Adult Neurogenesis and Psychiatric Disorders · suicide. The “adult neurogenesis hypothesis” of...

Adult Neurogenesis and Psychiatric Disorders

Eunchai Kang1,2, Zhexing Wen1,2, Hongjun Song1,2,3,4, Kimberly M. Christian1,2,and Guo-li Ming1,2,3,4,5

1Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland 212052Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland 212053The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine,Baltimore, Maryland 21205

4Graduate Program in Cellular and Molecular Medicine, Johns Hopkins University School of Medicine,Baltimore, Maryland 21205

5Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine,Baltimore, Maryland 21205

Correspondence: [email protected]; [email protected]

Psychiatric disorders continue to be among the most challenging disorders to diagnose andtreat because there is no single genetic or anatomical locus that is causative for the disease.Current treatments are often blunt tools used to ameliorate the most severe symptoms, at therisk of disrupting functional neural systems. There is a critical need to develop new thera-peutic strategies that can target circumscribed functional or anatomical domains of pathol-ogy. Adult hippocampal neurogenesis may be one such domain. Here, we review the evi-dence suggesting that adult hippocampal neurogenesis plays a role in emotional regulationand forms of learning and memory that include temporal and spatial memory encoding andcontext discrimination, and that its dysregulation is associated with psychiatric disorders,such as affective disorders, schizophrenia, and drug addiction. Further, adult neurogenesishas proven to be an effective model to investigate basic processes of neuronal developmentand converging evidence suggests that aberrant neural development may be an etiologicalfactor, even in late-onset diseases. Constitutive neurogenesis in the hippocampus of themature brain reflects large-scale plasticity unique to this region and could be a potentialhub for modulation of a subset of cognitive and affective behaviors that are affected bymultiple psychiatric disorders.

Adult neurogenesis is the process of continu-ously generating new neurons that can func-

tionally integrate into the adult mammalianbrain throughout life and a unique form ofstructural and functional plasticity in the hip-pocampus, a brain region key to learning, mem-ory and mood regulation (Ming and Song

2011). The subgranular zone (SGZ) of the den-tate gyrus in the hippocampus is one of twodiscrete “neurogenic” regions in the adult mam-malian brain that was initially identified usingtritiated thymidine labeling of proliferating cellsin rodents (Altman and Das 1965; Kemper-mann and Gage 1999). Importantly, adult neu-

Editors: Fred H. Gage, Gerd Kempermann, and Hongjun Song

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rogenesis is also present in the human hippo-campus, illustrating the intrinsic capacity of thehuman central nervous system to support new-born neurons and the possibility of exploitingthis phenomenon for repair of dysregulatedneural systems or recovery from injury (Eriks-son et al. 1998; Sahay and Hen 2007; Kernie andParent 2010). Adult neurogenesis recapitulatesthe developmental process of embryonic neuro-genesis, from proliferation and fate specificationof neural progenitors, to differentiation, migra-tion, axonal and dendritic development, and,finally, synaptic integration of newborn neurons(Ming and Song 2005; Braun and Jessberger2013). This unique form of neural developmenthas attracted much interest not only as a modelsystem to investigate brain development, butalso to understand hippocampal functions be-cause of the role of newborn granule neuronsin several cognitive functions, including spatiallearning and retention, memory retrieval, for-getting, and clearance of memory traces (Kita-batake et al. 2007; Deng et al. 2010; Christianet al. 2014). Impaired adult neurogenesis, on theother hand, has been associated with cognitiveimpairments that are often present in patientswith psychiatric disorders such as major depres-sion, schizophrenia, anxiety disorders, and ad-dictive behaviors (Christian et al. 2014).

Psychiatric disorders account for an estimat-ed 13% of the global disease burden and areamong the most challenging diseases to treat.These disorders typically manifest with a diversearray of symptoms, have complex genetic riskassociations, and poorly understood etiology.Currently, most available treatments are de-signed to ameliorate symptoms, rather than ad-dress the underlying pathology. Moving for-ward, it is imperative that we develop rationaltherapeutics based on a better understandingof the etiology and pathogenesis of the dis-eases. Different from neurodegenerative dis-eases that primarily affect specific cell types inthe nervous system, psychiatric disorders affectwidely distributed neural systems and cellu-lar subtypes. However, cumulative evidencestrongly suggests that structural and functionalabnormalities in the hippocampus are associat-ed with many mental disorders, indicating that

this circumscribed region may be an area thatis highly vulnerable to pathology relevant tothese disorders and a specific target for newtherapeutics.

Does impaired adult hippocampus neuro-genesis directly contribute to the pathogenesisof psychiatric disorders? Extensive studies havenow shown correlative changes in adult hip-pocampal neurogenesis under various patho-physiological conditions, such as aging, epi-lepsy, stroke, neurodegenerative disorders, andpsychiatric disorders (Parent 2003; Sahay andHen 2007; Kempermann et al. 2008; Winneret al. 2011). Whether these changes representadaptive responses to various pathophysio-logical conditions, part of the pathophysiologythat contributes to the disease, or both, remainsa key question for the field. Interestingly, formost psychiatric disorders, such as major de-pression, schizophrenia, anxiety disorders, andaddiction, a decrease in cell proliferation withinthe dentate gyrus and reduced hippocampal vol-ume have been reported, which are associatedwith impaired hippocampus-dependent func-tions, including working memory, context-de-pendent memory and recognition memory, andspatial pattern separation (Bremner 1999; Lie etal. 2004; Mirescu and Gould 2006; Reif et al.2007; Revest et al. 2009; Morris et al. 2010; Nixonet al. 2010). For example, a significant subpopu-lation of patients with major depression hasconsistently shown reduced hippocampal vol-ume and cognitive deficits (Sheline et al. 1996;Bremner 1999; Campbell and Macqueen 2004;Savitz and Drevets 2009; Kempton et al. 2011).Volumetric magnetic resonance imaging (MRI)studies have further shown that the degree ofhippocampal volume reduction correlates withtotal duration of major depression (Kemptonet al. 2011). The diagnosis of posttraumaticstress disorder (PTSD) has also been associatedwith hippocampal volume reduction and defi-cits in declarative memory function (Bremner1999, 2006; Villarreal and King 2001). In addi-tion, a number of studies have indicated that thehippocampus is smaller in juvenile and adultpatients with schizophrenia (Pfefferbaum andMarsh 1995; Csernansky et al. 1998; Nelsonet al. 1998; Wright et al. 2000; Heckers 2001;

E. Kang et al.

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Mattai et al. 2011). Hippocampal volume reduc-tion represents a loss of gray matter, which couldlead to memory deficits and impaired cogni-tive functions (Goldman and Mitchell 2004).Intriguingly, these structural and functionalchanges of the hippocampus in patients withpsychiatric disorders can be attenuated or evenreversed by treating patients with antidepres-sants, antipsychotics, or increasing physicalexercise, many of which are known to have aprofound impact on hippocampal neurogenesis(Sala et al. 2004; Dhikav and Anand 2007; Kem-permann et al. 2010; Erickson et al. 2014).

These studies and others raise the possibilitythat dysfunction of adult neurogenesis itselfmay play a causal role in psychiatric symptoma-tology and that adult neurogenesis could serveas a novel therapeutic target, particularly inlight of provocative findings related to neuro-genesis-mediated effects of antidepressants asdescribed below. Thus, understanding endoge-nous mechanisms that regulate adult neurogen-esis may give us critical insight into effector sys-tems of successful treatments for psychiatricdisorders and facilitate the development of morespecific therapeutic strategies. Here, we reviewroles of adult hippocampal neurogenesis inthree major psychiatric disorders, major de-pression, schizophrenia, and drug addiction,and discuss adult hippocampal neurogenesisas both a therapeutic target and a model systemfor drug development.

DEPRESSION

Major depression, or major depressive disorder,is a psychiatric disorder characterized by epi-sodes of all-encompassing low mood accompa-nied by low self-esteem, decreased ability to con-centrate, loss of interest or pleasure in normallyenjoyable activities and recurrent thoughts ofsuicide. The “adult neurogenesis hypothesis”of major depression was the first proposed linkbetween adult neurogenesis and a psychiatricdisorder (Jacobs et al. 2000). Jacobs and col-leagues proposed that a stress-induced reduc-tion in hippocampal neurogenesis is an impor-tant causal factor contributing to episodes ofdepression. Since the original proposal, numer-

ous studies have either argued in favor of oragainst the hypothesis, which has evolvedto postulate that decreased generation of newneurons in the hippocampus contributes tothe pathogenesis of depression, and enhancingadult hippocampal neurogenesis is necessary forsuccessful antidepressant treatments (Duman2004; Sahay and Hen 2007). This hypothesis issupported by the finding that antidepressantsstimulate production of newborn neurons inthe adult brain, which can partially repair struc-tural abnormalities in the hippocampus of de-pressed patients (Sheline et al. 2003; Bremnerand Vermetten 2004; Perera et al. 2008). Simi-larly, promoting adult hippocampal neurogen-esis is sufficient to mimic antidepressant action(Santarelli et al. 2003; Mirescu and Gould 2006;Reif et al. 2007; Sahay and Hen 2007). Still, somefindings do not fit into this idea, including thefact that ablation of neurogenesis by factors oth-er than stress, such as irradiation, fails to lead a“depressive-like” state in animals (Airan et al.2007) and that both neurogenesis-dependentand neurogenesis-independent antidepressantactions have been observed (Sahay and Hen2007; David et al. 2009). Although there is noclear functional theory that explains how new-born neurons in the adult hippocampus con-tribute to the induction or recurrence of depres-sion, antidepressant-induced increases in adultneurogenesis has nevertheless been consistentlyshown across species, including primates andhumans, by multiple laboratories and for mul-tiple treatments, and has been shown to affectlocal circuit activity in the dentate gyrus (Airanet al. 2007). In this section, three main lines ofevidence linking adult hippocampal neurogen-esis and depression will be discussed, includingpostmortem and structural imaging analyses ofpatients, roles of adult hippocampal neurogen-esis in cognitive and affective functions, andinteraction of antidepressant treatments withadult neurogenesis.

Clinical Observations of Patients withMajor Depression

The observation that patients with chronic de-pression have smaller hippocampi, as compared


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with an age- and sex-matched group of healthyindividuals, was the first evidence suggesting acorrelation between depression and abnormalhippocampal structure (Sheline et al. 1996).Meta-analyses from numerous MRI studies havesince confirmed this observation (Videbech andRavnkilde 2004; Geuze et al. 2005; McKinnonet al. 2009). This same correlation holds trueeven for late-onset depression (Sawyer et al.2012; Sexton et al. 2012). Postmortem observa-tions have also confirmed similar reductions inhippocampal volume (Rajkowska et al. 1999),but it is not yet known whether a decrease inadult neurogenesis is a contributing factor andto what extent. Using proliferation markers,such as Ki-67 or MCM2, a few postmortemstudies have reported lower levels of cell prolif-eration in the hippocampus of patients withmajor depression compared with healthy con-trols, but the reduction in hippocampal volumecould confound this interpretation in the ab-sence of stereological analyses and results havebeen contradictory (Reif et al. 2006; Boldriniet al. 2009; Lucassen et al. 2010). The Lucassengroup showed a reduction of MCM2þ cells andthe Boldrini group also observed a decrease ofKi-67þ cells, whereas Reif group observed nochange in Ki-67þ cells in the adult hippocam-pus of patients with depression. But cell prolif-eration is not the only parameter that could af-fect adult neurogenesis. Changes in the numberand properties of neural stem cells or the sur-vival rate of new neurons would also affect thenet outcome of adult hippocampal neurogene-sis. Further studies are needed to clarify the con-nection between the level of adult neurogenesisand hippocampal volume change.

Role of Adult Hippocampal Neurogenesisin Cognitive and Affective Functions

Since the discovery that the dentate gyrus is oneof two regions of the adult mammalian brain togenerate new neurons constitutively and robust-ly, this region has been the focus of many inves-tigations to understand functional consequenc-es of this phenomenon. Recent studies havefocused on behaviors associated with the den-tate gyrus, with specific emphasis on functions

ascribed to distinct anatomical regions. Basedon anatomical studies of efferent connectivityand behavioral reports, the hippocampus is of-ten divided into two functional domains thatspan the longitudinal axis. Dorsal hippocampusis thought to contribute to spatial memoryformation and the associative encoding of dis-crete stimuli. Behavioral analyses using differentapproaches for ablation of adult hippocampalneurogenesis have suggested a connection be-tween neurogenesis and cognitive functions,such as spatial and temporal encoding and con-textual discrimination (Aimone et al. 2014).Ventral hippocampus has been associated withmodulation of affective behaviors and emotion-ally salient memories (Kheirbek and Hen 2011;Kheirbek et al. 2013; Tannenholz et al. 2014; Wuand Hen 2014). The relationship between adulthippocampal neurogenesis and mood regula-tion is complex. After the initial study reportingthat adult hippocampal neurogenesis is requiredfor the effectiveness of antidepressants fluoxe-tine and imipramine in certain depressive-likeand anxiety-like behaviors in certain mouse spe-cies (Santarelli et al. 2003), subsequent studieshave shown variable degrees of dependence onadult neurogenesis for established antidepres-sant treatment efficacy (Sahay and Hen 2007).Enhancement of adult hippocampal neurogen-esis via exercise, pharmacological, or geneticmanipulations elicits anxiolytic and antidepres-sant effects on behaviors (Jang et al. 2013b;Wu and Hen 2014; Hill et al. 2015), suggestingthe sufficiency for an increase in adult hippo-campal neurogenesis to reduce depressive-likebehavior. Interestingly, several lines of evidencealso suggest a role of adult hippocampal neuro-genesis in stress adaptation via regulation of thehypothalamic–pituitary–adrenal (HPA) axis(Schloesser et al. 2009; Snyder et al. 2011; Surgetet al. 2011) and this function might affect de-pressive- or anxiety-like behavior in an indirectmanner. On the other hand, a recent study byHill and colleagues (2015) reports that increas-ing adult hippocampal neurogenesis producesantidepressant-like behaviors independent ofHPA axis. It is also important to consider thehippocampus as both an integrated structure, aswell as comprised of different functional do-

E. Kang et al.




mains, and that the dorsal hippocampus canalso be indirectly involved in the regulation ofemotion, as supported by the negative correla-tion between performance on a pattern separa-tion task and the Depression Anxiety StressScale (Shelton and Kirwan 2013). Further stud-ies are warranted to elucidate the functional do-mains of dorsal versus ventral hippocampus,their interaction, and how adult hippocampalneurogenesis contributes to the totality of hip-pocampal functions.

It is still challenging to even measure theextent of adult neurogenesis in humans, muchless to study its functional role in human cogni-tion and emotion. Nonetheless, there are somelinks to suggest the relationship between humanneurogenesis and cognition and emotion. Pa-tients with major depression show various hip-pocampal-dependent core symptoms related tocognitive and affective functions, including im-paired working and declarative memory andlearning deficits (Hasler et al. 2004). There arealso negative correlations of pathological condi-tions with both cognitive function and levels ofneurogenesis (Raber et al. 2004; Rola et al. 2004;Lupien et al. 2007; Bishop et al. 2010). Age-re-lated declines in adult human hippocampalneurogenesis do not appear as robust as in ro-dents, but the correlation between relative ratesof decline and cognitive impairment have yet tobe determined. A confirmation of direct or in-direct links between human adult hippocampalneurogenesis and pathoetiology will require thedevelopment of novel imaging technologies al-lowing tracing of neurogenesis in patients.

Role of Adult Neurogenesis in MediatingAntidepressant Action

Correlations between the efficacy of antidepres-sant treatments and the extent of adult neuro-genesis have been a driving force to pursue the“neurogenesis model” of depression (Jacobset al. 2000). The hypothesis that adult hippo-campal neurogenesis plays a critical role in affec-tive behavior and responsiveness to exogenousantidepressants gained early support from stud-ies in which dividing cells were targeted for ab-lation. In a pioneering study, Rene Hen and col-

leagues reported that inhibition of hippocampalneurogenesis by X-irradiation resulted in thestriking finding that the effects of fluoxetine onanxiety-like behavior were abolished (Santarelliet al. 2003). Given these provocative results,many studies attempted to replicate these find-ings, and the cumulative evidence now suggeststhat this effect depends on the strain of mice, aswell as the type of antidepressant (Surget et al.2008; David et al. 2009, 2010). For example, be-havioral effects of chronic fluoxetine in BALB/cJ mice do not require adult hippocampal neu-rogenesis or the 5-HT1A receptor, suggestingthat antidepressants, such as selective serotoninreuptake inhibitors (SSRIs), can lead to antide-pressant-like effects via distinct mechanisms indifferent mouse strains (Holick et al. 2008). Ge-netic manipulations of pathways that regulateneurogenesis have also been shown to interactwith antidepressant treatment. For example,conditional deletion of receptor tropomyosin-related kinase B (TrkB), the cognate receptor forbrain-derived neurotrophic factor (BDNF), re-sults in decreased adult hippocampal neurogen-esis, increased anxiety-like behavior, and abol-ishes the action of antidepressants (Bergamiet al. 2009; Revest et al. 2009). Although adultneurogenesis appears to be necessary for thebeneficial effects of some antidepressants, sup-pression of neurogenesis alone does not result ina depressive phenotype, suggesting that a reduc-tion in newborn neurons is not sufficient tocause depression (Airan et al. 2007; David et al.2009). Conversely, physical exercise can increaseperformance in many cognitive tasks and mayalso restore some degree of hippocampal func-tion in psychiatric patients or in healthy but ag-ing individuals by promoting adult neurogene-sis (van Praag et al. 1999a,b, 2005; Creer et al.2010; Lugert et al. 2010).

Effects of Antidepressant Treatmenton Adult Neurogenesis

In parallel, one of the most intriguing insightsinto the role of adult hippocampal neurogenesisin depression comes from the observation thatmany antidepressant treatments lead to con-comitant beneficial effects on behavior and





adult hippocampal neurogenesis. A large num-ber of studies have found that antidepressantsdramatically enhance adult hippocampal neu-rogenesis in species ranging from rodents tononhuman primates to humans (Fig. 1) (Mal-berg et al. 2000; Malberg and Duman 2003; San-tarelli et al. 2003; Encinas et al. 2006; Perera et al.2007; Boldrini et al. 2009; Pinnock et al. 2009).For example, SSRI or tricyclic antidepressant(TCA)-treated patient groups with major de-pression had more NESTINþ neural progenitorcells and Ki-67þ dividing cells compared withuntreated patients or control groups. Surpris-ingly, the untreated patient group had 50% few-er dividing cells than controls (Boldrini et al.2009). Although these results are consistentwith studies in animal models showing a corre-lation between levels of neurogenesis and affec-tive behavior, they are based on a relatively smallsample size. Replications with larger samples arewarranted for further conclusion. Table 1 sum-marizes the studies of antidepressant treatmentsin animal models in the context of adult hippo-campal neurogenesis and behavior. The mostwidely used antidepressants are SSRIs, whichincrease the action of serotonin at the synapse(Cipriani et al. 2005; Deshauer et al. 2008). Flu-oxetine, an SSRI, enhances adult hippocampalneurogenesis (Malberg and Duman 2003; Enci-nas et al. 2006; Pinnock et al. 2009; Jang et al.2013b). Classical TCAs, such as desipramineand imipramine, also up-regulate adult hippo-campal neurogenesis (Malberg et al. 2000; San-tarelli et al. 2003). Unlike most antidepressants,tianeptine is an atypical antidepressant that is aselective serotonin reuptake enhancer but alsoregulates AMPA and NMDA receptor activity.Tianeptine treatment ameliorates depressive-like behavioral effects following chronic stressin tree shrews and increases adult neurogenesis(Czeh et al. 2001; Fuchs et al. 2002).

Neurogenesis-induced structural and func-tional changes in the hippocampus could arisefrom increased proliferation and/or increasedsurvival of newborn cells. The effects of antide-pressants on specific stages of neurogenesis havebeen investigated in detail and revealed severalpotential mechanisms of action (Fig. 1) (Davidet al. 2010). For example, fluoxetine increases

the rate of symmetric divisions of amplifyingneural progenitors (Encinas et al. 2006). In ad-dition, it accelerates maturation of immatureneurons after chronic treatment, as shown byenhanced dendritic arborization and complex-ity (David et al. 2010). On the other hand, tia-neptine decreases apoptotic cell death in thedentate gyrus (Lucassen et al. 2004).

Strikingly, nonpharmacological antidepres-sant treatments have also been shown to up-regulate adult hippocampal neurogenesis. Elec-troconvulsive therapy (ECT), vagus nervestimulation, short-term sleep deprivation, envi-ronmental enrichment, and physical activityrepresent considerably different modes of ther-apy for major depression, all of which have beenshown to enhance adult hippocampal neuro-genesis and ameliorate depressive-like behavior(Madsen et al. 2000; Hellsten et al. 2002; Segi-Nishida et al. 2008; Ma et al. 2009). For example,a single ECT treatment in rodent models, sim-ilar to what is used clinically for the treatment ofmajor depression and schizophrenia, signifi-cantly increases the survival rate among new-born neurons for up to 2 months, whereas mul-tiple treatments also increase proliferation ofneural progenitors in the adult dentate gyrus(Madsen et al. 2000; Malberg et al. 2000; Wanget al. 2000; Segi-Nishida et al. 2008). Recentstudies have identified secreted frizzled-relatedprotein 3 (sFRP3), a Wnt signaling inhibitorthat regulates activity-induced adult neural pro-genitor proliferation and differentiation, as amolecular mediator of multiple antidepressanttreatments in rodent models and may correlateto response time to antidepressants in depres-sion patients (Jang et al. 2013a,b). Collectively,these studies suggest that reversal of stressor depression-induced structural and cellularchanges in the hippocampus is one mechan-ism for the therapeutic effect of antidepressanttreatments.

Animal Models of Depression

Many animal models rely on different forms ofstress to induce depressive-like behavior. Chron-ic or acute stress episodes have been identified asan etiological factor and trigger for the onset of

E. Kang et al.




Postmortem andfMRI studiesin patients

Antidepressant

Nonpharmacologicalantidepressant

Geneticanimal models

Postmortem andfMRI studiesin patients

Geneticanimal models

fMRI studiesin patients

Alcohol

Stimulants

Dru

g a

dd

icti

on

Sch

izo

ph

ren

iaD

epre

ssio

n

Decreasedhippocampal volume(alcohol addiction)

Decreased survival(μ-opioid receptor

agonist, short-term bingeMDMA administration,

long-term repeatedexposure to ethanol and

MDMA, prenatalexposure to MDMA,

chronic nicotineadministration)

Decreased survival(chronic alcoholconsumption)

Impaired maturation(chronic nicotineadministration)

Decreased proliferation(acute and chronic alcohol

consumption)Increased proliferation

(long-term voluntary alcoholconsumption (10 wk))

Decreased proliferation(DISC1 KD, Dgcr8+/–,

SREB2 Tg,SREB2 KO,Npas3 KO,

SNAP-25 Kl (A187S))

Impaired maturation(DISC1 KD, SREB2 Tg,

SREB2 KO,SNAP-25 Kl (A187S),

NLGN-1 KD, αCaMKII+/–)

Decreased survival(NLGN-1 KD)

Impaired maturation

Accelerated maturation(sFRP3 KO)

Increased survival(single ECT treatment)

Decreasedapoptotic cell death

(tianeptine)

Accelerated maturation(fluoxetine,

desipramine,lithium)

Increased proliferation(fluoxetine, escitalopram,desipramine, imipramine,

tianeptine, tranycyprominereboxetine, lithium)

NS(no significant

difference)

Decreasedhippocampal

volume

Decreased proliferation(TrkB cKO)

Increased proliferation(sFRP3 KO)

Recoveredhippocampalvolume (ECT)

Increased proliferation(multiple ECT treatment,vagus nerve stimulation,

short-term sleep deprivation,enriched environment,

physical activity)

Decreased proliferationDecreasedhippocampal volume

Decreased proliferation(μ-opioid receptor agonist,

prenatal exposure to MDMA/MDMA and alcohol)

Hippocampalvolume

RGL Neuralprogenitors

Immatureneuron

Matureneuron

Proliferation

Maturation

Survival

Figure 1. Adult hippocampal neurogenesis and psychiatric disorders. Shown at the top is a schematic illustrationof stages showing specific stages of adult hippocampal neurogenesis. Shown at the bottom is a summary of effectof three different classes of psychiatric disorders on hippocampal volume and adult hippocampal neurogenesis,including depression, schizophrenia or drug addiction. Note that multiple developmental stages during adultneurogenesis are shown to be affected. RGL, Radial glia-like cells; ECT, electroconvulsive therapy; KO, knockout;KD, knockdown; MDMA, 3,4-methylenedioxymethamphetamine.




Table 1. Studies of antidepressant treatments in animal models

Antidepressant

treatment Classification

Animal model

and experimental

approach

Effects on adult

hippocampal

neurogenesis

Effects on

behavior References

Fluoxetine Serotonin-selectivereuptakeinhibitor

BrdU labeling inadult rathippocampus,learnedhelplessnesstest

Increased cellproliferationand neuronalmaturation

Decreasedlearnedhelplessnessbehaviorinduced byinescapableshock

Malberget al.2000;MalbergandDuman2003


BrdU labeling in129/Sv mousebrain, NSF test


A decreasedlatency tofeed in NSFtest

Santarelliet al. 2003


BrdU labeling innestin-CFPnucmouse

Increasedproliferationof progenitors,but notquiescent neuralprogenitors

NS Encinaset al. 2006

Escitalopram Serotonin-selectivereuptakeinhibitor

BrdU labeling inadult rathippocampus

Increased cellproliferationwithescitalopramtreatment undermild stresscondition

Recovery fromanhedonic-like behaviorinduced bythe mildstress

Jayatissa etal. 2006

Desipramine Tricyclicantidepressant

Adult rat or 129/Sv mousebrain, learnedhelplessnesstest, NSF test


Decreasedlearnedhelplessnessbehavior, adecreasedlatency tofeed in NSFtest

Santarelliet al.2003;Chen etal. 2006

Imipramine Tricyclicantidepressant

BrdU labeling inadult rat or129/Sv mousebrain, NSF test

Increased cellproliferation

A decreasedlatency tofeed in NSFtest

Santarelliet al.2003;Kitamuraet al. 2011

Tianeptine Tricyclicantidepressant;selectiveserotoninreuptakeenhancer

BrdU labeling instressed treeshrews dentategyrus


NS Czeh et al.2001;Fuchs2002

Tranylcypromine Monomineoxidaseinhibitor



NS Malberget al. 2000

Continued

E. Kang et al.




anxiety and affective disorders in patients andshown to negatively regulate adult hippocampalneurogenesis in rodent models (Gould et al.1997; Santarelli et al. 2003; Surget et al. 2008).Moreover, physical stressors such as inescapablefoot shock (Malberg and Duman 2003) and re-peated restraint (Pham et al. 2003) have beenused to induce depressive-like behaviors in an-imal models and also have a negative impact onadult neurogenesis (Fig. 1). For example, chron-ic psychosocial stress via a social defeat protocolreduces cell proliferation and survival of new-born granule neurons (Czeh et al. 2002).

Although it is estimated that major depres-sion is moderately inheritable (40%–50%), thedevelopment of genetic animal models for ma-jor depression has been limited (Levinson2006). Increased levels of corticosterone, a glu-cocorticoid hormone secreted by the adrenalgland in response to stress, have been consistent-ly observed in patients with major depressionand in animals subjected to chronic stress. Adultneurogenesis in the dentate gyrus is known to besensitive to glucocorticoid levels (Gould and Ta-napat 1999; Mirescu and Gould 2006; Mirescuet al. 2006). In heterozygous knockout mice forthe glucocorticoid receptor, adult neurogenesiswas inhibited (Kronenberg et al. 2009). In addi-tion, mice treated chronically with corticoste-rone show anxiety-related and depressive-likebehaviors (David et al. 2009). Genetic mu-tations of serotonin receptor 1A (5-HT1A) inhumans that correlate with lowered expression

levels of 5-HT1A are risk factors for depressionand also reduced responsiveness to antidepres-sants (Le Francois et al. 2008). Comparatively, in5-HT1A knockout mice, the effect of fluoxetineon behavior, as well as neurogenesis, was abol-ished (Radley and Jacobs 2002). Thus far, manyanimal models appear to share many geneticand environmental risk factors for anxiety ordepression-like behaviors, and the potentialfor mechanistic overlap.

Converging evidence that includes neuroan-atomical and neurochemical abnormalities inthe hippocampus of patients with depression,behavioral studies implicating the hippocam-pus in cognitive and affective behavior, depen-dence of antidepressant efficacy on neurogene-sis in some cases, and modulation of adultneurogenesis by distinct classes of clinically ef-fective antidepressants, supports the adult neu-rogenesis hypothesis of depression, at least inpart. However, it remains to be determinedwhether impaired adult hippocampal neuro-genesis is a causal factor underlying the relevantpathology in depression. In addition, consider-able work is still required to understand hownewborn neurons could mediate the action ofantidepressants at the molecular, cellular, orsystem levels.

SCHIZOPHRENIA

Schizophrenia is a complex genetic disorderthat presents with variable cognitive deficits

Table 1. Continued

Antidepressant

treatment Classification

Animal model

and experimental

approach

Effects on adult

hippocampal

neurogenesis

Effects on

behavior References

Reboxetine Nerepinephrine-selectivereuptakeinhibitor



NS Malberget al. 2000

Lithium Mood stabilizer BruU labeling inadult mousehippocampus

Increasedproliferation,neuronalmaturation andglial maturation

Decreaseddepressivelike behavior

Chen et al.2000

BrdU, Bromodeoxyuridine; NSF, novelty-suppressed feeding; NS, not studied.





and affective symptoms. Patients typically showa subset of positive symptoms, which includedelusions, hallucinations, disorganized speechand behavior, and/or negative symptoms, whichinclude an inability to express emotion, cogni-tive deficits, memory impairments, and a lack ofmotivation, interest, and empathy.

Neurodevelopmental Modelof Schizophrenia

The neurodevelopmental model of schizophre-nia holds that schizophrenia is the behavioraloutcome of neural dysregulation that beginslong before the onset of clinical symptoms(Weinberger 1987; Cardno et al. 1999; Singh etal. 2004). This hypothesis has been supportedby diverse lines of research. First, structuralchanges have been documented in the brainsof children with prodromal symptoms (Rapo-port et al. 2012), many of which parallel neuro-anatomical studies of schizophrenic patientsthat have shown structural abnormalities in-cluding enlarged lateral and third ventriclesand decreased volumes of gray and white matter(Lawrie and Abukmeil 1998; Wright et al. 2000).These decreases occur predominantly in thehippocampus (Nelson et al. 1998), thalamus(Konick and Friedman 2001), and frontal lobes(Davidson and Heinrichs 2003). Second, mi-croarray gene expression studies have linked al-terations in gene expression in postmortem pa-tient tissue to presynaptic function, signaling,myelination, and migration, many of which areintegral stages in neural development. However,it should be noted that most of these results arefrom studies with relatively small sample sizesand were not controlled for pharmacologicaltreatment history (Kumarasinghe et al. 2012).The strongest evidence to date supporting theneurodevelopmental hypothesis comes fromrecent linkage and genome-wide analysis stud-ies that have identified a large number of sus-ceptibility genes for schizophrenia that areknown to function in neural development (Ra-poport et al. 2012).

The idea that abnormal adult hippocampalneurogenesis might be involved in the sympto-matology or pathogenesis of schizophrenia is

based on postmortem and functional imagingstudies, as well as clinical features of schizophre-nia. Postmortem samples from patients withschizophrenia show decreased expression ofthe cell proliferation marker, Ki-67 in the hip-pocampus (Fig. 1) (Reif et al. 2006). Correlatedwith this observation, reduced hippocampalvolume, using meta-analysis MRI, has been re-ported in patients (Steen et al. 2006). In addi-tion to changes to cell proliferation, impairedmaturation of adult-born dentate granule cellsin patients with schizophrenia has also been re-ported (Walton et al. 2012). Interestingly, sever-al studies show a correlation between ameliora-tion of the behavioral and cognitive symptomsof schizophrenia and normalization of hippo-campal volume, thus linking the anatomical andcognitive behavioral manifestations of this dis-order to the hippocampus (Sapolsky 2000; Salaet al. 2004; Dhikav and Anand 2007). Impairedadult hippocampal neurogenesis, as a distinctform of dysregulated neurodevelopment, mightcontribute to the structural changes and hip-pocampal-dependent affective and cognitivesymptoms.

Animal Models of Schizophrenia and AdultNeurogenesis

Modeling schizophrenia in animals is an ap-proximation of specific facets of the disorder,including behavioral abnormalities that resem-ble a subset of symptoms or neural mechanismsthat may contribute to the etiology. Althoughthere have been several studies demonstratingan association between a particular genetic ma-nipulation and behavioral effects that appear tobe related to symptoms of schizophrenia, a one-to-one relationship between a single gene anda specific behavior is unlikely. It is largely un-known whether the risk genes identified in ge-nome-wide association studies interact or con-verge on common signaling pathways. There is,however, an increased appreciation for the ideathat deficits in shared signaling cascades maycontribute to comorbid endophenotypes. Ex-ploring the functional role of schizophreniarisk genes in neurodevelopment and adult neu-rogenesis and identifying the underlying molec-

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ular mechanisms has therefore been an im-portant approach to understand the etiologyof psychiatric disorders. Table 2 summarizesthe studies of schizophrenia susceptibility genesin animal models in the context of adult hippo-campal neurogenesis and behavior.

Disrupted-in-schizophrenia 1 (DISC1) isone of the most extensively studied susceptibil-ity genes for schizophrenia and has proven to bea useful model for how to investigate complexgenetic disorders starting with a single knownrisk factor. DISC1 was originally identified in alarge Scottish pedigree in which a translocationin this locus cosegregates with mental disord-ers such as schizophrenia and major depres-sion (Millar et al. 2000; Blackwood et al. 2001;Taylor et al. 2003). DISC1 is highly expressedin the hippocampus, both during develop-ment and in adulthood, suggesting it has a func-tional role in both neurodevelopment and adultneurogenesis (Austin et al. 2004; Schurov etal. 2004). Behavioral assays of several geneticDISC1 mouse models, such as single nucleotidemutations oroverexpression of truncated DISC1resulting in altered DISC1 expression, revealedschizophrenic-like or depressive-like behaviors(Thomson et al. 2013). DISC1 has been shownto regulate precursor cell proliferation duringadult neurogenesis through the GSK-3b/b-catenin pathway, thus linking DISC1 to Wnt sig-naling (Mao et al. 2009). Furthermore, severalstudies have described a critical cell-autono-mous role for DISC1 in regulating the tempoof newborn neuron maturation in the adult hip-pocampus. Retrovirus-mediated expression ofshort hairpin RNA (shRNA) against DISC1,specifically in newborn granule neurons, resultsin enhanced dendritic outgrowth, enlargedsoma size, mispositioning of the cell body, ec-topic dendrites, aberrant connectivity of axonalmossy fibers, and arrested maturation of presyn-aptic output (Duan et al. 2007; Faulkner et al.2008; Kang et al. 2011). DISC1-dependentregulation of neurodevelopment is modulatedthrough the AKT/mammalian target of rapa-mycin (mTOR) pathway. DISC1 directly inter-acts with KIAA1212 (girdin) and suppresses theactivation of AKT (Kim et al. 2009). Pharmaco-logical inhibition of the AKT downstream effec-

tor mTOR, via rapamycin, largely rescues thecellular defects caused by DISC1 deficiency. In-terestingly, depolarizing g-aminobutyric acid(GABA) signaling has been identified to regulatedendritic development of immature neuronsvia the AKT-mTOR pathway and is subject toDISC1 regulation. Release of neurotransmitters,such as glutamate and GABA, can serve as anindicator of general circuitry activity. Therefore,this study showed an interaction between localneural activity and a schizophrenia susceptibil-ity gene, a gene-environment interaction inthe regulation of neuronal development in themammalian brain (Kim et al. 2012). Intriguing-ly, hippocampal-dependent cognitive and affec-tive deficits in mice resulting from DISC1 defi-ciency, specifically in newborn granule neuronsof the hippocampus, were partially rescued byrapamycin (Zhou et al. 2013). Taken together,these studies suggest that the mental disordersusceptibility gene DISC1 regulates discretecomponents of neurogenesis and neuronal de-velopment through distinct signaling pathways,which is consistent with the neurodevelop-mental hypothesis. Understanding the biologi-cal role of key players in this pathway may revealnovel therapeutic targets to modulate neurogen-esis and relevant behaviors, which could be ef-fective even in adulthood.

Another prominent risk gene for schizo-phrenia, NPAS3 (neuronal PAS domain-con-taining protein 3), was identified through link-age and association studies (Kamnasaran et al.2003; Pickard et al. 2005, 2009; Huang et al.2010). NPAS3 encodes a transcription factor ofthe hHLH (basic helix–loop–helix)-PAS familyand is mainly expressed in the developing cen-tral nervous system and the adult brain (Bruns-kill et al. 1999). Npas3 knockout mice showedreduced cell proliferation in the adult hip-pocampus, conferring a potential inability toappropriately remodel neural connections inhippocampal circuitry in response to envi-ronmental stimuli or psychological challenges(Pieper et al. 2005). Moreover, these mice haveshown schizophrenia-like behaviors, such as hy-peractivity, impaired prepulse inhibition, defi-cits in memory formation, and anxiety-like be-havior (Brunskill et al. 2005; Pieper et al. 2005).





Table 2. Studies of schizophrenia susceptibility genes in animal models

Gene

Animal model and

experimental

approach

Effects on adult

hippocampal

neurogenesis Effects on behavior References

Genetic

study

references

DISC1 Retrovirus-mediatedknockdown ofDISC1 innewborn neurons

Enhanceddendriticoutgrowth,somahypertrophy,mispositioningof cell body,acceleratedexcitability, andsynaptogenesisin hippocampalnewbornneurons

NS Duan et al.2007

Chubb et al.2008


Mistargeting ofaxonal mossyfibers, failure ofmaturation ofpresynapticoutput

NS Faulkneret al.2008

Chubb et al.2008

DISC1 Lentivirus-mediatedknockdown ofDISC1

Decreased cellproliferation

Hyperlocomotionin a novelenvironment,depressive-likebehavior (forcedswim test)

Mao et al.2009

Chubb et al.2008


NS Cognitive (objectplace recognitiontest, Morris watermaze test), andaffective deficits(elevated placemaze, forced swimtest) rescued byrapamycintreatment

Zhou et al.2013

Chubb et al.2008

Dgcr8 (22q11.2deletion)

Dgcr8þ/2mice Reduced cellproliferationandneurogenesis,reduced neuralprogenitormarkersdecrease, DCXdecrease,rescued byinsulin-likegrowth factor(IGF)-2

Defects in spatialworking memory(Y-maze test,Morris water mazetest) anddepressive-likebehavior (forcedswim test) rescuedby IGF-2

Stark et al.2008;Ouchiet al.2013

Pulver et al.1994;Murphyet al. 1999

Continued

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Many genes encoding proteins that are in-volved in synaptic function have been shownto be susceptibility genes for schizophrenia.One such gene is synaptosomal-associated pro-tein, 25 kDa (SNAP-25). SNAP-25 is a solubleN-ethylmaleimide-sensitive factor attachmentprotein receptor (SNARE) protein, which playsa critical role in regulating synaptic vesicle exo-cytosis (Chapman 2002; Jahn et al. 2003; Sudhof

2004; Corradini et al. 2009). Human geneticstudies have identified the association betweenSNAP-25 and neurological disorders, includ-ing schizophrenia, attention-deficit/hyperac-tivity disorder (ADHD), and epilepsy. More-over, SNAP-25 was identified as one of the top42 candidate genes for schizophrenia in a ge-nome-wide meta-analysis (Lewis et al. 2003).In SNAP-25 mutant knock-in mice (Ala187Ser),

Table 2. Continued

Gene

Animal model and

experimental

approach

Effects on adult

hippocampal

neurogenesis Effects on behavior References

Genetic

study

references

SREB2/GBR85 SREB2 Tg,SREB2KO

Negativelyregulateshippocampaladultneurogenesisand dendriticgrowth

Deficits in spatiallearning andmemory (spatialpattern separationtest, delayed inspontaneousalteration, Y-maze)

Chen et al.2012

Matsumotoet al. 2008

FEZ1 Retrovirus-mediated KD ofFEZ1 inhippocampus/FEZ1KO

Enhanceddendriticoutgrowth,somahypertrophy

Hyperactivity,enhancedbehavioralresponses to thepsychostimulantsMK-801

Sakae et al.2008;Kanget al.2011

Yamada et al.2004

NPAS3 Npas3 KO Reduce cellproliferation inNpas3KO

Hyperactivity,subtle gait deficits,impaired PPI,defects in cognitivememory, alteredanxiety-likebehavior

Brunskillet al.2005;Pieperet al.2005

Kamnasaranet al. 2003;Pickardet al. 2005,2009;Huanget al. 2010

SNAP-25 SNAP-25 KI (Ala187Ser)

Decreasedneurogenesisimmaturity ofdentate granulecells

Working memorydeficit(spontaneousforced alterationtask, T-maze)

Ohira et al.2013

Lewis et al.2003

aCaMKII aCaMKIIþ/2 Increased DG, butdecreasednumber ofmature neuronsin DG,immaturity inmorphologicalandphysiologicalfeatures of DGneurons

Severe workingmemory deficit andan exaggeratedinfradian rhythm

Yamasakiet al.2008

Xing et al.2002

NS, Not studied; KO, knockout; KD, knockdown; DG, dentate gyrus.





adult hippocampal neurogenesis was sup-pressed. Furthermore, significant numbers ofdentate gyrus granule cells were histologicallyand electrophysiologically immature, morethan would be predicted based on proliferationrates and the tempo of normal development, andthese mice showed severe impairments in work-ing memory (Ohira et al. 2013). Neurexins(NRXNs) and neuroligins (NLGNs) are familiesof synaptic proteins, which are known to be riskfactors for schizophrenia (Novak et al. 2009; Ru-jescu et al. 2009; Ikeda et al. 2010; Gauthier et al.2011; Mozhui et al. 2011; Sun et al. 2011; Yueet al. 2011). These proteins are synaptic cell-ad-hesion molecules involved in various neuronalprocesses, including differentiation, matura-tion, stabilization, and plasticity of both inhibi-tory and excitatory synapses (Bang and Ow-czarek 2013). Although the functional role ofNRXNs in adult hippocampal neurogenesis isunknown, one study has shown that neuroli-gin-1 plays a critical role in determining themorphology and survival rate of newborn gran-ule neurons in the hippocampus (Schnell et al.2014).

Similar to SNAP-25 mutant mice, a dispro-portionate number of immature granule cellshave also been observed in other animal modelsof schizophrenia, such as heterozygous calmod-ulin-dependent protein kinase II (aCaMKII)knockout mice (Yamasaki et al. 2008) andSchnurri-2 knockout mice (Takao et al. 2013).Importantly, aCaMKII knockout mice andShn-2 knockout mice also show schizophrenic-like behaviors including working memorydeficits and hyperlocomotive activity. Theseanimal studies thus suggest a link between dis-rupted maturation processes of adult-borncells and hippocampal dysfunction.

DiGeorge syndrome chromosomal criticalregion 8 (DGCR8), is a gene within 22q11.2and the encoded protein is a component of themicroprocessor complex involved in microRNAbiogenesis (Wang et al. 2007). The 22q11.2 mi-crodeletion is the most commonly occurringcopy number variation (CVN) (Botto et al.2003) and is a well-established risk factor forschizophrenia (Pulver et al. 1994; Murphy etal. 1999). Heterozygote Dgcr8 knockout mice

(Dgcr8þ/2) show a significant decrease in theproliferation of adult hippocampal neural pro-genitor cells and corresponding deficits in spa-tial working memory (Stark et al. 2008; Ouchiet al. 2013). Interestingly, rescue of decreasedproliferation in adult hippocampus by admin-istration of insulin-like growth factor (IGF)-2was sufficient to reverse the behavioral defectsin hippocampal-dependent learning, suggestinga potential role of defective adult hippocampalneurogenesis in mediating deficits in learningobserved in schizophrenia patients. These stud-ies suggest that enhancement of IGF-2 signalingand adult neurogenesis could serve as a potentialtherapeutic strategy for the treatment of cogni-tive deficits associated with schizophrenia.

In summary, impaired adult hippocampalneurogenesis and arrested growth of developingneurons appear to be consistent across multipleanimal models of schizophrenia (Fig. 1) andhave also been observed in patients with schiz-ophrenia (Walton et al. 2012), often linked to aparticular genetic risk factor. Together, thesestudies suggest a critical role for a functionallymature dentate gyrus in cognitive functionand a potential contribution of dysregulatedadult neurogenesis in the pathogenesis of schiz-ophrenia.

DRUG ABUSE AND ADDICTION

Drug addiction involves the acquisition andmaintenance of a drug-taking habit, which oftenbecomes a recurrent problem wherein affectedindividuals can spend weeks, months, or yearsabstaining from substance abuse, and yet remainhighly susceptible to relapse and drug-seekingbehavior. Hippocampal modulation of drugaddiction has received increasing attention be-cause of the putative role of the hippocampus inmediating associative memories of drug-relatedbehavior that can trigger a relapse on re-expo-sure to similar contexts. It is well established thatdopaminergic reward circuitry in the brain, thatis, dopaminergic projections from the midbrainventral tegmental area (VTA) to the nucleus ac-cumbens (NAc) and frontal cortex, plays an im-portant role in drug addiction by enhancingdopamine efflux in the NAc, either directly or

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indirectly (Koob et al. 1992; Spanagel and Weiss1999). The hippocampus, on the other hand, ispositioned to influence brain reward pathwaysby receiving inputs from both the NAc and VTAand establishing a feedback loop through effer-ent projections to the NAc (Gasbarri et al. 1991,1994; Floresco et al. 2001; Bannerman et al.2004). These neuroanatomical observationssuggesting that the hippocampus interacts withreward circuitry were further substantiated byfunctional studies showing that manipulationsof hippocampal subfields alter the firing of VTAdopaminergic cells and dopaminergic responsesin NAc (Mitchell et al. 2000; Floresco et al. 2001;Charara and Grace 2003; Won et al. 2003; Zor-noza et al. 2005a,b). The recent discovery thataddictive drugs alter adult hippocampal neuro-genesis in animal models has added new insightinto the neurobiology of drug addiction. Themost intriguing findings are the negative cor-relations between the level of hippocampalneurogenesis and drug-taking or drug-seekingbehaviors. Manipulations that enhance adulthippocampal neurogenesis, such as exposureto enriched environments, chronic treatmentwith antidepressants, or exercise, are associatedwith reduced drug-taking and a lower rate ofrelapse in animal models (Kanarek et al. 1995;Baker et al. 2001; Green et al. 2002; Stairs et al.2006; Smith et al. 2008). On the other hand,conditions that decrease neurogenesis in hu-mans, including schizophrenia or stress (Mir-escu and Gould 2006; Reif et al. 2006), areassociated with increased likelihood of drugaddiction (Erb et al. 1996; Chambers and Self2002; Covington and Miczek 2005).

Alcohol has been one of the most intensivelystudied drugs in the field of addiction. Gener-ally, there is a negative correlation betweenalcohol consumption and the level of adulthippocampal neurogenesis, but the effects ofalcohol on neurogenesis vary greatly with dos-age, intake patterns and duration of exposure(Fig. 1). In an early study, acute alcohol con-sumption was shown to reduce cell prolifera-tion in the dentate gyrus (Nixon and Crews2002). Interestingly, this suppression was par-tially compensated for by a burst of proliferationafter withdrawal, suggesting homeostatic main-

tenance of neurogenesis levels over the shortterm (Nixon and Crews 2004). Exercise in arunning wheel also counteracts the inhibitoryeffect of alcohol on neural stem-cell prolifera-tion (Crews et al. 2004). Chronic consumptionof moderate doses of alcohol, on the other hand,has a negative effect on the survival of newborngranule neurons in mice, with no alteration inthe proliferation rate of neural progenitors. Thisincrease in the cell death of newborn neurons isprevented by administration of the antioxidantebselen, suggesting a possible oxidative mecha-nism for toxicity in hippocampal cells (Herreraet al. 2003). In mice, long-term voluntary alco-hol self-administration for 10 weeks in a two-bottle free-choice test enhanced proliferation inthe dentate gyrus, with new cells surviving anddifferentiating normally (Aberg et al. 2005).Chronic alcohol treatment over 11 months inadolescent macaque monkeys, on the otherhand, resulted in long-lasting reduction innumber of proliferating neural stem cells indentate gyrus (Taffe et al. 2010). Moreover,in the abstinence state following withdrawalfrom chronic alcohol consumption, depres-sive-like behavior and reduced numbers of neu-ral progenitors and immature neurons were ob-served in the dentate gyrus of adult mice andboth structural and behavioral phenotypes arealleviated by the antidepressant desipramine(Stevenson et al. 2009). These studies suggestthat hippocampal neurogenesis might mediatethe comorbidity of depressive symptoms asso-ciated with alcohol dependence and provide apotential explanation for the clinical observa-tion that hippocampal volume is reduced in al-coholic patients (Bengochea and Gonzalo 1990;Sullivan et al. 1995; Agartz et al. 1999). Chronicalcohol treatment is also associated with long-lasting changes in synaptic plasticity and learn-ing and memory deficits. Thus, the hippocam-pus may be important for some shared cognitivefeatures of addiction, depression, and schizo-phrenia (Walker and Freund 1971; Santin et al.2000; Roberto et al. 2002).

Stimulants are psychoactive drugs that havebeen used to temporarily enhance mental and/or physical performance. They are used clinical-ly to treat certain conditions, but they are also





used recreationally and are a common drug ofabuse. Opiates were the first psychostimulantsassociated with adult neurogenesis and in vivoexposure of m-opioid receptor agonists in ro-dent models leads to reduced progenitor prolif-eration and deficits in the maturation and sur-vival of new neurons in the hippocampus (Eischet al. 2000). Likewise, cocaine abuse is also neg-atively associated with some facets of adult hip-pocampal neurogenesis. Both short- and long-term treatment of cocaine reduces proliferationin the dentate gyrus, but the effect on survivaland dendritic maturation is not always consis-tent, possibly caused by the use of different an-imal strains and various drug administrationprotocols (Eisch 2002; Yamaguchi et al. 2004;Dominguez-Escriba et al. 2006; Noonan et al.2008; Mustroph et al. 2011). Negative effects ofcocaine on cell proliferation were concomitantwith impairments in working memory, evenduring abstinence from high dosage cocaineself-administration (Sudai et al. 2011). Ablationof adult hippocampal neurogenesis using X-ray irradiation results in an increase in cocaineself-administration and drug-seeking behav-iors, suggesting that impaired neurogenesisleads to increased susceptibility to drug addic-tion (Noonan et al. 2010). Enhancing adult hip-pocampal neurogenesis has been suggested toprotect against cocaine-primed relapse (Des-chaux et al. 2014). These studies indicate thatrecalibrating baseline levels of neurogenesis fol-lowing chronic cocaine administration may re-duce susceptibility to relapse. MDMA (ecstasy)is a drug with hallucinogenic properties. Short-term binge MDMA administration in rats hasbeen shown to decrease the survival of neuralprogenitor cells without affecting the prolifera-tion rate (Hernandez-Rabaza et al. 2006). Long-term repeated exposure to ethanol and MDMAtogether leads to prominent cognitive im-pairments associated with neuronal loss andmicrogliosis in the dentate gyrus of adolescentrats, implying that simultaneous use of alcoholand MDMA may pose serious health risks (Her-nandez-Rabaza et al. 2010). Simultaneous useof MDMA and alcohol during pregnancy in ratsresulted in long-lasting effects on pups overthe course of development and into adulthood.

Rats with prenatal exposure to MDMA andalcohol had decreased proliferation, reducedadult neurogenesis and showed significant ab-normalities in cognitive function and ex-ploratory activity (Canales and Ferrer-Donato2014). Similarly, in utero exposure to MDMAreduces proliferation and survival of newbornneurons in the adult mouse hippocampus (Choet al. 2008). Together, these studies suggestthat there may be irreversible adverse effects ofMDMA exposure during neural development.Nicotine is a stimulant drug used widely aroundthe world. The impact of nicotine on adult neu-rogenesis appears to be more complicated. Arecent study reported that ZY-1, a nicotinic an-alog, shows a positive effect on cell proliferationand migration of hippocampal neural stem cellsin vitro (He et al. 2013), whereas in vivo chronicnicotine administration decreases the survivaland maturation of new neurons, without affect-ing cell proliferation, in the adult rodent hippo-campus (Abrous et al. 2002; Wei et al. 2012).

Collectively, most addictive drugs, especial-ly when administered chronically, decrease theproliferation or survival rate of neural progen-itors, leading to global deficits in hippocampalplasticity (Fig. 1). However, the role of neuro-genesis in addiction has not yet been studied insufficient detail. The studies performed so farhave been primarily descriptive and correlative.Future studies are needed to address the func-tional interaction between addiction and adultneurogenesis, including the effects and under-lying mechanisms of drugs on adult hippo-campal neurogenesis and the extent to whichadult neurogenesis mediates addiction anddrug abuse.

ADULT NEUROGENESIS AND DRUGDEVELOPMENT

Psychiatric disorders are usually comprised of adiverse array of symptoms. The treatments thathave proven effective for major psychiatric dis-eases include psychotherapy (such as cognitive,behavior, and group therapy) (Hofmann andSmits 2008; Rathod et al. 2008), brain-stimula-tion treatments (such as ECT, transcranial mag-netic stimulation, vagus nerve stimulation, and

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deep brain stimulation) (George et al. 2000;Mayberg et al. 2005; Fink and Taylor 2007;O’Reardon et al. 2007), and psychopharmacol-ogy (drugs such as lithium, haloperidol, TCAs,atypical antipsychotics, SSRIs, and meman-tine). However, because of a lack of knowledgeregarding the underlying genetic and neurobi-ological mechanisms of psychiatric disease, weare mostly treating symptoms with blunt ap-proaches that can have many off-target effectson well-functioning neural systems. In addition,only �65% of patients with mood disordersrespond adequately to available medications(Al-Harbi 2012). As for schizophrenia, existingtreatments are usually targeted toward the sub-set of symptoms that is the most disruptive andfail to ameliorate all categories of symptoms.Furthermore, currently available medicationsare difficult to tolerate and can cause seriousside effects, and patients with schizophreniamay be particularly prone to noncompliance(Miyamoto et al. 2005). For example, clozapineis an effective medication that treats psychoticsymptoms, hallucinations, and breaks with re-ality, but can frequently cause agranulocytosis(Wahlbeck et al. 1999; Chakos et al. 2001; Tuu-nainen et al. 2002), a life-threatening side effectin which the immune system is seriously im-paired. Therefore, there is an urgent need fordeveloping new strategies for prevention andtreatment of psychiatric disorders. Increasingevidence supports that dysfunction of adult hip-pocampal neurogenesis itself plays a causal rolein psychiatric symptomatology, thus raising thehope that manipulation of this endogenousphenomenon can be a target for the ameliora-tion or prevention of some aspects of psychiatricillness, with fewer side effects.

Adult Neurogenesis as a PotentialTherapeutic Target

Identification of pathological lesions in specificbrain regions or degeneration of specific celltypes has contributed greatly to the rapid prog-ress in understanding the etiology of some neu-rological disorders and the subsequent develop-ment of targeted treatments. A large body ofevidence now suggests that impaired adult neu-

rogenesis in the hippocampus is associated withvarious mental disorders, including major de-pression, schizophrenia, mood, and anxiety dis-orders as well as addictive behaviors. Impor-tantly, decreased adult neurogenesis correlateswith reduced cognitive and affective functions,a common symptom in patients and a frequentphenotype in animal models of these diseases,and often coincides with a decrease in cell pro-liferation in the dentate gyrus and reduced hip-pocampal volume (Bremner 1999; Lie et al.2004; Mirescu and Gould 2006; Reif et al.2007; Revest et al. 2009; Morris et al. 2010; Ni-xon et al. 2010; Noonan et al. 2010). As adulthippocampal neurogenesis is directly linked tothe action of antidepressants, it has been sug-gested that adult neurogenesis could be a targetfor treatment of depression (Banasr et al. 2006;Dranovsky and Hen 2006; Drew and Hen 2007;Sahay and Hen 2007). Using strategies to mi-mic physiological or environmental neurogenicstimuli may thus facilitate the development ofnovel therapeutics.

Based on the findings that hippocampalneurogenesis is down-regulated under patho-logical psychiatric conditions in patients andanimal models, and up-regulated by antidepres-sant drugs and other antidepressant treatments(Table 1), a neurogenic hypothesis of depres-sion emerged, proposing that neurogenesis inthe adult hippocampus may involve mood con-trol and is necessary for some of the behavioraleffects of antidepressants. Further studies onanimal models of psychiatric disease provideddirect evidence to support the hypothesis thatrestoration of adult hippocampal neurogenesiscan rescue some cognitive impairments. For ex-ample, work performed by the McKnight groupdiscovered that the proneurogenic chemicalP7C3 leads to enhanced cognitive capacity inaged rats on administration (Pieper et al. 2010).Importantly, treatment with P7C3 elicits anti-depressant efficacy in mice by increasing hip-pocampal neurogenesis (Walker et al. 2015). Inaddition, a study on fragile-X syndrome showedthat, although ablation of fragile-X mental re-tardation protein (FMRP) in neural progenitorcells leads to reduced hippocampal neurogene-sis in vitro and in vivo, resulting in significantly





impaired hippocampus-dependent learningin mice, restoration of adult neurogenesis viaFMRP expression in neural progenitor cells(NPCs) rescues these learning deficits (Guoet al. 2011). Furthermore, DISC1 knockdownspecifically in adult-born dentate gyrus neuronshas been shown to result in increased mTORsignaling and pronounced cognitive and affec-tive deficits. Importantly, suppression of mTORsignaling with treatment of the Food and DrugAdministration (FDA)-approved inhibitor rap-amycin can rescue the behavioral deficits (Zhouet al. 2013). These studies provide evidence thatdysregulated adult neurogenesis may contributeto the cognitive impairments seen in psychiatricdiseases, and that the cognitive deficits in ani-mal models can be at least partially rescued byrestoration of neurogenesis in the adult brain,suggesting that adult neurogenesis is a viabletherapeutic target.

Adult Neurogenesis as a Platformfor Understanding PsychiatricDisorders

Although the causes of many severe mental dis-orders are still poorly understood, cumulativeevidence suggests a role for neurodevelopmen-tal dysregulation, even in late-onset disorders.Both genetic and environmental factors play arole in disease onset and progression. Recentadvances in genome-wide sequencing technol-ogy and analyses have identified a large numberof susceptibility genes for psychiatric disorders,but a major challenge is to understand the roleof these genes in neural development and func-tion and how they contribute to causally rele-vant pathology (Abdolmaleky et al. 2005;O’Donovan et al. 2009; Kleinman et al. 2011).Adult hippocampal neurogenesis provides anattractive cellular model to understand themechanisms mediating the etiopathophysiol-ogy of mental disorders with several unique ad-vantages (Christian et al. 2010). First, adultneurogenesis recapitulates each step of neuronaldevelopment, including proliferation, cell fatespecification, migration, axonal and dendriticdevelopment, and synapse formation. Second,the time course of these developmental events is

significantly prolonged in the adult brain com-pared with the developing brain, which allowsfor increased temporal resolution in the analysisof each developmental step and is thus moreamenable to dissecting the cellular and molec-ular mechanisms regulating each stage. Third,adult hippocampal neurogenesis is not onlyregulated by intrinsic factors, but is also affectedby external stimuli, such as neuronal activity,environmental factors, and psychotropic drugs.Thus, the system provides a unique platform tostudy the interactions between genes and envi-ronment. Finally, transgenic or retroviral tech-niques allow for inducible and reversible ma-nipulation of genes and proteins of interest inspecific neuronal or stem-cell populations, al-lowing the opportunity to investigate how sus-ceptibility genes contribute to the pathologyunderlying psychiatric disorders. Thus, adultneurogenesis may not only play a role in psychi-atric symptomatology, but is also useful for in-vestigating the developmental mechanisms thatcontribute to psychiatric diseases. The utility ofadult neurogenesis as a model to explore thegenetic basis of neurodevelopmental disordersis constrained by the number of identified ge-netic risk factors. For some disorders, includingschizophrenia and autism spectrum disorders,numerous risk factors have been reported, al-though the biological functions of most of theidentified genetic variants in neurodevelop-ment are still unknown. For other psychiatricdisorders, including depression and addiction,we know much less about the genetic risk factorsand thus it is much more difficult at the mo-ment to capitalize on the potential of this systemto explore the consequences of disease-relevantgenetic mutations on neuronal development.But exploiting this cellular model through tar-geted genetic or environmental perturbationsshould further our understanding of the molec-ular basis of neuronal development to diagnose,treat, and potentially prevent some of the mostdebilitating psychiatric illnesses.

CLOSING REMARKS

The discovery of neurogenesis and neural stemcells in the adult mammalian hippocampus has

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enhanced our understanding of the plasticity ofthe mature brain and provided a unique modelto explore neuronal development and the inte-gration of newly born cells into existing neuralcircuitry. It has also raised questions regardingthe functional contribution of these cells in es-tablished neural circuits. As the role of adulthippocampal neurogenesis in cognitive and af-fective functions is slowly being revealed, stud-ies are now focusing on how dysregulation ofneurogenesis in the adult brain is related to thepathogenesis and progression of mental disor-ders. Although much work remains to be per-formed in this regard, a wealth of provocativedata support that intact neurogenesis promotescognitive function, prenatal or adult exposureto detrimental factors impair adult neurogene-sis and hippocampal function, disparate anti-depressant treatments enhance neurogenesisand require neurogenesis to be effective, andmany psychiatric risk genes affect both perinatalbrain development and adult neurogenesis. Thecontribution of these two phases of neurogen-esis to psychiatric diseases are not known, espe-cially in patients, and begs for further investiga-tion. As a model system to investigate neuronaldevelopment, adult neurogenesis is invaluablein our attempt to identify key signaling path-ways and cellular processes affected by riskgenes, which can pave the way to a deeper un-derstanding of the biology underlying psychiat-ric disorders. As an endogenous phenomenonthat modulates affective and cognitive behav-iors, we are only beginning to understand howthis constitutive reshaping of local hippocampalcircuitry impacts neural systems, and how itcould be a therapeutic target to restore somefunctions in patients with psychiatric disorders.

ACKNOWLEDGMENTS

The research in the authors’ laboratories is sup-ported by National Institutes of Health (NIH)Grants (NS048271, MH105128, NS047344,NS0937772), Brain & Behavior Research Foun-dation (formerly, National Alliance for Re-search on Schizophrenia and Depression, NAR-SAD), and Maryland Stem Cell Research Fund(MSCRF).

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