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Substantia Nigra, Ventral Tegmental Area,and Retrorubral Fields

Glenda Halliday, Stefanie Reyes, Kay DoubleUniversity of New South Wales and Neuroscience Research Australia, Randwick, New South Wales, Australia

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Introduction 439

he Hum

Embryogenesis 440

Substantia Nigra 440

Delineation 440 Neuronal Types 440 Cytoarchitecture 443

an N

Pars Compacta (SNC) 445

Pars Reticulata (SNR) 446

Ventral Tegmental Area 446

Delineation 447 Neuronal Types 447

439ervous System, Third Edition DOI: 10.1016/B978-0-12-374236-0.10013-6

Cytoarchitecture 447

Retrorubral Fields 447

Delineation and Cytoarchitecture 448 Neuronal Types 448

Functional Connections 448

SNC, VTA, and RRF Dopaminergic Projections 448 SNR GABAergic Projections 451 Other VTA and RRF Projections 451

Conclusion 451

INTRODUCTION

The substantia nigra (SN), ventral tegmental area(VTA), and retrorubral field (RRF) contain the largestcollection of dopaminergic neurons in the human brain,although these are not the only type of neuron in theseregions. Dopamine is a key neurotransmitter in thebrain, involved in reinforcement learning (Schultz,1998), reward seeking (Pessiglione et al., 2006), hippo-campal plasticity (Frey and Morris, 1998), workingmemory (Williams and Goldman-Rakic, 1995), addiction(Chao and Nestler, 2004; Hyman et al., 2006), behavioraldrive (Robbins and Everitt, 2007), and incentive motiva-tion (Berridge, 2004). The main target of midbrain dopa-minergic neurons is to the caudate and putamen (fromnigrostriatal neurons), and to limbic (from mesolimbicneurons) and other cerebral cortical areas (from meso-cortical neurons) (Berger et al., 1974; Fallon and Moore,

1978; Gerfen et al., 1987). Hence these midbrain areasare heavily involved in the control of cognitive andmotor behaviors, and their dysregulation underliesmany neurological and neuropsychiatric disorders(Carlsson et al., 2001; Goto and Grace, 2007; Murrayet al., 2008).

Dahlstrom and Fuxe (1964) developed an alphanu-meric nomenclature for monoaminergic neurons in therat brain and showed that 75–90% of dopaminergicneurons are found in the midbrain SN (A9 region),VTA (A10 region), and RRF (A8 region). In humans thereare approximately 600 000 midbrain dopaminergicneurons (German and Manaye, 1993; Wallen andPerlmann, 2003; Chinta and Andersen, 2005), as wellas small numbers of dopaminergic neurons in the peria-queductal grey (A11), zona incerta (A13), hypothalamus(A12, A14 and A15), olfactory bulb (A16), and retina(A17) (Dahlstrom and Fuxe, 1964; Gaspar et al., 1987).

Copyright � 2012 Elsevier Inc. All rights reserved.

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The three anatomically and functionally distinct groupsof midbrain dopaminergic neurons are well defined butform a continuum (Dahlstrom and Fuxe, 1964; Gasparet al., 1987). To anatomically separate these groupsseveral cellular characteristics are used, including cellpigmentation (Bazelon et al., 1967), tachykinin innerva-tion (Gerfen et al., 1985; Gibb, 1992), projection patterns(Braak and Braak, 1986; Fearnley and Lees, 1991), andneurochemical profiles (McRitchie et al., 1996). A9 cellgroups correspond to the dopaminergic neurons foundin the SN pars compacta (SNC, nigrostriatal neurons)involved in the control of voluntary movements. TheA10 and A8 cell groups (mesocortical and mesolimbicneurons) are involved in emotional behavior and mech-anisms of reward (Tzschentke and Schmidt, 2000).

Embryogenesis

The midbrain dopaminergic neurons originate froma single embryological cell domain delineated rostrallyby the ventral thalamus/hypothalamus border andcaudally by the midbrain/hindbrain border (Dahlstromand Fuxe, 1964; Marin et al., 2005). Early expression ofsignals such as sonic hedgehog and fibroblast growthfactor 8 are essential for the induction and regional spec-ification of these neurons. The area where these twosignals intersect is the region where the midbrain dopa-minergic neurons are born (reviewed in Smidt and Bur-bach, 2007). Midbrain dopaminergic neurons begin asprogenitor cells which express specific intracellular tran-scription factors that differentiate them from other CNSprogenitors. These factors include: Raldh1, Otx2, Lmx1a,Lmx1b, Engrailed 1 and 2, Msx1, Msx2, Neurogenin 2,and Mash1 (Simon et al., 2001; Puelles et al., 2004;Andersson et al., 2006; Kele et al., 2006). The functionsand expression of each of the factors varies duringneuronal development (reviewed in Ang, 2006) withmultiple factors required for differentiation, as expres-sion of only individual factors fails to differentiatemature dopaminergic neurons (Andersson et al., 2006;Kele et al., 2006). The young dopaminergic neuronsundergo further development and differentiation underthe influence of Nurr1, and the engrailed genes, Lmx1band Pitx3 (reviewed in Alavian et al., 2008). The dopami-nergic neurons of the SNC, RRF, and VTA migrate todifferent positions along the mediolateral axis of themidbrain and develop different axonal projections. Themolecules responsible for these differences are currentlyunknown.

SUBSTANTIA NIGRA

The substantia nigra (SN) is considered an integralpart of the basal ganglia, containing the A9 dopaminergic

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neurons (nigrostriatal neurons that provide a feedbackloop to the striatum) as well as the GABAergic neuronsthat relay basal ganglia output to the thalamus, colliculi,and tegmentum. It therefore plays a major role in thecontrol of actions and thought.

Delineation

The human SN is a large structure bordered anteri-orly by the cerebral peduncle and posteriorly by thered nucleus and superior cerebellar decussation (Gibband Lees, 1991; McRitchie et al., 1996). Different popula-tions of dopaminergic neurons are found medially (VTAA10 cell groups) and dorsally (RRF A8 cells), and theterritory of the SN can best be defined and separatedfrom these groups by its dense innervation from thestriatum (Mai et al., 1986; Gibb, 1992; McRitchie andHalliday, 1995; McRitchie et al., 1996). The separatepopulations of dopaminergic and GABAergic neuronswithin the SN are called the pars compacta (SNC) andpars reticulata (SNR), respectively (Halliday and Tork,1986). The striatal axons innervating the substantia nigracontain the tachykinin substance P (Ljungdahl et al.,1978; Gerfen et al., 1985; Pioro et al., 1990), and thispathway identifies the midbrain relay neurons impor-tant for direct basal ganglia feedback and output. Thedense tachykinin staining of the SN can be used todefine its boundaries, and covers a larger cross-sectionalarea of the ventral midbrain than similar dense immu-nostaining for either enkephalin or calbindin(Figure 13.1).

Neuronal Types

All dopaminergic neurons contain the rate-limitingenzyme tyrosine hydroxylase (TH) and SNC dopami-nergic neurons also contain neuromelanin pigment,a byproduct of dopamine synthesis (Double et al.,2008). SNC TH-immunopositive pigmented neuronsare typically medium sized to large, triangular, andmultipolar, with a smaller proportion of spindle,bitufted neurons (Figure 13.2C). The medial part of theSNC (pars medialis or SNM) contains significantlysmaller neurons than neurons found elsewhere in theSNC (Halliday et al., 2005), while the lateral part of theSNC (pars lateralis or SNL) contains more highly pig-mented dopaminergic neurons (55% of the cell cyto-plasm contains neuromelanin; Halliday et al., 2005). Inthe remaining SNC cells, neuromelanin pigmentoccupies approximately 50% of the soma (Figure 13.2Binset; Halliday et al., 2005). SNC neurons also containsubstantial amounts of high molecular weight non-phosphorylated neurofilament (Gai et al., 1994) andmicrotubule-associated protein-2 (MAP 2; D’Andrea

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FIGURE 13.1 The SN (substantia nigra) can be defined as the midbrain region receiving striatal innervation. This innervation is clearly seenin immunohistochemical preparations identifying the peptide substance P. The dense substance P immunostaining consistently covers a largercross-sectional area of the ventral midbrain than similar dense immunostaining for either enkephalin or calbindin. cp, cerebral peduncle; R, rednucleus.

SUBSTANTIA NIGRA 441

et al., 2001). They tend to have one large and two smallerprimary dendrites, which may become obscured by theplethora of similar processes surrounding the neuron.SNC dopaminergic neurons also express the dopaminetransporter (Harrington et al., 1996; Bannon and Whitty,1997; Ma et al., 1999), and the amount of this transporter

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within the soma region may decline with age (Maet al., 1999).

Dopamine receptors are abundant in the SN. Six typesof dopamine receptors are found in the brain and aretermed D1 to D5, with the D2 autoreceptor existing asboth a long and short isoform (Giros et al., 1989; Sokoloff

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FIGURE 13.2 Location and cell types found in the SN (substantia nigra), VTA (ventral tegmental area). and RRF (retrorubral field). Scale in Fequivalent for C–D. (A,B) Schematic diagram (A) and photomicrograph (B, cresyl violet stain) of the ventrolateral quandrant of the humanmidbrain showing the cytoarchitectonic regions and major cell clusters. Insets in B show the difference in size and pigmentation between SNCneurons and VTA or RRF neurons. The SN is divided into the non-dopaminergic SNR (pars reticulata) and dopaminergic SNC (pars compacta),with several of the densely pigmented cell clusters making up the SNC visible (dorsal tier or SNCd clusters, ventral tier or SNCv clusters, theSNL or pars lateralis and the SNM or pars medialis). The VTA in humans is divided into several mixed cell groups that include the PBP(parabrachial pigmented nucleus), RLi (rostral linear nucleus), IF (interfasciculus nucleus), and PN (paranigral nucleus) observed at the leveldepicted. 3n, occulomotor nerve roots; cp, cerebral peduncle; R, red nucleus. (C,D) Tyrosine hydroxylase (TH)-immunoreactive dopaminergicneurons differ in morphology between the SNC (C) and VTA (D) or RRF. SNC dopaminergic neurons (C) are typically medium-sized to large,triangular and multipolar. They contain large amounts of neuromelanin pigment and tend to have one large and two smaller primary dendriteswhich usually become obscured within the local plethora of similar processes (seen at top of figure). VTA or RRF dopaminergic neurons aresmaller, contain less neuromelanin pigment and are bipolar in shape, as shown in the PBP neuron found dorsal to the highly pigmented SNCdneurons (bottom of figure). (E,F) There are two types of non-pigmented, non-dopaminergic neurons found within the SN containing distinctcalcium binding proteins. Non-pigmented calretinin-containing neurons are typically bipolar, while non-pigmented parvalbumin-containingneurons are typically multipolar, with round or triangular somas. Parvalbumin-containing neurons concentrate in the SNR, while the calretinin-containing neurons are only found between the cell clusters of the SNC (pigmented neurons arrowed). dl, dorsolateral; dm, dorsomedial ; vi,ventrointermediate; vl, ventrolateral.

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SUBSTANTIA NIGRA 443

and Schwartz, 1995). Within the SNC the D2 autorecep-tor is richly expressed on neuronal soma, dendrites,axons, and synapses (Creese et al., 1983; Charuchindaet al., 1987; Hurd et al., 2001; Hurley and Jenner, 2006),but is less abundant in the SNR where D1 receptors aremore abundant (Hurley and Jenner, 2006). DopamineD2 receptors are G-protein coupled receptors (Kebabianand Calne, 1979). Activation of these receptors inhibitscellular activity, contributing to the maintenance ofa spontaneous pacemaker-like firing pattern (Shiet al., 2000).

In contrast to rats, human SNC neurons expressneurokinin-1 receptors, rather than neurokinin-3 recep-tors, which mediate the effects of the striatum-derivedsubstance P and neurokinin A (Whitty et al., 1997).SNC neurons abundantly express a2-adrenoreceptors(Palacios et al., 1987; Jones et al., 1990) and both nicotinicand muscarinic acetylcholine receptors (Nastuk andGraybiel, 1991; Sorenson et al., 1998). Human SNneurons are relatively lacking in EF-hand calciumbinding proteins, with calbindin-immunoreactivityonly found in some neurons of the SNM (McRitchieand Halliday, 1995), while parvalbumin is expressed innon-pigmented SNR neurons (Figure 13.2F) and calreti-nin in only a small proportion of SNC neurons(Figure 13.2E; McRitchie et al., 1996). The calbindin-immunoreactive neurons are pigmented and similar inmorphology to the TH-immunoreactive SNM neurons,although fewer in number (McRitchie et al., 1996). Thenon-pigmented calretinin-containing SNC neurons aretypically bipolar (Figure 13.2E), although some multi-polar neurons also contain this calcium-binding protein.The processes of these neurons have small varicosities atirregular intervals. SNC neurons are also rich in a-synuclein, parkin, and LRRK2 (Solano et al., 2000; Gavinet al., 2001; Han et al., 2008). While no physiological rolehas been assigned to these proteins in this region, all areimplicated in neurodegenerative movement disordersaffecting SNC neurons.

The SN also contains a variety of growth and trophicfactors thought to play a role in the development, matu-ration and survival of the dopaminergic neurons. Levelsof glial-derived neurotrophic factor (GDNF) within mel-aninized SNC neurons are described as moderate(Chauhan et al., 2001), and may be retrogradely trans-ported to the SNC from the striatum (Barroso-Chineaet al., 2005), while three other members of this familyof neurotrophins, neurturin, persephin, and artemin(also known as neublastin), are sparely present in thisbrain region (Quartu et al., 2007). Further, componentsof the receptor complex through which GDNF preferen-tially signals have also been identified (Sarabi et al.,2001; He et al., 2008). Another family of trophic factors,the neurotrophin family, consists of four factors, brain-derived neurotrophic factor (BDNF), nerve growth

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factor, neurotrophin-3, and neurotrophin-4. These neu-rotrophins bind with low affinity to the p75 neurotro-phin receptor (p75NTR), a member of the tumornecrosis receptor superfamily, as well as three membersof the tyrosine kinase (Trk) receptor family. All four neu-rotrophic factors and all three Trk receptors are found inthe SNC (Nishio et al., 1998; Chauhan et al., 2001).mRNA for epidermal growth factor receptor (EGF-R)is also foundwithin the SNC (Seroogy et al., 1994). Othergrowth and trophic factors identified within SNCneurons include Pitx3 (Smidt et al., 1997), Nurr1 (Chuet al., 2002), mesencephalic-astrocyte-derived neurotro-phic factor (Lindholm et al., 2008), engrailed-1 (Simonet al., 2001; Bannon et al., 2004), engrailed-2 (Simonet al., 2001), and leucine-rich repeat Ig-containingprotein (Inoue et al., 2007).

Less is known regarding the non-pigmented neuronsin the human SN. Non-pigmented parvalbumin-containing SNR neurons are small and typically multi-polar, with round or triangular somas (Figure 13.2F),similar in morphology to neurons in the globus pallidus(Yelnik et al., 1987), with sparsely branching dendrites.

Cytoarchitecture

The SN contains three broad sheets or tiers ofneuronal columns abutting the cerebral peduncleoriented ventromedial to dorsolateral in cross-section.Dorsally the closely related parabrachial pigmentednucleus is found in a similar alignment between theSN and the red nucleus. In humans there is a complexarrangement of SN dopaminergic cell clusters in twoof the three neuronal sheets, epitomized by the 21 subdi-visions identified by Hassler (1937, 1938). The followingcytoarchitectural descriptions are based on the broadagreement of the majority of studies in this area (Braakand Braak, 1986; Fearnley and Lees, 1991; Gibb andLees, 1991; van Domburg and ten Donkelaar, 1991;Gibb, 1992; McRitchie and Halliday, 1995; McRitchieet al., 1995, 1996) and incorporates calbindin terminalimmunostaining to define SNC dopaminergic cell clus-ters (Damier et al., 1999).

Within the SN, the most ventral sheet of neuronslargely comprises the GABAergic SNR neurons(288 000� 32 000 neurons in humans; Hardman et al.,2002) while more dorsally there are two sheets of pig-mented dopaminergic SNC neurons (SNCv and SNCdtotaling 382 000� 20 000 neurons in humans; Hardmanet al., 2002). These three sheets of neurons arecompressed together at both the ventromedial anddorsolateral extremes (Figure 13.3) where they arereferred to as the SN pars medialis (SNM) and SN parslateralis (SNL). In these regions there is considerablemixing of neuronal types.

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FIGURE 13.3 (A–C)Three rostrocaudal transverse levels of themidbrain immunohistochemically stained for tyrosinehydroxylase (TH) showingthe twodopaminergic tiersof theSNC(dorsal, SNCd,andventral, SNCv)with thepositionof themoreventral pars reticulata (SNR) indicated.Note thehuman interpeduncular nucleus is located more caudally deep in the base of the interpeduncular fossa. The pars lateralis (SNL) is located dorso-laterallywithin theSN,while theparsmedialis (SNM) is locatedcaudallyon thedorsomedial border.The less celldenseparanigralnucleus (PN,part oftheA10 cell group)mediallyabutsdirectlyonto this regionof theSN.Theverydiffuseparabrachialpigmentednucleus (PBP) containingdopaminergicA10 cells can be seen dorsally between the red nucleus (R) and cerebral peduncle (cp). Other midbrain dopaminergic nuclei are indicated – rostrallinear nucleus (A10 RLi), caudal linear nucleus (A10 CLi), interfasicular nucleus (A10 IF), and retrorubral fields (A8 RRF). 3n, third nerve; R, rednucleus; scp, superior cerebellar peduncle. (Reproduced with permission from The Human Nervous System, 2nd Edition by Paxinos and Mai, 2004.)

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FIGURE 13.4 Diagramatic (right), photographic (cresyl violet photo at left) and graphical (lower left) representation of the consistently founddopaminergic cell clusters at different rostrocaudal levels of the midbrain. The level of the photograph is indicated by the transverse line on thediagram at right of the SNC cell clusters and the graphical representation in the lower right of the VTA and RRF cell clusters. Data taken from

McRitchie et al., 1995, 1996, 1997. (Upper left) Photomicrograph of the transverse level indicated by the lines in the diagram of the SNC cellclusters at left and the graph of the VTA and RRF cell clusters below. (Lower left) Graphical representation of the rostrocaudal extent of the VTAand RRF cell clusters (McRitchie et al., 1997). The location of some of these cell groups can be seen in the photomicrograph of the transversesection above and are detailed in (McRitchie et al., 1996, 1997). (Right) SNC cell clusters represented as two-dimensional cell columns orientedlongitudinally and obliquely in the brainstem. The diagrams were drawn from three-dimensional reconstructions of transverse sections of thecell clusters which clearly show that these clusters form longitudinal aggregations of neurons (McRitchie et al., 1995). The shading gives someindication of the cell density with variable regions of cell clusters indicated by dotted lines. The dorsomedial (dm) column is equivalent tonigrosome 2, the dorsolateral (dl) column is equivalent to nigrosomes 4 caudally and 5 rostrally, SNR is equivalent to nigrosome 3, and theventral intermediate (vi) and ventrolateral (vl) columns are equivalent to nigrosome 1 (Damier et al., 1999). CLi, caudal linear nucleus;MRF, Midbrain reticular fields; PaP, parapeduncular nucleus; for definition of other abbreviations, see legend to Figure 13.2.

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Pars Compacta (SNC)

The SNM, SNCd, and SNL appear aligned along thedorsal border of the SN. The SNCd and SNCv aremore conspicuous at different rostrocaudal levels(Figure 13.3). SNCd is significantly larger than SNCvand predominates both caudally and rostrally(Figure 13.4). SNCv is most noticeable at intermediatelevels of the midbrain (Figure 13.4). Equal numbers ofdopaminergic neurons are found in these tiers (Hardmanet al., 2002). In humans these tiers are arranged in longi-tudinal cell clusters with small bridges of pigmentedneurons interspersed between the clusters (Figures13.3, 13.4). These bridges comprise dorsomedial-to-ventrolateral aligned neurons, whereas there is a morerandom orientation of neurons and processes in thecell clusters. Both the SNCd and SNCv can be subdi-vided into medial, intermediate, and lateral longitudinalcell cluster regions based on the density and aggrega-tions of pigmented neurons (Figure 13.4). The densest

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cell clusters in SNCd correspond to a dorsomedialcolumn (McRitchie et al., 1995), called nigrosome 2(Damier et al., 1999), and a dorsolateral column(McRitchie et al., 1995), called nigrosomes 4 and 5(Damier et al., 1999). Nigrosome cell clusters can be visu-alized by the significant decrease in calbindin immuno-reactive fiber terminals which surround them (Damieret al., 1999). The dorsomedial column or nigrosome 2 isthe most consistent and densely packed cell column,with the dorsolateral column (particularly nigrosome 5)always found at the rostral levels (Figure 13.4). WithinSNCv, the intermediate and lateral cell columns(McRitchie et al., 1995), together called nigrosome 1(Damier et al., 1999), are highly cell dense, with thelateral cell column concentrating caudally (Figure 13.4).The other cell columns (dorsointermediate and ventro-medial) contain significantly fewer neurons (Figure 13.4)and are found embedded within the calbindin-immunoreactive matrix (Damier et al., 1999).

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SNM is present only in the caudal midbrain withinthe dense substance P- and calbindin-immunoreactivestriatonigral fiber matrix (Figures 13.3, 13.4). This matrixseparates the nigra from the medial A10 VTA cell clus-ters. SNM is characterized by densely packed neuronsthat are smaller than SNCd. Caudally the medialterminal nucleus of the accessory optic tract and the exit-ing third-nerve fibers separate SNM from SNCd. Aproportion of pigmented neurons in SNM contain cal-bindin or calretinin immunoreactivity. SNL (McRitchieet al., 1995), called nigrosome 3 (Damier et al., 1999), isfound at the dorsolateral extreme of the SN (Figures13.3, 13.4), lateral to the corticonigral and pallidonigralfiber tracts, and exhibits a significantly decreased cellpacking density compared to the SNCd. In addition topigmented dopaminergic neurons, the SNL containsnon-pigmented parvalbumin-containing TH-positiveneurons.

Pars Reticulata (SNR)

In humans, neurons of the SNR aggregate rostrallyand ventrally (Figure 13.5), although non-pigmentedneurons are also found between the dense cell clustersof the SNC. The non-pigmented SNC neurons containeither calretinin or parvalbumin immunoreactivity,whereas the neurons comprising the ventral sheet ofSNR neurons contain only parvalbumin immunoreac-tivity (Figure 13.5).

FIGURE 13.5 Parvalbumin-immunoreactive transverse section ofthe rostral midbrain and distribution plot of the immunoreactiveneurons (crosses) within the SN. While many immunoreactive neuronsare found within the SNR (arrowed), these neurons are widelydispersed within the SN. Note the high neuropil immunostaining forparvalbumin in the red nucleus (R). cp, cerebral peduncle. (Reproducedwith permission from The Human Nervous System, 2nd Edition by Paxinos

and Mai, 2004.)

VENTRAL TEGMENTAL AREA

The ventral tegmental area (VTA) is considered inte-gral in reward behaviors and cognitive functions(Goldman-Rakic et al., 2004; Ikemoto, 2007), and isnotably active in circumstances of arousal, stress, moti-vation, or memory retrieval (Wise, 2004; Nicola et al.,2005). Tsai (1925) was the first to identify the VTA inthe opossum brain and in rodents; initially this areawas considered to be the A10 cell group (Dahlstromand Fuxe, 1964; Fallon and Moore, 1978; Moore andBloom, 1978). More careful analyses, however, identifiedseveral cytoarchitectural regions containing A10 cells inrodents (Phillipson, 1979b; Swanson, 1982; McRitchieet al., 1996) and in humans these A10 cell clusters areexpanded, with the pigmented and non-pigmentedTH-immunoreactive neurons dispersed more widely(McRitchie et al., 1996). The VTA of the rat containsapproximately 30 000 neurons, of which 60% are dopa-minergic, whilst the VTA of humans contains around690 000 neurons (Halliday and Tork, 1986; German andManaye, 1993; Margolis et al., 2006) of which ~120 000(<20%) are tyrosine hydroxylase positive (McRitchieet al., 1997).

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RETRORUBRAL FIELDS 447

Delineation

The human VTA is less cell dense compared to the SNand, therefore, delineated by its boundary structures.The human VTA is found medial, ventral and dorsal tothe red nucleus in the midbrain reticular formation(Figures 13.3, 13.4). It is dorsal and, in humans, morerostral to the interpeduncular nucleus, ventral to theocculomotor nucleus in the periaqueductal gray, anddorsal and medial to the SN (McRitchie et al., 1996).

Neuronal Types

There are very limited studies on the types of VTAneurons in humans. Compared with SN neurons,human VTA neurons are rather loosely arranged andsmall, with an average diameter ranging from 10 to53mm (Halliday and Tork, 1986). TH-immunoreactiveneurons in the VTA differ from those in the SN by theirsmaller size (Figure 13.2C,D), complexity (bipolar,Figure 13.2C,D), and degree of pigmentation(Figure 13.2B–D). Only 50% of the TH-immunoreactiveneurons in the VTA regions contain neuromelaninpigment (Hirsch et al., 1988), although when pigmentedthey have similar levels of neuromelanin in their cyto-plasm as SNC neurons (Figure 13.2B inset; Hallidayet al., 2005). Like their SNC counterparts, VTA neuronsrichly express D2 autoreceptors (Adell and Artigas,2004), but express significantly lower levels of the dopa-mine transporter compared with SNC cells (Gonzalez-Hernandez et al., 2004). Their reduced capacity fordopamine reuptake is suggested to decrease theirvulnerability to neurodegeneration.

Growth factor expression in VTA neurons is similar tothat reported for SNC neurons (see above). Human VTAneurons also express neurokinin-1 receptors, but inlower concentrations than their SNC counterparts(Whitty et al., 1997). This is consistent with the reducedtachykinin innervation of VTA regions. It has beenshown that VTA neurons do not express LRRK2 (Hanet al., 2008), and higher levels of a-synuclein and parkinare found in more highly melanized neurons (Solanoet al., 2000), suggesting lower levels in the majority ofVTA neurons compared with SNC neurons. In contrastto SNC neurons, VTA neurons express EF-hand calciumbinding proteins (McRitchie et al., 1996). A smallproportion of calbindin-immunoreactive VTA neuronsalso contain neuromelanin pigment, but many are notpigmented (McRitchie et al., 1996). A few non-pigmented calretinin-immunoreactive neurons arefound in most VTA regions, with a large midline popu-lation of serotonergic neurons found in the caudal linearnucleus (McRitchie et al., 1996). The number of seroto-nergic neurons found in this region is about 10� lessthan that in the dorsal or median raphe nuclei

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(Hornung, 2003). Small, non-pigmented multipolar orbipolar parvalbumin-immunoreactive neurons aresparsely located within the VTA (McRitchie et al.,1996). In the SNC parvalbumin-immunoreactive SNRneurons are GABAergic, and 15–20% of VTA neuronsin other species are also GABAergic (Bayer and Pickel,1991; Kalivas et al., 1992; Kalivas, 1993). These GABAcells are thought to inhibit VTA dopaminergic neuronsvia collaterals, as these GABAergic cells are in factprojection neurons (Steffensen et al., 2006).

Cytoarchitecture

The VTA contains several cytoarchitectonic regionsbased on the distribution and density of cell types(McRitchie et al., 1996; Ikemoto, 2007) with significantspecies differences identified. In humans, the parabra-chial pigmented nucleus (PBP) is a cell sparse areafound dorsal to the SNC and ventral to the red nucleuswith neurons aligned parallel to the circumference ofthis nucleus (Figures 13.3, 13.4). The VTA nucleus issituated medial to the PBP among and ventral to theexiting third nerve fibres on the ventromedial aspectof the red nucleus (Figures 13.3, 13.4). The paranigralnucleus (PN) is situated adjacent to the interpeduncu-lar nucleus next to the SNM in the caudal midbrain(Figures 13.3, 13.4). In a similar position rostrallynext to the fasciculus retroflexus, the parapeduncularnucleus (PaP) is situated (Figure 13.4). The interfascic-ular nucleus (IF) is situated on the rostral pole of theinterpeduncular nucleus and comprises denselypacked small pigmented TH-immunoreactive neuronsthat straddle the midline. The cell dense caudal linearnucleus (CLi) and the rostral linear nucleus (RLi) arefound just lateral to the midline, with CLi extendingfrom the decussation of the superior cerebellarpeduncle to around the level of IF, while RLi is ina slightly more lateral position in the rostral midbrain(Figures 13.3, 13.4). As discussed, different nomencla-tures for these regions may be used in studies on therodent brain (Perrotti et al., 2005; Ikemoto, 2007;Ferreira et al., 2008).

RETRORUBRAL FIELDS

The retrorubral field (RRF) is considered an integralpart of the midbrain dopaminergic system, but is theleast studied of all the midbrain dopaminergicregions. Due to minimal exploration of RRF cell typesand their possible projections in humans, much of theliterature reviewed in the following sections comesfrom studies on laboratory animals, rather thanhumans.

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Delineation and Cytoarchitecture

The RRF is situated caudal and lateral to the rednucleus and lateral to the decussation of the superiorcerebellar peduncle in the human midbrain (Gibb,1992; McRitchie et al., 1996) (Figures 13.3, 13.4) and isdefined as the A8 group of dopaminergic cells, a cellgroup first described in the rat by Dahlstrom et al.(Dahlstrom and Fuxe, 1964; McRitchie et al., 1996). Itis bordered by the SN anteriorly, the VTA medially,and the locus coeruleus posteriorly (Francois et al.,1999). Exact borders are difficult to find because inthe caudal midbrain there is confluence between theRRF, VTA, and SN (Figure 13.3; Deutch et al., 1988;Gasbarri et al., 1996; Francois et al., 1999). In caudalregions of the human midbrain the RRF and SN cellsare hard to differentiate, as the medial lemniscus usedto separate them rostrally, contains dopaminergic pig-mented cells which transverse this structure (McRitchieet al., 1996). The RRF is also in close association withsurrounding landmarks including the PBP and CLi(Figures 13.3, 13.4). Similar to the more mediallylocated PBP, the RRF also curves around the lateraland ventral aspects of the red nucleus, and hugs thedecussation of the superior cerebellar peduncle in itsdorsal aspect, infringing on the dorsal cells of the CLi(Figure 13.3). The RRF is succeeded rostrally by thehuman specific midbrain reticular fields (MRF, Figures13.3, 13.4), and together these areas compose the lateralmidbrain reticular formation A8 cell group (McRitchieet al., 1998).

Neuronal Types

ThehumanRRF contains a heterogeneouspopulationof large multipolar neurons as well as small spindle-shaped neurons (McRitchie et al., 1996). In humansmost of these neurons are not TH-immunoreactiveand few contain neuromelanin pigment (Gibb, 1992;McRitchie et al., 1996). In primates TH-immunoreactiveRRF neurons have smaller somata and more brancheddendrites than SNC neurons (Arsenault et al., 1988).In both humans and rats the TH-immunoreactiveneurons found in the RRF account for 10% of the totalmidbrain TH neurons (human: Hirsch et al., 1992;McRitchie et al., 1996; primate: Francois et al., 1999;rat: German and Manaye, 1993; Nair-Roberts et al.,2008). While TH-immunoreactive RRF neurons arelikely to express D2 autoreceptors and the dopaminetransporter, the levels of these proteins in these dopa-minergic neurons remains unknown. Possible expres-sion of neurokinin-1 receptors, LRRK2, a-synuclein,or parkin in these neurons has also not beeninvestigated.

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Like VTA neurons, calcium binding proteins arefound within both the TH-immunopositive and nega-tive cells of the human RRF. These proteins includecalbindin-D28k, parvalbumin, and calretinin (Gibb,1992; McRitchie et al., 1996). Many contain calbindin-immunoreactivity and only a small proportion are pig-mented. These neurons are large and multipolar withrandomly oriented processes. A small number of largemultipolar non-pigmented calretinin-immunoreactiveRRF neurons are observed, similar in morphology tothe non-pigmented TH-immunoreactive neurons inthis region. In addition, the RRF contains small,spindle-shaped calretinin-immunoreactive neurons.Two populations of neurons containing parvalbumin-immunoreactivity are observed in the RRF. Largedarkly staining parvalbumin-immunoreactive RRFneurons of similar morphology to the non-pigmentedTH-immunoreactive RRF neurons intermingle withsmall, pale-staining parvalbumin-immunoreactiveneurons similar to those observed in the SNR(McRitchie et al., 1996). In the SN and VTA thesesmaller parvalbumin-immunoreactive neurons areGABAergic (Bayer and Pickel, 1991; Kalivas et al.,1992; Kalivas, 1993).

FUNCTIONAL CONNECTIONS

As may be expected, there is a significant literatureon the dopaminergic projections from these midbrainregions which shows a continuum of topographicdopaminergic projections to forebrain regions, withconsiderable species differences (Berger et al., 1991;Joel and Weiner, 2000; Garcia-Cabezas et al., 2009),although the majority of data pertains to the rodentbrain. Except for the SNR which has been widelystudied (Deniau et al., 2007), little is known regardingthe projections of non-dopaminergic neurons in theseregions.

SNC, VTA, and RRF DopaminergicProjections

The dopaminergic SNC is an integral part of the basalganglia, which regulates the pyramidal system, particu-larly the incoming cortical information at the level of thestriatum (see Chapter 21). SNC neurons form an integralfeedback system to the striatum, with about 100 striatalneurons funneling information to each SNC neuron(Percheron et al., 1994). In turn each SNC neuronprojects back to approximately 5% of the striatum (Mat-suda et al., 2009). SNCd neurons receive projectionsfrom and project back to striatal regions innervated byassociation cortices (caudate and anterior putamen,

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FUNCTIONAL CONNECTIONS 449

Figure 13.6C; Haber et al., 2000). SNCv neurons receiveinnervation from both associative and sensorimotorregions of the striatum. SNCv neurons, particularly theventrolateral cell group, nearly selectively innervatesensorimotor innervated regions of the striatum (inter-mediate and posterior putamen, Figure 13.6C) (Haberet al., 2000). SNL dopaminergic neurons receive innerva-tion from the caudate region innervated by visual andoculomotor cortical regions. This lateral region projectsdirectly to the inferior and superior colliculi(Figure 13.6B) (Francois et al., 1984; Tokuno et al., 1993;Harting et al., 2001).

The dopaminergic SNM, VTA, and RRF also inner-vate the striatum but only the SNM receives striatalinnervation. The major telencephalic target of the RRFis the striatum (Figure 13.6C; Deutch et al., 1988) and itreceives noradrenergic innervation from the medullaand locus coeruleus for visceral input to reward path-ways (Mejias-Aponte et al., 2009). The VTA regionsreceive a variety of reciprocal projections from brain-stem (locus coeruleus noradrenergic projection; Herveet al., 1982; Grenhoff et al., 1995), dorsal and medianraphe serotonergic projection (Herve et al., 1987; Oadesand Halliday, 1987; Vertes et al., 1999), pedunculopon-tine (pedunculotegmental) and lateral dorsal tegmentalcholinergic and GABAergic projections (Semba andFibiger, 1992; Oakman et al., 1995; Yeomans and Bap-tista, 1997), hypothalamus, forebrain (GABAergicaccumbens and pallidal projections, but not caudate,putamen, septum or nucleus basalis), limbic regions(but not entorhinal or hippocampal cortices), and neo-cortices (Phillipson, 1979a; Oades and Halliday, 1987;Adell and Artigas, 2004; Geisler and Zahm, 2005). TheSNM and VTA were recently proposed to contain twomain subpopulations of projection neurons, ventrome-dial and dorsolateral neurons, which project to thelimbic and lateral regions of the striatum respectively(Ikemoto, 2007). The limbic projection is involved inlearning a stimulus outcome association (rewardcircuitry), while the lateral projection is linked to a stim-ulus-action association (Ikemoto, 2007). The RRF alsoprojects to lateral striatum (Francois et al., 1999) and isthought to play a role in the control of orofacial move-ments (von Krosigk et al., 1992; Spooren et al., 1993).RRF cell loss has been suggested to contribute to themask-like expression of the face seen in patientssuffering Parkinson’s disease (Spooren et al., 1993).

Apart from the dopaminergic projection to the stria-tum, direct limbic and cortical projections have beenassessed in detail (Albanese and Minciacchi, 1983; Ses-ack et al., 1995; Krimer et al., 1997). The mesolimbicprojection originates in the paranigral VTA and RRFregions (Figure 13.6E) while the mesocortical projectioncomes from the parabrachial VTA regions (Figure 13.6F;Fallon et al., 1984; Margolis et al., 2006). The mesolimbic

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projection densely innervates the accumbens nucleus,lateral hypothalamus, amygdala, and pregenual andsubgenual limbic prefrontal cortices (Ungerstedt, 1971;Berger et al., 1974; Lindvall and Bjorklund, 1974; Lind-vall et al., 1974; Langer and Graybiel, 1989; Haberet al., 1990) and the hippocampal dentate gyrus inhumans (Lewis et al., 2001) with smaller projections tothe lateral septum, hippocampus, and entorhinal cortex(Beckstead et al., 1979; Swanson, 1982; Deutch et al.,1988). These mesolimbic projections work in conjunctionwith the striatal projections in these reward pathways(Schultz, 1998; Spanagel and Weiss, 1999).

The reciprocal projections between the midbraindopaminergic neurons and the neocortex differ substan-tially between species (Berger et al., 1991; Williams andGoldman-Rakic, 1998; Frankle et al., 2006). In rodentsthe prefrontal cortex directly innervates the midbrainand plays a central role in regulating the firing patternof the dopaminergic neurons (Carr and Sesack, 2000),while in primates there is little evidence for directcortical control of dopaminergic neurons (Frankleet al., 2006). In primates the preferential targeting ofthese VTA neurons by cholinergic afferents stemmingfrom the pedunculopontine tegmental (pedunculoteg-mental) and laterodorsal tegmental nuclei may bemore dominant (Semba and Fibiger, 1992; Oakmanet al., 1995; Yeomans and Baptista, 1997; Garzon et al.,1999). In rodents the dorsolateral regions of the VTAproject almost exclusively to the prefrontal and insularcortices, while in primates there are substantive projec-tions from these regions to many neocortical regions,but particularly dense projections to motor and poste-rior parietal cortices (Berger et al., 1991; Lewis et al.,2001). The mesocortical projection is thought to beinvolved in the modulation of cognitive functions, andin Parkinson’s disease cortical (rather than the limbicor striatal) VTA projections are selectively affected(McRitchie et al., 1997; Williams and Goldman-Rakic, 1998).

Another species difference is the large dopaminergicinnervation of the primate thalamus arising from theVTA and RRF regions (Figure 13.6D; Sanchez-Gonzalezet al., 2005). This thalamic dopaminergic projection hasbeen identified in the human thalamus (Garcia-Cabezaset al., 2007). Across species there is also a large connec-tion between the RRF and the dopaminergic cell groupsof the SNC and VTA (Figure 13.6B; Deutch et al., 1988;Arts et al., 1996). These connections are thought to bevital in coordinating and modulating the cognitive andmotor function of the SN and VTA neurons (Deutchet al., 1988; Arts et al., 1996), as subtle bilateral lesionsin the RRF produce a series of long-lasting motorprogramming deficits, of which at least a part occursdue to the disrupted RRF projections to the SN andVTA (Arts and Cools, 1998).

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(A) (D)

(B) (E)

(C) (F)

FIGURE 13.6 Schematic representation of the major regions of the SN (substantia nigra), VTA (ventral tegmental area). and RRF (retrorubralfield) and the organization of their major projections as detailed in the text. (A) Stylized diagram of the tiered arrangement of the cell clusters of theSN and VTA observed around the red nucleus (R) and the position of the RRF in transverse sections of the midbrain (3n represents exiting thirdnerve fibres). Just dorsal to the cerebral peduncle (cp), the three major tiers of the SN are found: the ventral SNR, the SNCv, and the more dorsal

13. SUBSTANTIA NIGRA, VENTRAL TEGMENTAL AREA, AND RETRORUBRAL FIELDS450

III. BRAINSTEM AND CEREBELLUM

=

CONCLUSION 451

SNR GABAergic Projections

The GABAergic SNR is one of the two major outputnuclei of the basal ganglia, channeling information tothalamocortical relays (Figure 13.6D) and brainstemtargets (see also Chapters 20 and 21). In addition theSNR has two smaller projections to the colliculi(located rostrally and laterally) and the midbrainreticular formation (located caudally; Beckstead,1983; Francois et al., 1984; Percheron et al., 1994).These projections are largely non-overlapping inprimates.

Other VTA and RRF Projections

Unlike the SN which concentrates its neuronalpopulations into relatively segregated regions (SNCand SNR), the VTA and RRF contain intermixed cellpopulations, only a proportion of which are dopami-nergic. As described above, approximately 50%of VTA neurons, and a larger proportion of RRFneurons, are non-dopaminergic. The projections ofthese neurons in primates remains largelyundetermined.

The majority of the mesolimbic pathway is dopami-nergic (65–85%), the remainder being largely GABAer-gic (Figure 13.6E; Conrad and Pfaff, 1976; vanBockstaele and Pickel, 1995; Steffensen et al., 1998;Carr and Sesack, 2000; Chuhma et al., 2004; Margoliset al., 2006). The hippocampal and limbic corticalprojections from the RRF are all non-dopaminergic(Figure 13.6E; Swanson, 1982; Deutch et al., 1988;Gasbarri et al., 1996) and are thought to play a rolein modulating declarative and spatial memory.A minority of the mesocortical projection in rodentsis dopaminergic (30–40%, but see comments onprimates above, Figure 13.6F). In rodents most ofthe mesocortical projection is GABAergic (Carr andSesack, 2000; Lavin et al., 2005; Margolis et al., 2006).

continuum of the SNM, SNCd, and SNL. There are two major pigmented ceand two major pigmented cell clusters in the SNCd, the dorsomedial (dm)appear to be organized into two main tiers, a ventromedial tier (vm VTA)nucleus (PN), interfascicular nucleus (IF) and caudal linear nucleus (CLi),consisting of the parabrachial pigmented nucleus (PBP), classic ventral tegrostral linear nucleus (RLi). SNC, pars compacta; SNL, pars lateralis; SNmidbrain considered important for eye movements and internal regulatthe regulation of eye movements), and from the RRF to the SN and VTprojections from the midbrain to the striatum considered important for theSNCd) as well as from the dorsolateral tier of the VTA (dl VTA) and the RRprojections from the midbrain to the thalamus that regulate thalamocortiganglia output to thalamus, see Chapter 20) and also from dopaminergicet al., 2009) that concentrate in the SNM, the ventromedial tier of the VTAconsidered important for the regulation of limbic regions in the reward sSNM, from dopaminergic (~75%) and GABAergic (~25%) neurons of the vethe RRF. (F) The major projections from the midbrain to the cortex considerefrom both dopaminergic and GABAergic neurons located in the dorsolate

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CONCLUSION

The SN, VTA, and RRF regions of themidbrain containthemajority of the dopaminergic neurons in the brain andare expanded in their territorial extent and complexity inhumans compared to rodents, reflecting the expansionand complexity of the basal ganglia, thalamus and cortexin humans. The SN has developed an elongated laminararchitecture with each lamina concentrating relativelyuniform cell types (GABAergic neurons in the mostventral SNR tier, and dopaminergic neurons in theSNCv and SNCd tiers). Its dopaminergic neurons inhumans are strikingly uniformly heavily pigmentedand arranged in several longitudinally oriented discretecell clusters. The VTA also has two major subdivisionsventromedially and dorsolaterally, with the ventromedialcell clusters forming a continuum with the RRF. Thedorsolateral cell clusters form an additional tier ofneurons dorsal to the SNCd and surrounding the rednucleus medially. In contrast to the more distinctly sepa-rated neuronal types in the SN, the cell clusters of theVTA and RRF contain a diversity of cell types with onaverage only 50% of their neurons being dopaminergic.These dopaminergic neurons differ substantially fromtheir SN counterparts in that they are smaller and only50% contain neuromelanin pigment. Several distinctprojection pathways have been identified that are associ-ated with these different cytoarchitectural regions(Figure 13.6), including the GABAergic nigrothalamicpathway (from the SNR), the dopaminergic nigrostriatalpathway (primarily from the SNC), the dopaminergicnigrotectal pathway (from the SNL), the mixed mesolim-bic pathway (from the VTA and RRF), the dopaminergicmesothalamic pathway (from the VTA and RRF), themixed mesocortical pathway (from the VTA), and theinternal dopaminergic regulation of thesemidbrain dopa-minergic regions (from RRF). These pathways regulatea variety of motor and cognitive functions, and facilitatelearning and reward mechanisms.

ll clusters in the SNCv, the ventrointermediate (vi) and ventrolateral (vl),and dorsolateral (dl). The projections of the cell clusters of the VTA alsopositioned more caudally and medially and consisting of the paranigraland a dorsolateral tier (dl VTA) hugging the borders of the red nucleusmental area (VTA), parapeduncular nucleus (PaP not shown), and theM, pars medialis. (B) The major dopaminergic projections within theion of the dopaminergic system are from the SNL to the tectum (forA (for local innervation and regulation). (C) The major dopaminergicregulation of movement are from the two tiers of the SNC (SNCv andF. Reciprocal striatal innervation is restricted to the SNC. (D) The majorcal pathways are from the GABAergic SNR (considered a major basalneurons across the ventromedial and lateral midbrain (Garcia-Cabezas(vm VTA), and the RRF. (E) The major projections from the midbrain

ystem (mesolimbic pathway) come from dopaminergic neurons in thentromedial tier of the VTA (vm VTA), and from GABAergic neurons ind important for the regulation of movement and cognitive functions areral tier of the VTA (dl VTA).

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13. SUBSTANTIA NIGRA, VENTRAL TEGMENTAL AREA, AND RETRORUBRAL FIELDS452

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