917ndash924 2006
[128] K Bhaskar M Konerth O N Kokiko-Cochran A Cardona RM Ransohoff and B T Lamb ldquoRegulation of tau pathology bythe microglial fractalkine receptorrdquo Neuron vol 68 no 1 pp19ndash31 2010
[129] A D Bachstetter J M Morganti J Jernberg et al ldquoFractalkineand CX3CR1 regulate hippocampal neurogenesis in adult andaged ratsrdquo Neurobiology of Aging vol 32 no 11 pp 2030ndash20442011
[130] S Jung J Aliberti P Graemmel et al ldquoAnalysis of fractalkinereceptor CX3CR1 function by targeted deletion and greenfluorescent protein reporter gene insertionrdquo Molecular andCellular Biology vol 20 no 11 pp 4106ndash4114 2000
[131] J T Rogers J M Morganti A D Bachstetter et al ldquoCX3CR1deficiency leads to impairment of hippocampal cognitive func-tion and synaptic plasticityrdquo Journal of Neuroscience vol 31 no45 pp 16241ndash16250 2011
[132] W S T Griffin L C Stanley C Ling et al ldquoBrain interleukin1 and S-100 immunoreactivity are elevated in Down syndromeand Alzheimer diseaserdquo Proceedings of the National Academy ofSciences of the United States of America vol 86 no 19 pp 7611ndash7615 1989
[133] W C Benzing J RWujek E KWard et al ldquoEvidence for glial-mediated inflammation in aged APP(SW) transgenic micerdquoNeurobiology of Aging vol 20 no 6 pp 581ndash589 1999
[134] T J Seabrook L Jiang M Maier and C A Lemere ldquoMinocy-cline affects microglia activation A120573 deposition and behaviorin APP-tg micerdquo GLIA vol 53 no 7 pp 776ndash782 2006
[135] B Biscaro O Lindvall G Tesco C T Ekdahl and RM NitschldquoInhibition of microglial activation protects hippocampal neu-rogenesis and improves cognitive deficits in a transgenic mousemodel for Alzheimerrsquos diseaserdquoNeurodegenerative Diseases vol9 no 4 pp 187ndash198 2012
[136] P A Zunszain C Anacker A Cattaneo et al ldquoInterleukin-1120573a new regulator of the kynurenine pathway affecting humanhippocampal neurogenesisrdquo Neuropsychopharmacology vol 37no 4 pp 939ndash949 2012
[137] R De Simone M Antonietta Ajmone-Cat P Tirassa and LMinghetti ldquoApoptotic PC12 cells exposing phosphatidylserinepromote the production of anti-inflammatory and neuropro-tective molecules bymicroglial cellsrdquo Journal of Neuropathologyand Experimental Neurology vol 62 no 2 pp 208ndash216 2003
[138] M S Buckwalter M Yamane B S Coleman et al ldquoChroni-cally increased transforming growth factor-1205731 strongly inhibitshippocampal neurogenesis in aged micerdquo American Journal ofPathology vol 169 no 1 pp 154ndash164 2006
[139] O Butovsky Y Ziv A Schwartz et al ldquoMicroglia activatedby IL-4 or IFN-120574 differentially induce neurogenesis and oligo-dendrogenesis from adult stemprogenitor cellsrdquoMolecular andCellular Neuroscience vol 31 no 1 pp 149ndash160 2006
[140] C T Ekdahl ldquoMicroglial activationmdashtuning and pruning adultneurogenesisrdquo Frontiers in Pharmacology vol 3 article 41 2012
[141] HWakeA JMoorhouse S Jinno S Kohsaka and JNabekuraldquoResting microglia directly monitor the functional state ofsynapses in vivo and determine the fate of ischemic terminalsrdquoJournal of Neuroscience vol 29 no 13 pp 3974ndash3980 2009
[142] M E Tremblay R L Lowery and A K Majewska ldquoMicroglialinteractions with synapses are modulated by visual experiencerdquoPLoS Biology vol 8 no 11 Article ID e1000527 2010
[143] M E Tremblay M L Zettel J R Ison P D Allen and A KMajewska ldquoEffects of aging and sensory loss on glial cells inmouse visual and auditory corticesrdquo GLIA vol 60 no 4 pp541ndash558 2012
[144] D P Schafer E K Lehrman A G Kautzman et al ldquoMicrogliasculpt postnatal neural circuits in an activity and complement-dependent mannerrdquo Neuron vol 74 no 4 pp 691ndash705 2012
[145] H Nakanishi ldquoMicroglial functions and proteasesrdquo MolecularNeurobiology vol 27 no 2 pp 163ndash176 2003
[146] M E Tremblay and A K Majewska ldquoA role for microglia insynaptic plasticityrdquoCommunicative and Integrative Biology vol4 no 2 pp 220ndash222 2011
[147] R C Paolicelli G Bolasco F Pagani et al ldquoSynaptic pruning bymicroglia is necessary for normal brain developmentrdquo Sciencevol 333 no 6048 pp 1456ndash1458 2011
[148] GKempermannHGKuhn and FHGage ldquoMore hippocam-pal neurons in adult mice living in an enriched environmentrdquoNature vol 386 no 6624 pp 493ndash495 1997
[149] M Nilsson E Perfilieva U Johansson O Orwar and P SEriksson ldquoEnriched environment increases neurogenesis in theadult rat dentate gyrus and improves spatial memoryrdquo Journalof Neurobiology vol 39 no 4 pp 569ndash578 1999
[150] H van Praag G Kempermann and F H Gage ldquoRunningincreases cell proliferation and neurogenesis in the adult mousedentate gyrusrdquo Nature Neuroscience vol 2 no 3 pp 266ndash2701999
[151] D Young P A Lawlor P Leone M Dragunow and MJ During ldquoEnvironmental enrichment inhibits spontaneousapoptosis prevents seizures and is neuroprotectiverdquo NatureMedicine vol 5 no 4 pp 448ndash453 1999
[152] L L Williamson A Chao and S D Bilbo ldquoEnvironmentalenrichment alters glial antigen expression and neuroimmunefunction in the adult rat hippocampusrdquo Brain Behavior andImmunity vol 26 no 3 pp 500ndash510 2012
[153] L Maggi M Scianni I Branchi I DrsquoAndrea C Lauro and CLimatola ldquoCX(3)CR1 deficiency alters hippocampal-dependentplasticity phenomena blunting the effects of enriched environ-mentrdquo Frontiers in Cellular Neuroscience vol 5 article 22 2011
[154] I Goshen A Avital T Kreisel T Licht M Segal and RYirmiya ldquoEnvironmental enrichment restores memory func-tioning in mice with impaired IL-1 signaling via reinstatementof long-term potentiation and spine size enlargementrdquo Journalof Neuroscience vol 29 no 11 pp 3395ndash3403 2009
[155] Y Ziv N Ron O Butovsky et al ldquoImmune cells contribute tothe maintenance of neurogenesis and spatial learning abilitiesin adulthoodrdquo Nature Neuroscience vol 9 no 2 pp 268ndash2752006
[156] J Kipnis H Cohen M Cardon Y Ziv and M Schwartz ldquoTcell deficiency leads to cognitive dysfunction implications fortherapeutic vaccination for schizophrenia and other psychiatricconditionsrdquo Proceedings of the National Academy of Sciences ofthe United States of America vol 101 no 21 pp 8180ndash8185 2004
[157] S A Wolf B Steiner A Akpinarli et al ldquoCD4-positive Tlymphocytes provide a neuroimmunological link in the control
Neural Plasticity 15
of adult hippocampal neurogenesisrdquo Journal of Immunologyvol 182 no 7 pp 3979ndash3984 2009
[158] G J Huang A L Smith D H D Gray et al ldquoA genetic andfunctional relationship between T cells and cellular prolifera-tion in the adult hippocampusrdquo PLOS Biology vol 8 no 12Article ID e1000561 2010
[159] R M Ransohoff and B Engelhardt ldquoThe anatomical andcellular basis of immune surveillance in the central nervoussystemrdquoNature Reviews Immunology vol 12 no 9 pp 623ndash6352012
[160] M Olah G Ping A H De Haas et al ldquoEnhanced hippocampalneurogenesis in the absence of microglia T cell interactionand microglia activation in the murine running wheel modelrdquoGLIA vol 57 no 10 pp 1046ndash1061 2009
[161] E Gebara S Sultan J Kocher-Braissant and N Toni ldquoAdulthippocampal neurogenesis inversely correlates with microgliain conditions of voluntary running and agingrdquo Frontiers inNeuroscience vol 7 article 145 2013
[162] R Aharoni B Kayhan R Eilam M Sela and R ArnonldquoGlatiramer acetate-specific T cells in the brain express T helper23 cytokines and brain-derived neurotrophic factor in siturdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 100 no 2 pp 14157ndash14162 2003
[163] C Rossi A Angelucci L Costantin et al ldquoBrain-derivedneurotrophic factor (BDNF) is required for the enhancementof hippocampal neurogenesis following environmental enrich-mentrdquo European Journal of Neuroscience vol 24 no 7 pp 1850ndash1856 2006
Neural Plasticity 11
[27] K Striedinger and E Scemes ldquoInterleukin-1120573 affects calciumsignaling and in vitro cell migration of astrocyte progenitorsrdquoJournal of Neuroimmunology vol 196 no 1-2 pp 116ndash123 2008
[28] Y B Lee A Nagai and S U Kim ldquoCytokines chemokines andcytokine receptors in humanmicrogliardquo Journal of NeuroscienceResearch vol 69 no 1 pp 94ndash103 2002
[29] G Kempermann and H Neumann ldquoMicroglia the enemywithinrdquo Science vol 302 no 5651 pp 1689ndash1690 2003
[30] M F Mehler R Rozental M Dougherty D C Spray and JA Kessler ldquoCytokine regulation of neuronal differentiation ofhippocampal progenitor cellsrdquo Nature vol 362 no 6415 pp62ndash65 1993
[31] U Gurok C Steinhoff B Lipkowitz H H Ropers C Scharffand U A Nuber ldquoGene expression changes in the course ofneural progenitor cell differentiationrdquo Journal of Neurosciencevol 24 no 26 pp 5982ndash6002 2004
[32] J B Demoulin M Enarsson J Larsson A Essaghir C HHeldin and K Forsberg-Nilsson ldquoThe gene expression profileof PDGF-treated neural stem cells corresponds to partiallydifferentiated neurons and gliardquo Growth Factors vol 24 no 3pp 184ndash196 2006
[33] F C Mansergh M A Wride and D E Rancourt ldquoNeuronsfrom stem cells implications for understanding nervous systemdevelopment and repairrdquo Biochemistry and Cell Biology vol 78no 5 pp 613ndash628 2000
[34] F C Alcantara Gomes V De Oliveira Sousa and L RomaoldquoEmerging roles for TGF-1205731 in nervous system developmentrdquoInternational Journal of Developmental Neuroscience vol 23 no5 pp 413ndash424 2005
[35] S Elkabes E M DiCicco-Bloom and I B Black ldquoBrainmicrogliamacrophages express neurotrophins that selectivelyregulate microglial proliferation and functionrdquo Journal of Neu-roscience vol 16 no 8 pp 2508ndash2521 1996
[36] U K Hanisch and H Kettenmann ldquoMicroglia active sensorand versatile effector cells in the normal and pathologic brainrdquoNature Neuroscience vol 10 no 11 pp 1387ndash1394 2007
[37] H J Klassen T F Ng Y Kurimoto et al ldquoMultipotent retinalprogenitors express developmental markers differentiate intoretinal neurons and preserve light-mediated behaviorrdquo Inves-tigative Ophthalmology and Visual Science vol 45 no 11 pp4167ndash4173 2004
[38] W J Streit S D Hurley T S McGraw and S L Semple-Rowland ldquoComparative evaluation of cytokine profiles andreactive gliosis supports a critical role for interleukin-6 inneuron-glia signaling during regenerationrdquo Journal of Neuro-science Research vol 61 no 1 pp 10ndash20 2000
[39] A Suzumura M Sawada H Yamamoto and T MarunouchildquoEffects of colony stimulating factors on isolated microglia invitrordquo Journal of Neuroimmunology vol 30 no 2-3 pp 111ndash1201990
[40] Z Lu M R Elliott Y Chen et al ldquoPhagocytic activity ofneuronal progenitors regulates adult neurogenesisrdquoNature CellBiology vol 13 no 9 pp 1076ndash1084 2011
[41] K Nakajima Y Kikuchi E Ikoma et al ldquoNeurotrophinsregulate the function of cultured microgliardquo GLIA vol 24 no3 pp 272ndash289 1998
[42] P A Lodge and S Sriram ldquoRegulation of microglial activationby TGF-120573 IL-10 and CSF-1rdquo Journal of Leukocyte Biology vol60 no 4 pp 502ndash508 1996
[43] W S Sheng S Hu F H Kravitz P K Peterson and C C ChaoldquoTumor necrosis factor alpha upregulates humanmicroglial cell
production of interleukin-10 in vitrordquo Clinical and DiagnosticLaboratory Immunology vol 2 no 5 pp 604ndash608 1995
[44] G LMing andH Song ldquoAdult neurogenesis in themammalianbrain significant answers and significant questionsrdquo Neuronvol 70 no 4 pp 687ndash702 2011
[45] E Bruel-Jungerman S Davis C Rampon and S LarocheldquoLong-term potentiation enhances neurogenesis in the adultdentate gyrusrdquo Journal of Neuroscience vol 26 no 22 pp 5888ndash5893 2006
[46] E Drapeau M F Montaron S Aguerre and D N AbrousldquoLearning-induced survival of new neurons depends on thecognitive status of aged ratsrdquo Journal of Neuroscience vol 27no 22 pp 6037ndash6044 2007
[47] A Mouret G Gheusi M M Gabellec F De Chaumont J COlivo-Marin and P M Lledo ldquoLearning and survival of newlygenerated neurons when timemattersrdquo Journal of Neurosciencevol 28 no 45 pp 11511ndash11516 2008
[48] N Kee C M Teixeira A H Wang and P W FranklandldquoPreferential incorporation of adult-generated granule cellsinto spatial memory networks in the dentate gyrusrdquo NatureNeuroscience vol 10 no 3 pp 355ndash362 2007
[49] F Massa M Koelh T Wiesner et al ldquoConditional reduction ofadult neurogenesis impairs bidirectional hippocampal synapticplasticityrdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 108 no 16 pp 6644ndash6649 2011
[50] T J Shors G Miesegaes A Beylin M Zhao T Rydel and EGould ldquoNeurogenesis in the adult is involved in the formationof tracememoriesrdquoNature vol 410 no 6826 pp 372ndash376 2001
[51] W Deng M D Saxe I S Gallina and F H Gage ldquoAdult-born hippocampal dentate granule cells undergoingmaturationmodulate learning and memory in the brainrdquo Journal of Neuro-science vol 29 no 43 pp 13532ndash13542 2009
[52] M Arruda-Carvalho M Sakaguchi K G Akers S A Josselynand P W Frankland ldquoPosttraining ablation of adult-generatedneurons degrades previously acquired memoriesrdquo Journal ofNeuroscience vol 31 no 42 pp 15113ndash15127 2011
[53] A Sahay K N Scobie A S Hill et al ldquoIncreasing adulthippocampal neurogenesis is sufficient to improve patternseparationrdquo Nature vol 472 no 7344 pp 466ndash470 2011
[54] G LMing andH Song ldquoAdult neurogenesis in themammaliancentral nervous systemrdquoAnnual Review of Neuroscience vol 28pp 223ndash250 2005
[55] K Newton and V M Dixit ldquoSignaling in innate immunity andinflammationrdquo Cold Spring Harbor Perspectives in Biology vol4 no 3 2012
[56] H K Jeong K Ji K Min and E H Joe ldquoBrain inflammationand microglia facts and misconceptionsrdquo Experimental Neuro-biology vol 22 no 2 pp 59ndash67 2013
[57] D Stellwagen and R CMalenka ldquoSynaptic scalingmediated byglial TNF-120572rdquo Nature vol 440 no 7087 pp 1054ndash1059 2006
[58] M Pickering D Cumiskey and J J OrsquoConnor ldquoActions of TNF-120572 on glutamatergic synaptic transmission in the central nervoussystemrdquo Experimental Physiology vol 90 no 5 pp 663ndash6702005
[59] K Belarbi T Jopson D Tweedie et al ldquoTNF-120572 protein synthe-sis inhibitor restores neuronal function and reverses cognitivedeficits induced by chronic neuroinflammationrdquo Journal ofNeuroinflammation vol 9 article 23 2012
[60] C T Ekdahl J H Claasen S Bonde Z Kokaia andO LindvallldquoInflammation is detrimental for neurogenesis in adult brainrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 100 no 23 pp 13632ndash13637 2003
12 Neural Plasticity
[61] M L Monje H Toda and T D Palmer ldquoInflammatoryblockade restores adult hippocampal neurogenesisrdquo Sciencevol 302 no 5651 pp 1760ndash1765 2003
[62] A Sierra J M Encinas J J P Deudero et al ldquoMicroglia shapeadult hippocampal neurogenesis through apoptosis-coupledphagocytosisrdquo Cell Stem Cell vol 7 no 4 pp 483ndash495 2010
[63] D Chugh P Nilsson S A Afjei A Bakochi and C T EkdahlldquoBrain inflammation induces post-synaptic changes duringearly synapse formation in adult-born hippocampal neuronsrdquoExperimental Neurobiology vol 250 pp 176ndash188 2013
[64] K Belarbi C Arellano R Ferguson T Jopson and S RosildquoChronic neuroinflammation impacts the recruitment of adult-born neurons into behaviorally relevant hippocampal net-worksrdquo Brain Behavior and Immunity vol 26 no 1 pp 18ndash232012
[65] S Johann E Kampmann B Denecke et al ldquoExpression ofenzymes involved in the prostanoid metabolism by corticalastrocytes after LPS-induced inflammationrdquo Journal of Molec-ular Neuroscience vol 34 no 2 pp 177ndash185 2008
[66] P V B Reddy K V Rama Rao and M D NorenbergldquoInhibitors of the mitochondrial permeability transition reduceammonia-induced cell swelling in cultured astrocytesrdquo Journalof Neuroscience Research vol 87 no 12 pp 2677ndash2685 2009
[67] H Nie H Zhang and H R Weng ldquoMinocycline preventsimpaired glial glutamate uptake in the spinal sensory synapsesof neuropathic ratsrdquo Neuroscience vol 170 no 3 pp 901ndash9122010
[68] F Cerbai D Lana D Nosi et al ldquoThe neuron-astrocyte-microglia triad in normal brain ageing and in a model ofneuroinflammation in the rat hippocampusrdquo PLoS ONE vol 7no 9 Article ID e45250 2012
[69] W J Jin S W Feng Z Feng S M Lu T Qi and Y N QianldquoMinocycline improves postoperative cognitive impairment inaged mice by inhibiting astrocytic activationrdquo NeuroReport2013
[70] K A Ji M S Yang H K Jeong et al ldquoResident microgliadie and infiltrated neutrophils and monocytes become majorinflammatory cells in lipopolysaccharide-injected brainrdquoGLIAvol 55 no 15 pp 1577ndash1588 2007
[71] N J van Wagoner J W Oh P Repovic and E N BenvenisteldquoInterleukin-6 (IL-6) production by astrocytes autocrine reg-ulation by IL-6 and the soluble IL-6 receptorrdquo Journal ofNeuroscience vol 19 no 13 pp 5236ndash5244 1999
[72] L Vallieres I L Campbell F H Gage and P E SawchenkoldquoReduced hippocampal neurogenesis in adult transgenic micewith chronic astrocytic production of interleukin-6rdquo Journal ofNeuroscience vol 22 no 2 pp 486ndash492 2002
[73] B S McEwen ldquoPhysiology and neurobiology of stress andadaptation central role of the brainrdquo Physiological Reviews vol87 no 3 pp 873ndash904 2007
[74] V LuineMVillegas CMartinez and B SMcEwen ldquoRepeatedstress causes reversible impairments of spatial memory perfor-mancerdquo Brain Research vol 639 no 1 pp 167ndash170 1994
[75] S Rivest ldquoMolecular insights on the cerebral innate immunesystemrdquo Brain Behavior and Immunity vol 17 no 1 pp 13ndash192003
[76] S Nadeau and S Rivest ldquoEndotoxemia prevents the cerebralinflammatory wave induced by intraparenchymal lipopolysac-charide injection role of glucocorticoids and CD14rdquo Journal ofImmunology vol 169 no 6 pp 3370ndash3381 2002
[77] A Sierra A Gottfried-Blackmore T A Milner B S McEwenand K Bulloch ldquoSteroid hormone receptor expression andfunction in microgliardquo GLIA vol 56 no 6 pp 659ndash674 2008
[78] C Liston andW B Gan ldquoGlucocorticoids are critical regulatorsof dendritic spine development and plasticity in vivordquo Proceed-ings of the National Academy of Sciences of the United States ofAmerica vol 108 no 38 pp 16074ndash16079 2011
[79] C Liston J M Cichon F Jeanneteau Z Jia M V Chaoand W B Gan ldquoCircadian glucocorticoid oscillations pro-mote learning-dependent synapse formation andmaintenancerdquoNature Neuroscience vol 16 no 6 pp 698ndash705 2013
[80] M A Carrillo-de Sauvage L Maatouk I Arnoux et al ldquoPotentand multiple regulatory actions of microglial glucocorticoidreceptors during CNS inflammationrdquo Cell Death amp Differenti-ation vol 20 no 11 pp 1546ndash1557 2013
[81] S F Sorrells J R Caso C DMunhoz and RM Sapolsky ldquoThestressed CNS when glucocorticoids aggravate inflammationrdquoNeuron vol 64 no 1 pp 33ndash39 2009
[82] M A Bellavance and S Rivest ldquoThe neuroendocrine controlof the innate immune system in health and brain diseasesrdquoImmunological Reviews vol 248 no 1 pp 36ndash55 2012
[83] R J Tynan S Naicker M Hinwood et al ldquoChronic stress altersthe density and morphology of microglia in a subset of stress-responsive brain regionsrdquo Brain Behavior and Immunity vol24 no 7 pp 1058ndash1068 2010
[84] E S Wohleb N D Powell J P Godbout and J F SheridanldquoStress-induced recruitment of bone marrow-derived mono-cytes to the brain promotes anxiety-like behaviorrdquo The Journalof Neuroscience vol 33 no 34 pp 13820ndash13833 2013
[85] Y Diz-Chaves M Astiz M J Bellini and L M Garcia-SeguraldquoPrenatal stress increases the expression of proinflammatorycytokines and exacerbates the inflammatory response to LPS inthe hippocampal formation of adultmalemicerdquoBrain Behaviorand Immunity vol 28 pp 196ndash206 2013
[86] E S Wohleb A M Fenn A M Pacenta N D Powell J FSheridan and J P Godbout ldquoPeripheral innate immune chal-lenge exaggerated microglia activation increased the numberof inflammatory CNSmacrophages and prolonged social with-drawal in socially defeated micerdquo Psychoneuroendocrinologyvol 37 no 9 pp 1491ndash1505 2012
[87] C Mirescu and E Gould ldquoStress and adult neurogenesisrdquoHippocampus vol 16 no 3 pp 233ndash238 2006
[88] J LWarner-Schmidt andR SDuman ldquoHippocampal neuroge-nesis opposing effects of stress and antidepressant treatmentrdquoHippocampus vol 16 no 3 pp 239ndash249 2006
[89] N D Hanson M J Owens K A Boss-Williams J M Weissand C B Nemeroff ldquoSeveral stressors fail to reduce adulthippocampal neurogenesisrdquo Psychoneuroendocrinology vol 36no 10 pp 1520ndash1529 2011
[90] E Gould B S McEwen P Tanapat L A M Galea and EFuchs ldquoNeurogenesis in the dentate gyrus of the adult treeshrew is regulated by psychosocial stress and NMDA receptoractivationrdquo Journal of Neuroscience vol 17 no 7 pp 2492ndash24981997
[91] JW Koo andR S Duman ldquoIL-1120573 is an essentialmediator of theantineurogenic and anhedonic effects of stressrdquo Proceedings ofthe National Academy of Sciences of the United States of Americavol 105 no 2 pp 751ndash756 2008
[92] D C Lagace M H Donovan N A Decarolis et al ldquoAdulthippocampal neurogenesis is functionally important for stress-induced social avoidancerdquo Proceedings of the National Academy
Neural Plasticity 13
of Sciences of the United States of America vol 107 no 9 pp4436ndash4441 2010
[93] G Kronenberg I Kirste D Inta et al ldquoReduced hippocampalneurogenesis in the GR+- genetic mousemodel of depressionrdquoEuropean Archives of Psychiatry and Clinical Neuroscience vol259 no 8 pp 499ndash504 2009
[94] M B Howren D M Lamkin and J Suls ldquoAssociations ofdepression with c-reactive protein IL-1 and IL-6 a meta-analysisrdquo Psychosomatic Medicine vol 71 no 2 pp 171ndash1862009
[95] J W Koo S J Russo D Ferguson E J Nestler and R SDuman ldquoNuclear factor-120581B is a critical mediator of stress-impaired neurogenesis and depressive behaviorrdquo Proceedings ofthe National Academy of Sciences of the United States of Americavol 107 no 6 pp 2669ndash2674 2010
[96] I Goshen T Kreisel O Ben-Menachem-Zidon et al ldquoBraininterleukin-1 mediates chronic stress-induced depression inmice via adrenocortical activation and hippocampal neuroge-nesis suppressionrdquo Molecular Psychiatry vol 13 no 7 pp 717ndash728 2008
[97] C D Munhoz L B Lepsch E M Kawamoto et al ldquoChronicunpredictable stress exacerbates lipopolysaccharide-inducedactivation of nuclear factor-120581B in the frontal cortex andhippocampus via glucocorticoid secretionrdquo Journal of Neuro-science vol 26 no 14 pp 3813ndash3820 2006
[98] S J Sukoff Rizzo S J Neal Z A Hughes et al ldquoEvidence forsustained elevation of IL-6 in the CNS as a key contributorof depressive-like phenotypesrdquo Translational Psychiatry vol 2article e199 2012
[99] A Garcia B Steiner G Kronenberg A Bick-Sander and GKempermann ldquoAge-dependent expression of glucocorticoid-andmineralocorticoid receptors on neural precursor cell popu-lations in the adult murine hippocampusrdquoAging Cell vol 3 no6 pp 363ndash371 2004
[100] M G Frank B M Thompson L R Watkins and S F MaierldquoGlucocorticoids mediate stress-induced priming of microglialpro-inflammatory responsesrdquo Brain Behavior and Immunityvol 26 no 2 pp 337ndash345 2012
[101] S Sugama M Fujita M Hashimoto and B Conti ldquoStressinduced morphological microglial activation in the rodentbrain involvement of interleukin-18rdquoNeuroscience vol 146 no3 pp 1388ndash1399 2007
[102] A Sierra J M Encinas and M Maletic-Savatic ldquoAdult humanneurogenesis from microscopy to magnetic resonance imag-ingrdquo Frontiers in Neuroscience vol 5 article 47 2011
[103] H G Kuhn H Dickinson-Anson and F H Gage ldquoNeurogen-esis in the dentate gyrus of the adult rat age-related decrease ofneuronal progenitor proliferationrdquo Journal of Neuroscience vol16 no 6 pp 2027ndash2033 1996
[104] L N Manganas X Zhang Y Li et al ldquoMagnetic resonancespectroscopy identifies neural progenitor cells in the live humanbrainrdquo Science vol 318 no 5852 pp 980ndash985 2007
[105] K L Spalding O Bergmann K Alkass et al ldquoDynamics ofhippocampal neurogenesis in adult humansrdquo Cell vol 153 no6 pp 1219ndash1227 2013
[106] J M Encinas and A Sierra ldquoNeural stem cell deforestationas the main force driving the age-related decline in adulthippocampal neurogenesisrdquo Behavioural Brain Research vol227 no 2 pp 433ndash439 2012
[107] K S Krabbe M Pedersen andH Bruunsgaard ldquoInflammatorymediators in the elderlyrdquo Experimental Gerontology vol 39 no5 pp 687ndash699 2004
[108] B S Diniz A L Teixeira L Talib W F Gattaz andO V Forlenza ldquoInterleukin-1120573 serum levels is increased inantidepressant-free elderly depressed patientsrdquo American Jour-nal of Geriatric Psychiatry vol 18 no 2 pp 172ndash176 2010
[109] A Sierra A C Gottfried-Blackmore B S Mcewen and KBulloch ldquoMicroglia derived from aging mice exhibit an alteredinflammatory profilerdquo GLIA vol 55 no 4 pp 412ndash424 2007
[110] C FranceschiM Bonafe S Valensin et al ldquoInflamm-aging Anevolutionary perspective on immunosenescencerdquo Annals of theNew York Academy of Sciences vol 908 pp 244ndash254 2000
[111] R Sano and J C Reed ldquoER stress-induced cell death mecha-nismsrdquoBiochimica et BiophysicaActa vol 1833 no 12 pp 3460ndash3470 2013
[112] S Z Hasnain R Lourie I Das A C H Chen and MA McGuckin ldquoThe interplay between endoplasmic reticulumstress and inflammationrdquo Immunology and Cell Biology vol 90no 3 pp 260ndash270 2012
[113] S Matus L H Glimcher and C Hetz ldquoProtein folding stressin neurodegenerative diseases a glimpse into the ERrdquo CurrentOpinion in Cell Biology vol 23 no 2 pp 239ndash252 2011
[114] Y Ito M Yamada H Tanaka et al ldquoInvolvement of CHOP anER-stress apoptotic mediator in both human sporadic ALS andALS model micerdquo Neurobiology of Disease vol 36 no 3 pp470ndash476 2009
[115] D Papadimitriou V Le Verche A Jacquier B Ikiz S Przed-borski and D B Re ldquoInflammation in ALS and SMA sortingout the good from the evilrdquo Neurobiology of Disease vol 37 no3 pp 493ndash502 2010
[116] A R Johnson J J Milner and LMakowski ldquoThe inflammationhighway metabolism accelerates inflammatory traffic in obe-sityrdquo Immunological Reviews vol 249 no 1 pp 218ndash238 2012
[117] S Buch H Yao M Guo et al ldquoCocaine and HIV-1 interplayin CNS cellular and molecular mechanismsrdquo Current HIVResearch vol 10 no 5 pp 425ndash428 2012
[118] M K Brown and N Naidoo ldquoThe endoplasmic reticulumstress response in aging and age-related diseasesrdquo Frontiers inPhysiology vol 3 article 263 2012
[119] G Castro C Areias MF L Weissmann et al ldquoDiet-inducedobesity induces endoplasmic reticulum stress and insulin resis-tance in the amygdala of ratsrdquo FEBS Open Bio vol 3 pp 443ndash449 2013
[120] A A Pavlovsky D Boehning D Li Y Zhang X Fan andT A Green ldquoPsychological stress cocaine and natural rewardeach induce endoplasmic reticulum stress genes in rat brainrdquoNeuroscience vol 246 pp 160ndash169 2013
[121] G GargiuloM CesaroniM Serresi et al ldquoIn vivo RNAi screenfor BMI1 targets identifies TGF-betaBMP-ER stress pathwaysas key regulators of neural- and malignant glioma-stem cellhomeostasisrdquo Cancer Cell vol 23 no 5 pp 660ndash676 2013
[122] A Salminen K Kaarniranta and A Kauppinen ldquoInflammag-ing disturbed interplay between autophagy and inflamma-somesrdquo Aging vol 4 no 3 pp 166ndash175 2012
[123] E Latz T S Xiao andA Stutz ldquoActivation and regulation of theinflammasomesrdquoNature Reviews Immunology vol 13 no 6 pp397ndash411 2013
[124] C Gemma A D Bachstetter M J Cole M Fister C Hudsonand P C Bickford ldquoBlockade of caspase-1 increases neurogene-sis in the aged hippocampusrdquo European Journal of Neurosciencevol 26 no 10 pp 2795ndash2803 2007
[125] M D Wu A M Hein M J Moravan S S Shaftel J AOlschowka and M K OrsquoBanion ldquoAdult murine hippocampal
14 Neural Plasticity
neurogenesis is inhibited by sustained IL-1120573 and not rescued byvoluntary runningrdquo Brain Behavior and Immunity vol 26 no2 pp 292ndash300 2012
[126] Y Wolf S Yona K W Kim and S Jung ldquoMicroglia seen fromthe CX3CR1 anglerdquo Frontiers in Cellular Neuroscience vol 7article 26 2013
[127] A E Cardona E P Pioro M E Sasse et al ldquoControl ofmicroglial neurotoxicity by the fractalkine receptorrdquo NatureNeuroscience vol 9 no 7 pp 917ndash924 2006
[128] K Bhaskar M Konerth O N Kokiko-Cochran A Cardona RM Ransohoff and B T Lamb ldquoRegulation of tau pathology bythe microglial fractalkine receptorrdquo Neuron vol 68 no 1 pp19ndash31 2010
[129] A D Bachstetter J M Morganti J Jernberg et al ldquoFractalkineand CX3CR1 regulate hippocampal neurogenesis in adult andaged ratsrdquo Neurobiology of Aging vol 32 no 11 pp 2030ndash20442011
[130] S Jung J Aliberti P Graemmel et al ldquoAnalysis of fractalkinereceptor CX3CR1 function by targeted deletion and greenfluorescent protein reporter gene insertionrdquo Molecular andCellular Biology vol 20 no 11 pp 4106ndash4114 2000
[131] J T Rogers J M Morganti A D Bachstetter et al ldquoCX3CR1deficiency leads to impairment of hippocampal cognitive func-tion and synaptic plasticityrdquo Journal of Neuroscience vol 31 no45 pp 16241ndash16250 2011
[132] W S T Griffin L C Stanley C Ling et al ldquoBrain interleukin1 and S-100 immunoreactivity are elevated in Down syndromeand Alzheimer diseaserdquo Proceedings of the National Academy ofSciences of the United States of America vol 86 no 19 pp 7611ndash7615 1989
[133] W C Benzing J RWujek E KWard et al ldquoEvidence for glial-mediated inflammation in aged APP(SW) transgenic micerdquoNeurobiology of Aging vol 20 no 6 pp 581ndash589 1999
[134] T J Seabrook L Jiang M Maier and C A Lemere ldquoMinocy-cline affects microglia activation A120573 deposition and behaviorin APP-tg micerdquo GLIA vol 53 no 7 pp 776ndash782 2006
[135] B Biscaro O Lindvall G Tesco C T Ekdahl and RM NitschldquoInhibition of microglial activation protects hippocampal neu-rogenesis and improves cognitive deficits in a transgenic mousemodel for Alzheimerrsquos diseaserdquoNeurodegenerative Diseases vol9 no 4 pp 187ndash198 2012
[136] P A Zunszain C Anacker A Cattaneo et al ldquoInterleukin-1120573a new regulator of the kynurenine pathway affecting humanhippocampal neurogenesisrdquo Neuropsychopharmacology vol 37no 4 pp 939ndash949 2012
[137] R De Simone M Antonietta Ajmone-Cat P Tirassa and LMinghetti ldquoApoptotic PC12 cells exposing phosphatidylserinepromote the production of anti-inflammatory and neuropro-tective molecules bymicroglial cellsrdquo Journal of Neuropathologyand Experimental Neurology vol 62 no 2 pp 208ndash216 2003
[138] M S Buckwalter M Yamane B S Coleman et al ldquoChroni-cally increased transforming growth factor-1205731 strongly inhibitshippocampal neurogenesis in aged micerdquo American Journal ofPathology vol 169 no 1 pp 154ndash164 2006
[139] O Butovsky Y Ziv A Schwartz et al ldquoMicroglia activatedby IL-4 or IFN-120574 differentially induce neurogenesis and oligo-dendrogenesis from adult stemprogenitor cellsrdquoMolecular andCellular Neuroscience vol 31 no 1 pp 149ndash160 2006
[140] C T Ekdahl ldquoMicroglial activationmdashtuning and pruning adultneurogenesisrdquo Frontiers in Pharmacology vol 3 article 41 2012
[141] HWakeA JMoorhouse S Jinno S Kohsaka and JNabekuraldquoResting microglia directly monitor the functional state ofsynapses in vivo and determine the fate of ischemic terminalsrdquoJournal of Neuroscience vol 29 no 13 pp 3974ndash3980 2009
[142] M E Tremblay R L Lowery and A K Majewska ldquoMicroglialinteractions with synapses are modulated by visual experiencerdquoPLoS Biology vol 8 no 11 Article ID e1000527 2010
[143] M E Tremblay M L Zettel J R Ison P D Allen and A KMajewska ldquoEffects of aging and sensory loss on glial cells inmouse visual and auditory corticesrdquo GLIA vol 60 no 4 pp541ndash558 2012
[144] D P Schafer E K Lehrman A G Kautzman et al ldquoMicrogliasculpt postnatal neural circuits in an activity and complement-dependent mannerrdquo Neuron vol 74 no 4 pp 691ndash705 2012
[145] H Nakanishi ldquoMicroglial functions and proteasesrdquo MolecularNeurobiology vol 27 no 2 pp 163ndash176 2003
[146] M E Tremblay and A K Majewska ldquoA role for microglia insynaptic plasticityrdquoCommunicative and Integrative Biology vol4 no 2 pp 220ndash222 2011
[147] R C Paolicelli G Bolasco F Pagani et al ldquoSynaptic pruning bymicroglia is necessary for normal brain developmentrdquo Sciencevol 333 no 6048 pp 1456ndash1458 2011
[148] GKempermannHGKuhn and FHGage ldquoMore hippocam-pal neurons in adult mice living in an enriched environmentrdquoNature vol 386 no 6624 pp 493ndash495 1997
[149] M Nilsson E Perfilieva U Johansson O Orwar and P SEriksson ldquoEnriched environment increases neurogenesis in theadult rat dentate gyrus and improves spatial memoryrdquo Journalof Neurobiology vol 39 no 4 pp 569ndash578 1999
[150] H van Praag G Kempermann and F H Gage ldquoRunningincreases cell proliferation and neurogenesis in the adult mousedentate gyrusrdquo Nature Neuroscience vol 2 no 3 pp 266ndash2701999
[151] D Young P A Lawlor P Leone M Dragunow and MJ During ldquoEnvironmental enrichment inhibits spontaneousapoptosis prevents seizures and is neuroprotectiverdquo NatureMedicine vol 5 no 4 pp 448ndash453 1999
[152] L L Williamson A Chao and S D Bilbo ldquoEnvironmentalenrichment alters glial antigen expression and neuroimmunefunction in the adult rat hippocampusrdquo Brain Behavior andImmunity vol 26 no 3 pp 500ndash510 2012
[153] L Maggi M Scianni I Branchi I DrsquoAndrea C Lauro and CLimatola ldquoCX(3)CR1 deficiency alters hippocampal-dependentplasticity phenomena blunting the effects of enriched environ-mentrdquo Frontiers in Cellular Neuroscience vol 5 article 22 2011
[154] I Goshen A Avital T Kreisel T Licht M Segal and RYirmiya ldquoEnvironmental enrichment restores memory func-tioning in mice with impaired IL-1 signaling via reinstatementof long-term potentiation and spine size enlargementrdquo Journalof Neuroscience vol 29 no 11 pp 3395ndash3403 2009
[155] Y Ziv N Ron O Butovsky et al ldquoImmune cells contribute tothe maintenance of neurogenesis and spatial learning abilitiesin adulthoodrdquo Nature Neuroscience vol 9 no 2 pp 268ndash2752006
[156] J Kipnis H Cohen M Cardon Y Ziv and M Schwartz ldquoTcell deficiency leads to cognitive dysfunction implications fortherapeutic vaccination for schizophrenia and other psychiatricconditionsrdquo Proceedings of the National Academy of Sciences ofthe United States of America vol 101 no 21 pp 8180ndash8185 2004
[157] S A Wolf B Steiner A Akpinarli et al ldquoCD4-positive Tlymphocytes provide a neuroimmunological link in the control
Neural Plasticity 15
of adult hippocampal neurogenesisrdquo Journal of Immunologyvol 182 no 7 pp 3979ndash3984 2009
[158] G J Huang A L Smith D H D Gray et al ldquoA genetic andfunctional relationship between T cells and cellular prolifera-tion in the adult hippocampusrdquo PLOS Biology vol 8 no 12Article ID e1000561 2010
[159] R M Ransohoff and B Engelhardt ldquoThe anatomical andcellular basis of immune surveillance in the central nervoussystemrdquoNature Reviews Immunology vol 12 no 9 pp 623ndash6352012
[160] M Olah G Ping A H De Haas et al ldquoEnhanced hippocampalneurogenesis in the absence of microglia T cell interactionand microglia activation in the murine running wheel modelrdquoGLIA vol 57 no 10 pp 1046ndash1061 2009
[161] E Gebara S Sultan J Kocher-Braissant and N Toni ldquoAdulthippocampal neurogenesis inversely correlates with microgliain conditions of voluntary running and agingrdquo Frontiers inNeuroscience vol 7 article 145 2013
[162] R Aharoni B Kayhan R Eilam M Sela and R ArnonldquoGlatiramer acetate-specific T cells in the brain express T helper23 cytokines and brain-derived neurotrophic factor in siturdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 100 no 2 pp 14157ndash14162 2003
[163] C Rossi A Angelucci L Costantin et al ldquoBrain-derivedneurotrophic factor (BDNF) is required for the enhancementof hippocampal neurogenesis following environmental enrich-mentrdquo European Journal of Neuroscience vol 24 no 7 pp 1850ndash1856 2006
12 Neural Plasticity
[61] M L Monje H Toda and T D Palmer ldquoInflammatoryblockade restores adult hippocampal neurogenesisrdquo Sciencevol 302 no 5651 pp 1760ndash1765 2003
[62] A Sierra J M Encinas J J P Deudero et al ldquoMicroglia shapeadult hippocampal neurogenesis through apoptosis-coupledphagocytosisrdquo Cell Stem Cell vol 7 no 4 pp 483ndash495 2010
[63] D Chugh P Nilsson S A Afjei A Bakochi and C T EkdahlldquoBrain inflammation induces post-synaptic changes duringearly synapse formation in adult-born hippocampal neuronsrdquoExperimental Neurobiology vol 250 pp 176ndash188 2013
[64] K Belarbi C Arellano R Ferguson T Jopson and S RosildquoChronic neuroinflammation impacts the recruitment of adult-born neurons into behaviorally relevant hippocampal net-worksrdquo Brain Behavior and Immunity vol 26 no 1 pp 18ndash232012
[65] S Johann E Kampmann B Denecke et al ldquoExpression ofenzymes involved in the prostanoid metabolism by corticalastrocytes after LPS-induced inflammationrdquo Journal of Molec-ular Neuroscience vol 34 no 2 pp 177ndash185 2008
[66] P V B Reddy K V Rama Rao and M D NorenbergldquoInhibitors of the mitochondrial permeability transition reduceammonia-induced cell swelling in cultured astrocytesrdquo Journalof Neuroscience Research vol 87 no 12 pp 2677ndash2685 2009
[67] H Nie H Zhang and H R Weng ldquoMinocycline preventsimpaired glial glutamate uptake in the spinal sensory synapsesof neuropathic ratsrdquo Neuroscience vol 170 no 3 pp 901ndash9122010
[68] F Cerbai D Lana D Nosi et al ldquoThe neuron-astrocyte-microglia triad in normal brain ageing and in a model ofneuroinflammation in the rat hippocampusrdquo PLoS ONE vol 7no 9 Article ID e45250 2012
[69] W J Jin S W Feng Z Feng S M Lu T Qi and Y N QianldquoMinocycline improves postoperative cognitive impairment inaged mice by inhibiting astrocytic activationrdquo NeuroReport2013
[70] K A Ji M S Yang H K Jeong et al ldquoResident microgliadie and infiltrated neutrophils and monocytes become majorinflammatory cells in lipopolysaccharide-injected brainrdquoGLIAvol 55 no 15 pp 1577ndash1588 2007
[71] N J van Wagoner J W Oh P Repovic and E N BenvenisteldquoInterleukin-6 (IL-6) production by astrocytes autocrine reg-ulation by IL-6 and the soluble IL-6 receptorrdquo Journal ofNeuroscience vol 19 no 13 pp 5236ndash5244 1999
[72] L Vallieres I L Campbell F H Gage and P E SawchenkoldquoReduced hippocampal neurogenesis in adult transgenic micewith chronic astrocytic production of interleukin-6rdquo Journal ofNeuroscience vol 22 no 2 pp 486ndash492 2002
[73] B S McEwen ldquoPhysiology and neurobiology of stress andadaptation central role of the brainrdquo Physiological Reviews vol87 no 3 pp 873ndash904 2007
[74] V LuineMVillegas CMartinez and B SMcEwen ldquoRepeatedstress causes reversible impairments of spatial memory perfor-mancerdquo Brain Research vol 639 no 1 pp 167ndash170 1994
[75] S Rivest ldquoMolecular insights on the cerebral innate immunesystemrdquo Brain Behavior and Immunity vol 17 no 1 pp 13ndash192003
[76] S Nadeau and S Rivest ldquoEndotoxemia prevents the cerebralinflammatory wave induced by intraparenchymal lipopolysac-charide injection role of glucocorticoids and CD14rdquo Journal ofImmunology vol 169 no 6 pp 3370ndash3381 2002
[77] A Sierra A Gottfried-Blackmore T A Milner B S McEwenand K Bulloch ldquoSteroid hormone receptor expression andfunction in microgliardquo GLIA vol 56 no 6 pp 659ndash674 2008
[78] C Liston andW B Gan ldquoGlucocorticoids are critical regulatorsof dendritic spine development and plasticity in vivordquo Proceed-ings of the National Academy of Sciences of the United States ofAmerica vol 108 no 38 pp 16074ndash16079 2011
[79] C Liston J M Cichon F Jeanneteau Z Jia M V Chaoand W B Gan ldquoCircadian glucocorticoid oscillations pro-mote learning-dependent synapse formation andmaintenancerdquoNature Neuroscience vol 16 no 6 pp 698ndash705 2013
[80] M A Carrillo-de Sauvage L Maatouk I Arnoux et al ldquoPotentand multiple regulatory actions of microglial glucocorticoidreceptors during CNS inflammationrdquo Cell Death amp Differenti-ation vol 20 no 11 pp 1546ndash1557 2013
[81] S F Sorrells J R Caso C DMunhoz and RM Sapolsky ldquoThestressed CNS when glucocorticoids aggravate inflammationrdquoNeuron vol 64 no 1 pp 33ndash39 2009
[82] M A Bellavance and S Rivest ldquoThe neuroendocrine controlof the innate immune system in health and brain diseasesrdquoImmunological Reviews vol 248 no 1 pp 36ndash55 2012
[83] R J Tynan S Naicker M Hinwood et al ldquoChronic stress altersthe density and morphology of microglia in a subset of stress-responsive brain regionsrdquo Brain Behavior and Immunity vol24 no 7 pp 1058ndash1068 2010
[84] E S Wohleb N D Powell J P Godbout and J F SheridanldquoStress-induced recruitment of bone marrow-derived mono-cytes to the brain promotes anxiety-like behaviorrdquo The Journalof Neuroscience vol 33 no 34 pp 13820ndash13833 2013
[85] Y Diz-Chaves M Astiz M J Bellini and L M Garcia-SeguraldquoPrenatal stress increases the expression of proinflammatorycytokines and exacerbates the inflammatory response to LPS inthe hippocampal formation of adultmalemicerdquoBrain Behaviorand Immunity vol 28 pp 196ndash206 2013
[86] E S Wohleb A M Fenn A M Pacenta N D Powell J FSheridan and J P Godbout ldquoPeripheral innate immune chal-lenge exaggerated microglia activation increased the numberof inflammatory CNSmacrophages and prolonged social with-drawal in socially defeated micerdquo Psychoneuroendocrinologyvol 37 no 9 pp 1491ndash1505 2012
[87] C Mirescu and E Gould ldquoStress and adult neurogenesisrdquoHippocampus vol 16 no 3 pp 233ndash238 2006
[88] J LWarner-Schmidt andR SDuman ldquoHippocampal neuroge-nesis opposing effects of stress and antidepressant treatmentrdquoHippocampus vol 16 no 3 pp 239ndash249 2006
[89] N D Hanson M J Owens K A Boss-Williams J M Weissand C B Nemeroff ldquoSeveral stressors fail to reduce adulthippocampal neurogenesisrdquo Psychoneuroendocrinology vol 36no 10 pp 1520ndash1529 2011
[90] E Gould B S McEwen P Tanapat L A M Galea and EFuchs ldquoNeurogenesis in the dentate gyrus of the adult treeshrew is regulated by psychosocial stress and NMDA receptoractivationrdquo Journal of Neuroscience vol 17 no 7 pp 2492ndash24981997
[91] JW Koo andR S Duman ldquoIL-1120573 is an essentialmediator of theantineurogenic and anhedonic effects of stressrdquo Proceedings ofthe National Academy of Sciences of the United States of Americavol 105 no 2 pp 751ndash756 2008
[92] D C Lagace M H Donovan N A Decarolis et al ldquoAdulthippocampal neurogenesis is functionally important for stress-induced social avoidancerdquo Proceedings of the National Academy
Neural Plasticity 13
of Sciences of the United States of America vol 107 no 9 pp4436ndash4441 2010
[93] G Kronenberg I Kirste D Inta et al ldquoReduced hippocampalneurogenesis in the GR+- genetic mousemodel of depressionrdquoEuropean Archives of Psychiatry and Clinical Neuroscience vol259 no 8 pp 499ndash504 2009
[94] M B Howren D M Lamkin and J Suls ldquoAssociations ofdepression with c-reactive protein IL-1 and IL-6 a meta-analysisrdquo Psychosomatic Medicine vol 71 no 2 pp 171ndash1862009
[95] J W Koo S J Russo D Ferguson E J Nestler and R SDuman ldquoNuclear factor-120581B is a critical mediator of stress-impaired neurogenesis and depressive behaviorrdquo Proceedings ofthe National Academy of Sciences of the United States of Americavol 107 no 6 pp 2669ndash2674 2010
[96] I Goshen T Kreisel O Ben-Menachem-Zidon et al ldquoBraininterleukin-1 mediates chronic stress-induced depression inmice via adrenocortical activation and hippocampal neuroge-nesis suppressionrdquo Molecular Psychiatry vol 13 no 7 pp 717ndash728 2008
[97] C D Munhoz L B Lepsch E M Kawamoto et al ldquoChronicunpredictable stress exacerbates lipopolysaccharide-inducedactivation of nuclear factor-120581B in the frontal cortex andhippocampus via glucocorticoid secretionrdquo Journal of Neuro-science vol 26 no 14 pp 3813ndash3820 2006
[98] S J Sukoff Rizzo S J Neal Z A Hughes et al ldquoEvidence forsustained elevation of IL-6 in the CNS as a key contributorof depressive-like phenotypesrdquo Translational Psychiatry vol 2article e199 2012
[99] A Garcia B Steiner G Kronenberg A Bick-Sander and GKempermann ldquoAge-dependent expression of glucocorticoid-andmineralocorticoid receptors on neural precursor cell popu-lations in the adult murine hippocampusrdquoAging Cell vol 3 no6 pp 363ndash371 2004
[100] M G Frank B M Thompson L R Watkins and S F MaierldquoGlucocorticoids mediate stress-induced priming of microglialpro-inflammatory responsesrdquo Brain Behavior and Immunityvol 26 no 2 pp 337ndash345 2012
[101] S Sugama M Fujita M Hashimoto and B Conti ldquoStressinduced morphological microglial activation in the rodentbrain involvement of interleukin-18rdquoNeuroscience vol 146 no3 pp 1388ndash1399 2007
[102] A Sierra J M Encinas and M Maletic-Savatic ldquoAdult humanneurogenesis from microscopy to magnetic resonance imag-ingrdquo Frontiers in Neuroscience vol 5 article 47 2011
[103] H G Kuhn H Dickinson-Anson and F H Gage ldquoNeurogen-esis in the dentate gyrus of the adult rat age-related decrease ofneuronal progenitor proliferationrdquo Journal of Neuroscience vol16 no 6 pp 2027ndash2033 1996
[104] L N Manganas X Zhang Y Li et al ldquoMagnetic resonancespectroscopy identifies neural progenitor cells in the live humanbrainrdquo Science vol 318 no 5852 pp 980ndash985 2007
[105] K L Spalding O Bergmann K Alkass et al ldquoDynamics ofhippocampal neurogenesis in adult humansrdquo Cell vol 153 no6 pp 1219ndash1227 2013
[106] J M Encinas and A Sierra ldquoNeural stem cell deforestationas the main force driving the age-related decline in adulthippocampal neurogenesisrdquo Behavioural Brain Research vol227 no 2 pp 433ndash439 2012
[107] K S Krabbe M Pedersen andH Bruunsgaard ldquoInflammatorymediators in the elderlyrdquo Experimental Gerontology vol 39 no5 pp 687ndash699 2004
[108] B S Diniz A L Teixeira L Talib W F Gattaz andO V Forlenza ldquoInterleukin-1120573 serum levels is increased inantidepressant-free elderly depressed patientsrdquo American Jour-nal of Geriatric Psychiatry vol 18 no 2 pp 172ndash176 2010
[109] A Sierra A C Gottfried-Blackmore B S Mcewen and KBulloch ldquoMicroglia derived from aging mice exhibit an alteredinflammatory profilerdquo GLIA vol 55 no 4 pp 412ndash424 2007
[110] C FranceschiM Bonafe S Valensin et al ldquoInflamm-aging Anevolutionary perspective on immunosenescencerdquo Annals of theNew York Academy of Sciences vol 908 pp 244ndash254 2000
[111] R Sano and J C Reed ldquoER stress-induced cell death mecha-nismsrdquoBiochimica et BiophysicaActa vol 1833 no 12 pp 3460ndash3470 2013
[112] S Z Hasnain R Lourie I Das A C H Chen and MA McGuckin ldquoThe interplay between endoplasmic reticulumstress and inflammationrdquo Immunology and Cell Biology vol 90no 3 pp 260ndash270 2012
[113] S Matus L H Glimcher and C Hetz ldquoProtein folding stressin neurodegenerative diseases a glimpse into the ERrdquo CurrentOpinion in Cell Biology vol 23 no 2 pp 239ndash252 2011
[114] Y Ito M Yamada H Tanaka et al ldquoInvolvement of CHOP anER-stress apoptotic mediator in both human sporadic ALS andALS model micerdquo Neurobiology of Disease vol 36 no 3 pp470ndash476 2009
[115] D Papadimitriou V Le Verche A Jacquier B Ikiz S Przed-borski and D B Re ldquoInflammation in ALS and SMA sortingout the good from the evilrdquo Neurobiology of Disease vol 37 no3 pp 493ndash502 2010
[116] A R Johnson J J Milner and LMakowski ldquoThe inflammationhighway metabolism accelerates inflammatory traffic in obe-sityrdquo Immunological Reviews vol 249 no 1 pp 218ndash238 2012
[117] S Buch H Yao M Guo et al ldquoCocaine and HIV-1 interplayin CNS cellular and molecular mechanismsrdquo Current HIVResearch vol 10 no 5 pp 425ndash428 2012
[118] M K Brown and N Naidoo ldquoThe endoplasmic reticulumstress response in aging and age-related diseasesrdquo Frontiers inPhysiology vol 3 article 263 2012
[119] G Castro C Areias MF L Weissmann et al ldquoDiet-inducedobesity induces endoplasmic reticulum stress and insulin resis-tance in the amygdala of ratsrdquo FEBS Open Bio vol 3 pp 443ndash449 2013
[120] A A Pavlovsky D Boehning D Li Y Zhang X Fan andT A Green ldquoPsychological stress cocaine and natural rewardeach induce endoplasmic reticulum stress genes in rat brainrdquoNeuroscience vol 246 pp 160ndash169 2013
[121] G GargiuloM CesaroniM Serresi et al ldquoIn vivo RNAi screenfor BMI1 targets identifies TGF-betaBMP-ER stress pathwaysas key regulators of neural- and malignant glioma-stem cellhomeostasisrdquo Cancer Cell vol 23 no 5 pp 660ndash676 2013
[122] A Salminen K Kaarniranta and A Kauppinen ldquoInflammag-ing disturbed interplay between autophagy and inflamma-somesrdquo Aging vol 4 no 3 pp 166ndash175 2012
[123] E Latz T S Xiao andA Stutz ldquoActivation and regulation of theinflammasomesrdquoNature Reviews Immunology vol 13 no 6 pp397ndash411 2013
[124] C Gemma A D Bachstetter M J Cole M Fister C Hudsonand P C Bickford ldquoBlockade of caspase-1 increases neurogene-sis in the aged hippocampusrdquo European Journal of Neurosciencevol 26 no 10 pp 2795ndash2803 2007
[125] M D Wu A M Hein M J Moravan S S Shaftel J AOlschowka and M K OrsquoBanion ldquoAdult murine hippocampal
14 Neural Plasticity
neurogenesis is inhibited by sustained IL-1120573 and not rescued byvoluntary runningrdquo Brain Behavior and Immunity vol 26 no2 pp 292ndash300 2012
[126] Y Wolf S Yona K W Kim and S Jung ldquoMicroglia seen fromthe CX3CR1 anglerdquo Frontiers in Cellular Neuroscience vol 7article 26 2013
[127] A E Cardona E P Pioro M E Sasse et al ldquoControl ofmicroglial neurotoxicity by the fractalkine receptorrdquo NatureNeuroscience vol 9 no 7 pp 917ndash924 2006
[128] K Bhaskar M Konerth O N Kokiko-Cochran A Cardona RM Ransohoff and B T Lamb ldquoRegulation of tau pathology bythe microglial fractalkine receptorrdquo Neuron vol 68 no 1 pp19ndash31 2010
[129] A D Bachstetter J M Morganti J Jernberg et al ldquoFractalkineand CX3CR1 regulate hippocampal neurogenesis in adult andaged ratsrdquo Neurobiology of Aging vol 32 no 11 pp 2030ndash20442011
[130] S Jung J Aliberti P Graemmel et al ldquoAnalysis of fractalkinereceptor CX3CR1 function by targeted deletion and greenfluorescent protein reporter gene insertionrdquo Molecular andCellular Biology vol 20 no 11 pp 4106ndash4114 2000
[131] J T Rogers J M Morganti A D Bachstetter et al ldquoCX3CR1deficiency leads to impairment of hippocampal cognitive func-tion and synaptic plasticityrdquo Journal of Neuroscience vol 31 no45 pp 16241ndash16250 2011
[132] W S T Griffin L C Stanley C Ling et al ldquoBrain interleukin1 and S-100 immunoreactivity are elevated in Down syndromeand Alzheimer diseaserdquo Proceedings of the National Academy ofSciences of the United States of America vol 86 no 19 pp 7611ndash7615 1989
[133] W C Benzing J RWujek E KWard et al ldquoEvidence for glial-mediated inflammation in aged APP(SW) transgenic micerdquoNeurobiology of Aging vol 20 no 6 pp 581ndash589 1999
[134] T J Seabrook L Jiang M Maier and C A Lemere ldquoMinocy-cline affects microglia activation A120573 deposition and behaviorin APP-tg micerdquo GLIA vol 53 no 7 pp 776ndash782 2006
[135] B Biscaro O Lindvall G Tesco C T Ekdahl and RM NitschldquoInhibition of microglial activation protects hippocampal neu-rogenesis and improves cognitive deficits in a transgenic mousemodel for Alzheimerrsquos diseaserdquoNeurodegenerative Diseases vol9 no 4 pp 187ndash198 2012
[136] P A Zunszain C Anacker A Cattaneo et al ldquoInterleukin-1120573a new regulator of the kynurenine pathway affecting humanhippocampal neurogenesisrdquo Neuropsychopharmacology vol 37no 4 pp 939ndash949 2012
[137] R De Simone M Antonietta Ajmone-Cat P Tirassa and LMinghetti ldquoApoptotic PC12 cells exposing phosphatidylserinepromote the production of anti-inflammatory and neuropro-tective molecules bymicroglial cellsrdquo Journal of Neuropathologyand Experimental Neurology vol 62 no 2 pp 208ndash216 2003
[138] M S Buckwalter M Yamane B S Coleman et al ldquoChroni-cally increased transforming growth factor-1205731 strongly inhibitshippocampal neurogenesis in aged micerdquo American Journal ofPathology vol 169 no 1 pp 154ndash164 2006
[139] O Butovsky Y Ziv A Schwartz et al ldquoMicroglia activatedby IL-4 or IFN-120574 differentially induce neurogenesis and oligo-dendrogenesis from adult stemprogenitor cellsrdquoMolecular andCellular Neuroscience vol 31 no 1 pp 149ndash160 2006
[140] C T Ekdahl ldquoMicroglial activationmdashtuning and pruning adultneurogenesisrdquo Frontiers in Pharmacology vol 3 article 41 2012
[141] HWakeA JMoorhouse S Jinno S Kohsaka and JNabekuraldquoResting microglia directly monitor the functional state ofsynapses in vivo and determine the fate of ischemic terminalsrdquoJournal of Neuroscience vol 29 no 13 pp 3974ndash3980 2009
[142] M E Tremblay R L Lowery and A K Majewska ldquoMicroglialinteractions with synapses are modulated by visual experiencerdquoPLoS Biology vol 8 no 11 Article ID e1000527 2010
[143] M E Tremblay M L Zettel J R Ison P D Allen and A KMajewska ldquoEffects of aging and sensory loss on glial cells inmouse visual and auditory corticesrdquo GLIA vol 60 no 4 pp541ndash558 2012
[144] D P Schafer E K Lehrman A G Kautzman et al ldquoMicrogliasculpt postnatal neural circuits in an activity and complement-dependent mannerrdquo Neuron vol 74 no 4 pp 691ndash705 2012
[145] H Nakanishi ldquoMicroglial functions and proteasesrdquo MolecularNeurobiology vol 27 no 2 pp 163ndash176 2003
[146] M E Tremblay and A K Majewska ldquoA role for microglia insynaptic plasticityrdquoCommunicative and Integrative Biology vol4 no 2 pp 220ndash222 2011
[147] R C Paolicelli G Bolasco F Pagani et al ldquoSynaptic pruning bymicroglia is necessary for normal brain developmentrdquo Sciencevol 333 no 6048 pp 1456ndash1458 2011
[148] GKempermannHGKuhn and FHGage ldquoMore hippocam-pal neurons in adult mice living in an enriched environmentrdquoNature vol 386 no 6624 pp 493ndash495 1997
[149] M Nilsson E Perfilieva U Johansson O Orwar and P SEriksson ldquoEnriched environment increases neurogenesis in theadult rat dentate gyrus and improves spatial memoryrdquo Journalof Neurobiology vol 39 no 4 pp 569ndash578 1999
[150] H van Praag G Kempermann and F H Gage ldquoRunningincreases cell proliferation and neurogenesis in the adult mousedentate gyrusrdquo Nature Neuroscience vol 2 no 3 pp 266ndash2701999
[151] D Young P A Lawlor P Leone M Dragunow and MJ During ldquoEnvironmental enrichment inhibits spontaneousapoptosis prevents seizures and is neuroprotectiverdquo NatureMedicine vol 5 no 4 pp 448ndash453 1999
[152] L L Williamson A Chao and S D Bilbo ldquoEnvironmentalenrichment alters glial antigen expression and neuroimmunefunction in the adult rat hippocampusrdquo Brain Behavior andImmunity vol 26 no 3 pp 500ndash510 2012
[153] L Maggi M Scianni I Branchi I DrsquoAndrea C Lauro and CLimatola ldquoCX(3)CR1 deficiency alters hippocampal-dependentplasticity phenomena blunting the effects of enriched environ-mentrdquo Frontiers in Cellular Neuroscience vol 5 article 22 2011
[154] I Goshen A Avital T Kreisel T Licht M Segal and RYirmiya ldquoEnvironmental enrichment restores memory func-tioning in mice with impaired IL-1 signaling via reinstatementof long-term potentiation and spine size enlargementrdquo Journalof Neuroscience vol 29 no 11 pp 3395ndash3403 2009
[155] Y Ziv N Ron O Butovsky et al ldquoImmune cells contribute tothe maintenance of neurogenesis and spatial learning abilitiesin adulthoodrdquo Nature Neuroscience vol 9 no 2 pp 268ndash2752006
[156] J Kipnis H Cohen M Cardon Y Ziv and M Schwartz ldquoTcell deficiency leads to cognitive dysfunction implications fortherapeutic vaccination for schizophrenia and other psychiatricconditionsrdquo Proceedings of the National Academy of Sciences ofthe United States of America vol 101 no 21 pp 8180ndash8185 2004
[157] S A Wolf B Steiner A Akpinarli et al ldquoCD4-positive Tlymphocytes provide a neuroimmunological link in the control
Neural Plasticity 15
of adult hippocampal neurogenesisrdquo Journal of Immunologyvol 182 no 7 pp 3979ndash3984 2009
[158] G J Huang A L Smith D H D Gray et al ldquoA genetic andfunctional relationship between T cells and cellular prolifera-tion in the adult hippocampusrdquo PLOS Biology vol 8 no 12Article ID e1000561 2010
[159] R M Ransohoff and B Engelhardt ldquoThe anatomical andcellular basis of immune surveillance in the central nervoussystemrdquoNature Reviews Immunology vol 12 no 9 pp 623ndash6352012
[160] M Olah G Ping A H De Haas et al ldquoEnhanced hippocampalneurogenesis in the absence of microglia T cell interactionand microglia activation in the murine running wheel modelrdquoGLIA vol 57 no 10 pp 1046ndash1061 2009
[161] E Gebara S Sultan J Kocher-Braissant and N Toni ldquoAdulthippocampal neurogenesis inversely correlates with microgliain conditions of voluntary running and agingrdquo Frontiers inNeuroscience vol 7 article 145 2013
[162] R Aharoni B Kayhan R Eilam M Sela and R ArnonldquoGlatiramer acetate-specific T cells in the brain express T helper23 cytokines and brain-derived neurotrophic factor in siturdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 100 no 2 pp 14157ndash14162 2003
[163] C Rossi A Angelucci L Costantin et al ldquoBrain-derivedneurotrophic factor (BDNF) is required for the enhancementof hippocampal neurogenesis following environmental enrich-mentrdquo European Journal of Neuroscience vol 24 no 7 pp 1850ndash1856 2006
Neural Plasticity 13
of Sciences of the United States of America vol 107 no 9 pp4436ndash4441 2010
[93] G Kronenberg I Kirste D Inta et al ldquoReduced hippocampalneurogenesis in the GR+- genetic mousemodel of depressionrdquoEuropean Archives of Psychiatry and Clinical Neuroscience vol259 no 8 pp 499ndash504 2009
[94] M B Howren D M Lamkin and J Suls ldquoAssociations ofdepression with c-reactive protein IL-1 and IL-6 a meta-analysisrdquo Psychosomatic Medicine vol 71 no 2 pp 171ndash1862009
[95] J W Koo S J Russo D Ferguson E J Nestler and R SDuman ldquoNuclear factor-120581B is a critical mediator of stress-impaired neurogenesis and depressive behaviorrdquo Proceedings ofthe National Academy of Sciences of the United States of Americavol 107 no 6 pp 2669ndash2674 2010
[96] I Goshen T Kreisel O Ben-Menachem-Zidon et al ldquoBraininterleukin-1 mediates chronic stress-induced depression inmice via adrenocortical activation and hippocampal neuroge-nesis suppressionrdquo Molecular Psychiatry vol 13 no 7 pp 717ndash728 2008
[97] C D Munhoz L B Lepsch E M Kawamoto et al ldquoChronicunpredictable stress exacerbates lipopolysaccharide-inducedactivation of nuclear factor-120581B in the frontal cortex andhippocampus via glucocorticoid secretionrdquo Journal of Neuro-science vol 26 no 14 pp 3813ndash3820 2006
[98] S J Sukoff Rizzo S J Neal Z A Hughes et al ldquoEvidence forsustained elevation of IL-6 in the CNS as a key contributorof depressive-like phenotypesrdquo Translational Psychiatry vol 2article e199 2012
[99] A Garcia B Steiner G Kronenberg A Bick-Sander and GKempermann ldquoAge-dependent expression of glucocorticoid-andmineralocorticoid receptors on neural precursor cell popu-lations in the adult murine hippocampusrdquoAging Cell vol 3 no6 pp 363ndash371 2004
[100] M G Frank B M Thompson L R Watkins and S F MaierldquoGlucocorticoids mediate stress-induced priming of microglialpro-inflammatory responsesrdquo Brain Behavior and Immunityvol 26 no 2 pp 337ndash345 2012
[101] S Sugama M Fujita M Hashimoto and B Conti ldquoStressinduced morphological microglial activation in the rodentbrain involvement of interleukin-18rdquoNeuroscience vol 146 no3 pp 1388ndash1399 2007
[102] A Sierra J M Encinas and M Maletic-Savatic ldquoAdult humanneurogenesis from microscopy to magnetic resonance imag-ingrdquo Frontiers in Neuroscience vol 5 article 47 2011
[103] H G Kuhn H Dickinson-Anson and F H Gage ldquoNeurogen-esis in the dentate gyrus of the adult rat age-related decrease ofneuronal progenitor proliferationrdquo Journal of Neuroscience vol16 no 6 pp 2027ndash2033 1996
[104] L N Manganas X Zhang Y Li et al ldquoMagnetic resonancespectroscopy identifies neural progenitor cells in the live humanbrainrdquo Science vol 318 no 5852 pp 980ndash985 2007
[105] K L Spalding O Bergmann K Alkass et al ldquoDynamics ofhippocampal neurogenesis in adult humansrdquo Cell vol 153 no6 pp 1219ndash1227 2013
[106] J M Encinas and A Sierra ldquoNeural stem cell deforestationas the main force driving the age-related decline in adulthippocampal neurogenesisrdquo Behavioural Brain Research vol227 no 2 pp 433ndash439 2012
[107] K S Krabbe M Pedersen andH Bruunsgaard ldquoInflammatorymediators in the elderlyrdquo Experimental Gerontology vol 39 no5 pp 687ndash699 2004
[108] B S Diniz A L Teixeira L Talib W F Gattaz andO V Forlenza ldquoInterleukin-1120573 serum levels is increased inantidepressant-free elderly depressed patientsrdquo American Jour-nal of Geriatric Psychiatry vol 18 no 2 pp 172ndash176 2010
[109] A Sierra A C Gottfried-Blackmore B S Mcewen and KBulloch ldquoMicroglia derived from aging mice exhibit an alteredinflammatory profilerdquo GLIA vol 55 no 4 pp 412ndash424 2007
[110] C FranceschiM Bonafe S Valensin et al ldquoInflamm-aging Anevolutionary perspective on immunosenescencerdquo Annals of theNew York Academy of Sciences vol 908 pp 244ndash254 2000
[111] R Sano and J C Reed ldquoER stress-induced cell death mecha-nismsrdquoBiochimica et BiophysicaActa vol 1833 no 12 pp 3460ndash3470 2013
[112] S Z Hasnain R Lourie I Das A C H Chen and MA McGuckin ldquoThe interplay between endoplasmic reticulumstress and inflammationrdquo Immunology and Cell Biology vol 90no 3 pp 260ndash270 2012
[113] S Matus L H Glimcher and C Hetz ldquoProtein folding stressin neurodegenerative diseases a glimpse into the ERrdquo CurrentOpinion in Cell Biology vol 23 no 2 pp 239ndash252 2011
[114] Y Ito M Yamada H Tanaka et al ldquoInvolvement of CHOP anER-stress apoptotic mediator in both human sporadic ALS andALS model micerdquo Neurobiology of Disease vol 36 no 3 pp470ndash476 2009
[115] D Papadimitriou V Le Verche A Jacquier B Ikiz S Przed-borski and D B Re ldquoInflammation in ALS and SMA sortingout the good from the evilrdquo Neurobiology of Disease vol 37 no3 pp 493ndash502 2010
[116] A R Johnson J J Milner and LMakowski ldquoThe inflammationhighway metabolism accelerates inflammatory traffic in obe-sityrdquo Immunological Reviews vol 249 no 1 pp 218ndash238 2012
[117] S Buch H Yao M Guo et al ldquoCocaine and HIV-1 interplayin CNS cellular and molecular mechanismsrdquo Current HIVResearch vol 10 no 5 pp 425ndash428 2012
[118] M K Brown and N Naidoo ldquoThe endoplasmic reticulumstress response in aging and age-related diseasesrdquo Frontiers inPhysiology vol 3 article 263 2012
[119] G Castro C Areias MF L Weissmann et al ldquoDiet-inducedobesity induces endoplasmic reticulum stress and insulin resis-tance in the amygdala of ratsrdquo FEBS Open Bio vol 3 pp 443ndash449 2013
[120] A A Pavlovsky D Boehning D Li Y Zhang X Fan andT A Green ldquoPsychological stress cocaine and natural rewardeach induce endoplasmic reticulum stress genes in rat brainrdquoNeuroscience vol 246 pp 160ndash169 2013
[121] G GargiuloM CesaroniM Serresi et al ldquoIn vivo RNAi screenfor BMI1 targets identifies TGF-betaBMP-ER stress pathwaysas key regulators of neural- and malignant glioma-stem cellhomeostasisrdquo Cancer Cell vol 23 no 5 pp 660ndash676 2013
[122] A Salminen K Kaarniranta and A Kauppinen ldquoInflammag-ing disturbed interplay between autophagy and inflamma-somesrdquo Aging vol 4 no 3 pp 166ndash175 2012
[123] E Latz T S Xiao andA Stutz ldquoActivation and regulation of theinflammasomesrdquoNature Reviews Immunology vol 13 no 6 pp397ndash411 2013
[124] C Gemma A D Bachstetter M J Cole M Fister C Hudsonand P C Bickford ldquoBlockade of caspase-1 increases neurogene-sis in the aged hippocampusrdquo European Journal of Neurosciencevol 26 no 10 pp 2795ndash2803 2007
[125] M D Wu A M Hein M J Moravan S S Shaftel J AOlschowka and M K OrsquoBanion ldquoAdult murine hippocampal
14 Neural Plasticity
neurogenesis is inhibited by sustained IL-1120573 and not rescued byvoluntary runningrdquo Brain Behavior and Immunity vol 26 no2 pp 292ndash300 2012
[126] Y Wolf S Yona K W Kim and S Jung ldquoMicroglia seen fromthe CX3CR1 anglerdquo Frontiers in Cellular Neuroscience vol 7article 26 2013
[127] A E Cardona E P Pioro M E Sasse et al ldquoControl ofmicroglial neurotoxicity by the fractalkine receptorrdquo NatureNeuroscience vol 9 no 7 pp 917ndash924 2006
[128] K Bhaskar M Konerth O N Kokiko-Cochran A Cardona RM Ransohoff and B T Lamb ldquoRegulation of tau pathology bythe microglial fractalkine receptorrdquo Neuron vol 68 no 1 pp19ndash31 2010
[129] A D Bachstetter J M Morganti J Jernberg et al ldquoFractalkineand CX3CR1 regulate hippocampal neurogenesis in adult andaged ratsrdquo Neurobiology of Aging vol 32 no 11 pp 2030ndash20442011
[130] S Jung J Aliberti P Graemmel et al ldquoAnalysis of fractalkinereceptor CX3CR1 function by targeted deletion and greenfluorescent protein reporter gene insertionrdquo Molecular andCellular Biology vol 20 no 11 pp 4106ndash4114 2000
[131] J T Rogers J M Morganti A D Bachstetter et al ldquoCX3CR1deficiency leads to impairment of hippocampal cognitive func-tion and synaptic plasticityrdquo Journal of Neuroscience vol 31 no45 pp 16241ndash16250 2011
[132] W S T Griffin L C Stanley C Ling et al ldquoBrain interleukin1 and S-100 immunoreactivity are elevated in Down syndromeand Alzheimer diseaserdquo Proceedings of the National Academy ofSciences of the United States of America vol 86 no 19 pp 7611ndash7615 1989
[133] W C Benzing J RWujek E KWard et al ldquoEvidence for glial-mediated inflammation in aged APP(SW) transgenic micerdquoNeurobiology of Aging vol 20 no 6 pp 581ndash589 1999
[134] T J Seabrook L Jiang M Maier and C A Lemere ldquoMinocy-cline affects microglia activation A120573 deposition and behaviorin APP-tg micerdquo GLIA vol 53 no 7 pp 776ndash782 2006
[135] B Biscaro O Lindvall G Tesco C T Ekdahl and RM NitschldquoInhibition of microglial activation protects hippocampal neu-rogenesis and improves cognitive deficits in a transgenic mousemodel for Alzheimerrsquos diseaserdquoNeurodegenerative Diseases vol9 no 4 pp 187ndash198 2012
[136] P A Zunszain C Anacker A Cattaneo et al ldquoInterleukin-1120573a new regulator of the kynurenine pathway affecting humanhippocampal neurogenesisrdquo Neuropsychopharmacology vol 37no 4 pp 939ndash949 2012
[137] R De Simone M Antonietta Ajmone-Cat P Tirassa and LMinghetti ldquoApoptotic PC12 cells exposing phosphatidylserinepromote the production of anti-inflammatory and neuropro-tective molecules bymicroglial cellsrdquo Journal of Neuropathologyand Experimental Neurology vol 62 no 2 pp 208ndash216 2003
[138] M S Buckwalter M Yamane B S Coleman et al ldquoChroni-cally increased transforming growth factor-1205731 strongly inhibitshippocampal neurogenesis in aged micerdquo American Journal ofPathology vol 169 no 1 pp 154ndash164 2006
[139] O Butovsky Y Ziv A Schwartz et al ldquoMicroglia activatedby IL-4 or IFN-120574 differentially induce neurogenesis and oligo-dendrogenesis from adult stemprogenitor cellsrdquoMolecular andCellular Neuroscience vol 31 no 1 pp 149ndash160 2006
[140] C T Ekdahl ldquoMicroglial activationmdashtuning and pruning adultneurogenesisrdquo Frontiers in Pharmacology vol 3 article 41 2012
[141] HWakeA JMoorhouse S Jinno S Kohsaka and JNabekuraldquoResting microglia directly monitor the functional state ofsynapses in vivo and determine the fate of ischemic terminalsrdquoJournal of Neuroscience vol 29 no 13 pp 3974ndash3980 2009
[142] M E Tremblay R L Lowery and A K Majewska ldquoMicroglialinteractions with synapses are modulated by visual experiencerdquoPLoS Biology vol 8 no 11 Article ID e1000527 2010
[143] M E Tremblay M L Zettel J R Ison P D Allen and A KMajewska ldquoEffects of aging and sensory loss on glial cells inmouse visual and auditory corticesrdquo GLIA vol 60 no 4 pp541ndash558 2012
[144] D P Schafer E K Lehrman A G Kautzman et al ldquoMicrogliasculpt postnatal neural circuits in an activity and complement-dependent mannerrdquo Neuron vol 74 no 4 pp 691ndash705 2012
[145] H Nakanishi ldquoMicroglial functions and proteasesrdquo MolecularNeurobiology vol 27 no 2 pp 163ndash176 2003
[146] M E Tremblay and A K Majewska ldquoA role for microglia insynaptic plasticityrdquoCommunicative and Integrative Biology vol4 no 2 pp 220ndash222 2011
[147] R C Paolicelli G Bolasco F Pagani et al ldquoSynaptic pruning bymicroglia is necessary for normal brain developmentrdquo Sciencevol 333 no 6048 pp 1456ndash1458 2011
[148] GKempermannHGKuhn and FHGage ldquoMore hippocam-pal neurons in adult mice living in an enriched environmentrdquoNature vol 386 no 6624 pp 493ndash495 1997
[149] M Nilsson E Perfilieva U Johansson O Orwar and P SEriksson ldquoEnriched environment increases neurogenesis in theadult rat dentate gyrus and improves spatial memoryrdquo Journalof Neurobiology vol 39 no 4 pp 569ndash578 1999
[150] H van Praag G Kempermann and F H Gage ldquoRunningincreases cell proliferation and neurogenesis in the adult mousedentate gyrusrdquo Nature Neuroscience vol 2 no 3 pp 266ndash2701999
[151] D Young P A Lawlor P Leone M Dragunow and MJ During ldquoEnvironmental enrichment inhibits spontaneousapoptosis prevents seizures and is neuroprotectiverdquo NatureMedicine vol 5 no 4 pp 448ndash453 1999
[152] L L Williamson A Chao and S D Bilbo ldquoEnvironmentalenrichment alters glial antigen expression and neuroimmunefunction in the adult rat hippocampusrdquo Brain Behavior andImmunity vol 26 no 3 pp 500ndash510 2012
[153] L Maggi M Scianni I Branchi I DrsquoAndrea C Lauro and CLimatola ldquoCX(3)CR1 deficiency alters hippocampal-dependentplasticity phenomena blunting the effects of enriched environ-mentrdquo Frontiers in Cellular Neuroscience vol 5 article 22 2011
[154] I Goshen A Avital T Kreisel T Licht M Segal and RYirmiya ldquoEnvironmental enrichment restores memory func-tioning in mice with impaired IL-1 signaling via reinstatementof long-term potentiation and spine size enlargementrdquo Journalof Neuroscience vol 29 no 11 pp 3395ndash3403 2009
[155] Y Ziv N Ron O Butovsky et al ldquoImmune cells contribute tothe maintenance of neurogenesis and spatial learning abilitiesin adulthoodrdquo Nature Neuroscience vol 9 no 2 pp 268ndash2752006
[156] J Kipnis H Cohen M Cardon Y Ziv and M Schwartz ldquoTcell deficiency leads to cognitive dysfunction implications fortherapeutic vaccination for schizophrenia and other psychiatricconditionsrdquo Proceedings of the National Academy of Sciences ofthe United States of America vol 101 no 21 pp 8180ndash8185 2004
[157] S A Wolf B Steiner A Akpinarli et al ldquoCD4-positive Tlymphocytes provide a neuroimmunological link in the control
Neural Plasticity 15
of adult hippocampal neurogenesisrdquo Journal of Immunologyvol 182 no 7 pp 3979ndash3984 2009
[158] G J Huang A L Smith D H D Gray et al ldquoA genetic andfunctional relationship between T cells and cellular prolifera-tion in the adult hippocampusrdquo PLOS Biology vol 8 no 12Article ID e1000561 2010
[159] R M Ransohoff and B Engelhardt ldquoThe anatomical andcellular basis of immune surveillance in the central nervoussystemrdquoNature Reviews Immunology vol 12 no 9 pp 623ndash6352012
[160] M Olah G Ping A H De Haas et al ldquoEnhanced hippocampalneurogenesis in the absence of microglia T cell interactionand microglia activation in the murine running wheel modelrdquoGLIA vol 57 no 10 pp 1046ndash1061 2009
[161] E Gebara S Sultan J Kocher-Braissant and N Toni ldquoAdulthippocampal neurogenesis inversely correlates with microgliain conditions of voluntary running and agingrdquo Frontiers inNeuroscience vol 7 article 145 2013
[162] R Aharoni B Kayhan R Eilam M Sela and R ArnonldquoGlatiramer acetate-specific T cells in the brain express T helper23 cytokines and brain-derived neurotrophic factor in siturdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 100 no 2 pp 14157ndash14162 2003
[163] C Rossi A Angelucci L Costantin et al ldquoBrain-derivedneurotrophic factor (BDNF) is required for the enhancementof hippocampal neurogenesis following environmental enrich-mentrdquo European Journal of Neuroscience vol 24 no 7 pp 1850ndash1856 2006
14 Neural Plasticity
neurogenesis is inhibited by sustained IL-1120573 and not rescued byvoluntary runningrdquo Brain Behavior and Immunity vol 26 no2 pp 292ndash300 2012
[126] Y Wolf S Yona K W Kim and S Jung ldquoMicroglia seen fromthe CX3CR1 anglerdquo Frontiers in Cellular Neuroscience vol 7article 26 2013
[127] A E Cardona E P Pioro M E Sasse et al ldquoControl ofmicroglial neurotoxicity by the fractalkine receptorrdquo NatureNeuroscience vol 9 no 7 pp 917ndash924 2006
[128] K Bhaskar M Konerth O N Kokiko-Cochran A Cardona RM Ransohoff and B T Lamb ldquoRegulation of tau pathology bythe microglial fractalkine receptorrdquo Neuron vol 68 no 1 pp19ndash31 2010
[129] A D Bachstetter J M Morganti J Jernberg et al ldquoFractalkineand CX3CR1 regulate hippocampal neurogenesis in adult andaged ratsrdquo Neurobiology of Aging vol 32 no 11 pp 2030ndash20442011
[130] S Jung J Aliberti P Graemmel et al ldquoAnalysis of fractalkinereceptor CX3CR1 function by targeted deletion and greenfluorescent protein reporter gene insertionrdquo Molecular andCellular Biology vol 20 no 11 pp 4106ndash4114 2000
[131] J T Rogers J M Morganti A D Bachstetter et al ldquoCX3CR1deficiency leads to impairment of hippocampal cognitive func-tion and synaptic plasticityrdquo Journal of Neuroscience vol 31 no45 pp 16241ndash16250 2011
[132] W S T Griffin L C Stanley C Ling et al ldquoBrain interleukin1 and S-100 immunoreactivity are elevated in Down syndromeand Alzheimer diseaserdquo Proceedings of the National Academy ofSciences of the United States of America vol 86 no 19 pp 7611ndash7615 1989
[133] W C Benzing J RWujek E KWard et al ldquoEvidence for glial-mediated inflammation in aged APP(SW) transgenic micerdquoNeurobiology of Aging vol 20 no 6 pp 581ndash589 1999
[134] T J Seabrook L Jiang M Maier and C A Lemere ldquoMinocy-cline affects microglia activation A120573 deposition and behaviorin APP-tg micerdquo GLIA vol 53 no 7 pp 776ndash782 2006
[135] B Biscaro O Lindvall G Tesco C T Ekdahl and RM NitschldquoInhibition of microglial activation protects hippocampal neu-rogenesis and improves cognitive deficits in a transgenic mousemodel for Alzheimerrsquos diseaserdquoNeurodegenerative Diseases vol9 no 4 pp 187ndash198 2012
[136] P A Zunszain C Anacker A Cattaneo et al ldquoInterleukin-1120573a new regulator of the kynurenine pathway affecting humanhippocampal neurogenesisrdquo Neuropsychopharmacology vol 37no 4 pp 939ndash949 2012
[137] R De Simone M Antonietta Ajmone-Cat P Tirassa and LMinghetti ldquoApoptotic PC12 cells exposing phosphatidylserinepromote the production of anti-inflammatory and neuropro-tective molecules bymicroglial cellsrdquo Journal of Neuropathologyand Experimental Neurology vol 62 no 2 pp 208ndash216 2003
[138] M S Buckwalter M Yamane B S Coleman et al ldquoChroni-cally increased transforming growth factor-1205731 strongly inhibitshippocampal neurogenesis in aged micerdquo American Journal ofPathology vol 169 no 1 pp 154ndash164 2006
[139] O Butovsky Y Ziv A Schwartz et al ldquoMicroglia activatedby IL-4 or IFN-120574 differentially induce neurogenesis and oligo-dendrogenesis from adult stemprogenitor cellsrdquoMolecular andCellular Neuroscience vol 31 no 1 pp 149ndash160 2006
[140] C T Ekdahl ldquoMicroglial activationmdashtuning and pruning adultneurogenesisrdquo Frontiers in Pharmacology vol 3 article 41 2012
[141] HWakeA JMoorhouse S Jinno S Kohsaka and JNabekuraldquoResting microglia directly monitor the functional state ofsynapses in vivo and determine the fate of ischemic terminalsrdquoJournal of Neuroscience vol 29 no 13 pp 3974ndash3980 2009
[142] M E Tremblay R L Lowery and A K Majewska ldquoMicroglialinteractions with synapses are modulated by visual experiencerdquoPLoS Biology vol 8 no 11 Article ID e1000527 2010
[143] M E Tremblay M L Zettel J R Ison P D Allen and A KMajewska ldquoEffects of aging and sensory loss on glial cells inmouse visual and auditory corticesrdquo GLIA vol 60 no 4 pp541ndash558 2012
[144] D P Schafer E K Lehrman A G Kautzman et al ldquoMicrogliasculpt postnatal neural circuits in an activity and complement-dependent mannerrdquo Neuron vol 74 no 4 pp 691ndash705 2012
[145] H Nakanishi ldquoMicroglial functions and proteasesrdquo MolecularNeurobiology vol 27 no 2 pp 163ndash176 2003
[146] M E Tremblay and A K Majewska ldquoA role for microglia insynaptic plasticityrdquoCommunicative and Integrative Biology vol4 no 2 pp 220ndash222 2011
[147] R C Paolicelli G Bolasco F Pagani et al ldquoSynaptic pruning bymicroglia is necessary for normal brain developmentrdquo Sciencevol 333 no 6048 pp 1456ndash1458 2011
[148] GKempermannHGKuhn and FHGage ldquoMore hippocam-pal neurons in adult mice living in an enriched environmentrdquoNature vol 386 no 6624 pp 493ndash495 1997
[149] M Nilsson E Perfilieva U Johansson O Orwar and P SEriksson ldquoEnriched environment increases neurogenesis in theadult rat dentate gyrus and improves spatial memoryrdquo Journalof Neurobiology vol 39 no 4 pp 569ndash578 1999
[150] H van Praag G Kempermann and F H Gage ldquoRunningincreases cell proliferation and neurogenesis in the adult mousedentate gyrusrdquo Nature Neuroscience vol 2 no 3 pp 266ndash2701999
[151] D Young P A Lawlor P Leone M Dragunow and MJ During ldquoEnvironmental enrichment inhibits spontaneousapoptosis prevents seizures and is neuroprotectiverdquo NatureMedicine vol 5 no 4 pp 448ndash453 1999
[152] L L Williamson A Chao and S D Bilbo ldquoEnvironmentalenrichment alters glial antigen expression and neuroimmunefunction in the adult rat hippocampusrdquo Brain Behavior andImmunity vol 26 no 3 pp 500ndash510 2012
[153] L Maggi M Scianni I Branchi I DrsquoAndrea C Lauro and CLimatola ldquoCX(3)CR1 deficiency alters hippocampal-dependentplasticity phenomena blunting the effects of enriched environ-mentrdquo Frontiers in Cellular Neuroscience vol 5 article 22 2011
[154] I Goshen A Avital T Kreisel T Licht M Segal and RYirmiya ldquoEnvironmental enrichment restores memory func-tioning in mice with impaired IL-1 signaling via reinstatementof long-term potentiation and spine size enlargementrdquo Journalof Neuroscience vol 29 no 11 pp 3395ndash3403 2009
[155] Y Ziv N Ron O Butovsky et al ldquoImmune cells contribute tothe maintenance of neurogenesis and spatial learning abilitiesin adulthoodrdquo Nature Neuroscience vol 9 no 2 pp 268ndash2752006
[156] J Kipnis H Cohen M Cardon Y Ziv and M Schwartz ldquoTcell deficiency leads to cognitive dysfunction implications fortherapeutic vaccination for schizophrenia and other psychiatricconditionsrdquo Proceedings of the National Academy of Sciences ofthe United States of America vol 101 no 21 pp 8180ndash8185 2004
[157] S A Wolf B Steiner A Akpinarli et al ldquoCD4-positive Tlymphocytes provide a neuroimmunological link in the control
Neural Plasticity 15
of adult hippocampal neurogenesisrdquo Journal of Immunologyvol 182 no 7 pp 3979ndash3984 2009
[158] G J Huang A L Smith D H D Gray et al ldquoA genetic andfunctional relationship between T cells and cellular prolifera-tion in the adult hippocampusrdquo PLOS Biology vol 8 no 12Article ID e1000561 2010
[159] R M Ransohoff and B Engelhardt ldquoThe anatomical andcellular basis of immune surveillance in the central nervoussystemrdquoNature Reviews Immunology vol 12 no 9 pp 623ndash6352012
[160] M Olah G Ping A H De Haas et al ldquoEnhanced hippocampalneurogenesis in the absence of microglia T cell interactionand microglia activation in the murine running wheel modelrdquoGLIA vol 57 no 10 pp 1046ndash1061 2009
[161] E Gebara S Sultan J Kocher-Braissant and N Toni ldquoAdulthippocampal neurogenesis inversely correlates with microgliain conditions of voluntary running and agingrdquo Frontiers inNeuroscience vol 7 article 145 2013
[162] R Aharoni B Kayhan R Eilam M Sela and R ArnonldquoGlatiramer acetate-specific T cells in the brain express T helper23 cytokines and brain-derived neurotrophic factor in siturdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 100 no 2 pp 14157ndash14162 2003
[163] C Rossi A Angelucci L Costantin et al ldquoBrain-derivedneurotrophic factor (BDNF) is required for the enhancementof hippocampal neurogenesis following environmental enrich-mentrdquo European Journal of Neuroscience vol 24 no 7 pp 1850ndash1856 2006
Neural Plasticity 15
of adult hippocampal neurogenesisrdquo Journal of Immunologyvol 182 no 7 pp 3979ndash3984 2009
[158] G J Huang A L Smith D H D Gray et al ldquoA genetic andfunctional relationship between T cells and cellular prolifera-tion in the adult hippocampusrdquo PLOS Biology vol 8 no 12Article ID e1000561 2010
[159] R M Ransohoff and B Engelhardt ldquoThe anatomical andcellular basis of immune surveillance in the central nervoussystemrdquoNature Reviews Immunology vol 12 no 9 pp 623ndash6352012
[160] M Olah G Ping A H De Haas et al ldquoEnhanced hippocampalneurogenesis in the absence of microglia T cell interactionand microglia activation in the murine running wheel modelrdquoGLIA vol 57 no 10 pp 1046ndash1061 2009
[161] E Gebara S Sultan J Kocher-Braissant and N Toni ldquoAdulthippocampal neurogenesis inversely correlates with microgliain conditions of voluntary running and agingrdquo Frontiers inNeuroscience vol 7 article 145 2013
[162] R Aharoni B Kayhan R Eilam M Sela and R ArnonldquoGlatiramer acetate-specific T cells in the brain express T helper23 cytokines and brain-derived neurotrophic factor in siturdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 100 no 2 pp 14157ndash14162 2003
[163] C Rossi A Angelucci L Costantin et al ldquoBrain-derivedneurotrophic factor (BDNF) is required for the enhancementof hippocampal neurogenesis following environmental enrich-mentrdquo European Journal of Neuroscience vol 24 no 7 pp 1850ndash1856 2006
