Dopaminergic cell group A8 in the monkey: Anatomical organization and projections to the striatum

Dopaminergic Cell Group A8 in the Monkey:Anatomical Organization and Projections

to the Striatum

C. FRANCOIS,* J. YELNIK, D. TANDE, Y. AGID, AND E.C. HIRSCH

INSERM U289, Mecanismes et Consequences de la Mort Neuronale,Hopital de la Salpetriere, 75013, Paris, France

ABSTRACTThe first part of the study was a quantitative analysis of the distribution of A8 neurons

compared with that of A9 and A10 neurons by means of tyrosine hydroxylase and calbindin-D28K immunohistochemistry and image analysis in monkeys. Then the striatal projection ofA8 neurons was studied using retrograde and anterograde tracing methods. It was comparedwith that originating in cell groups A9 and A10 by performing injections of the retrogradetracer wheat germ agglutinin conjugated to horseradish peroxidase into different regions ofthe striatum. Ten percent of all mesencephalic dopaminergic neurons are located in cell groupA8. This cell group, along with A10 and the dorsal part of A9, constitutes the dorsal tier, whichaccounts for 28% of mesencephalic dopaminergic neurons. Double-staining experimentsshowed that the neurons located in the dorsal tier were calbindin positive, whereas those fromthe ventral tier were not. In terms of anatomical projection, the dorsal tier mainly projects tothe ventral part of the associative striatum, with preferential projections of A8 neurons to theventrocaudal putamen, of A10 neurons to the nucleus accumbens, and of dorsal A9 neurons toboth. Conversely, the main targets of the ventral tier of mesencephalic neurons (ventral part ofA9) are the sensorimotor putamen and the associative caudate nucleus. In conclusion, eachmesencephalic cell group projects primarily to one specific striatal region but also partici-pates, albeit to a lesser extent, in the innervation of all the remaining striatal parts. J. Comp.Neurol. 414:334–347, 1999. r 1999 Wiley-Liss, Inc.

Indexing terms: basal ganglia; substantia nigra; retrorubral cell group; primates

The three main groups of dopaminergic neurons, theperi- and retrorubral dopaminergic cell group (A8), thesubstantia nigra dopaminergic cell group (A9), and theventral tegmental area dopaminergic cell group (A10),were first described using a fluorescence histochemicalmethod in the rat (Dahlstrom and Fuxe, 1964), in monkeys(Di Carlo et al., 1973; Felten et al., 1974; Garver andSladek, 1975; Tanaka et al., 1982), and in humans (Nobinand Bjorklund, 1973; for review, see Felten and Sladek,1983). The anatomical limits of the different dopaminergiccell groups were later defined in the brain of monkey on thebasis of the distribution of Nissl-stained neurons (Francoiset al., 1985; Feigenbaum Langer et al., 1991), or theirimmunoreactivity for dopamine (Arsenault et al., 1988),tyrosine hydroxylase (TH) (German et al., 1988; Gaspar etal., 1992; Kastner et al., 1994) or calbindin-D28K (Cb)(Lavoie and Parent, 1991; Gaspar et al., 1992). However,most of these studies focused on cell groups A9 and A10,and cell group A8 was not usually analyzed. Furthermore,whereas the striatal projection of mesencephalic cell groupsA9 and A10 is well known in primates (Parent et al., 1983;

Smith and Parent, 1986; Hedreen and DeLong, 1991;Lynd-Balta and Haber, 1994a,b), there has been only oneprevious publication devoted to the striatal projection ofcell group A8 and only one striatal level was analyzed(Feigenbaum Langer and Graybiel, 1989).

The present study was therefore undertaken to analyzequantitatively the distribution of neurons in cell group A8in the monkey by means of TH and Cb immunohistochem-istry and image analysis. In a second step, the striatalprojection of cell group A8 was studied using anterogradeand retrograde tracing methods and compared with thestriatal projection of dopaminergic cell groups A9 and A10.

Grant sponsor: INSERM; Grant sponsor:AFIRST (Franco-Israelian Associa-tion for Technological and Scientific Research); Grant number: 970 MAEN09; Grant sponsor: National Parkinson’s Disease Fundation (Miami).

*Correspondence to: Dr. C. Francois, INSERM U289, Mecanismes etConsequences de la Mort Neuronale, Hopital de la Salpetriere, 47 Boule-vard de l’Hopital, 75013, Paris, France. E-mail: [email protected]

Received 18 August 1998; Revised 6 July 1999; Accepted 5 August 1999

THE JOURNAL OF COMPARATIVE NEUROLOGY 414:334–347 (1999)

r 1999 WILEY-LISS, INC.

MATERIALS AND METHODS

This study is based on data collected from two genera ofAfrican cercopithecine monkeys, the Cercopithecus andthe Macaca. Anatomical topography of the different mesen-cephalic areas was studied in one Macaca mulatta (MM16).The anatomical distribution of dopaminergic neurons inmesencephalic cell groups was investigated in three Afri-can green monkeys (Cercopithecus aethiops; CA1, CA4,and CA8), and the striatal projection of dopaminergicneurons was studied in one African green monkey (CA8)and in five macaques: four Macaca fascicularis (MI34,MI38, MI42, and MI49) and one Macaca mulatta (MM27).In total, three African green monkeys and six macaqueswere used. All studies were carried out in accordance withthe Declaration of Helsinki and with the Guide for theCare and Use of Laboratory Animals as adopted andpromulgated by the National Institutes of Health, USA.

Surgery

The stereotaxic procedure was based on the visualiza-tion of ventricular landmarks, the anterior and posteriorcommissures (CA and CP, respectively; Percheron et al.,1986). Monkeys were anesthetized through intratrachealintubation (fluothane 1%, nitrogen protoxyde 50%, andoxygen 50%) and placed in a stereotaxic apparatus withwhich ventriculography could be performed using orthogo-nal teleradiography (Percheron et al., 1986). Injections ofwheat germ agglutinin conjugated to horseradish peroxi-dase (WGA-HRP, Sigma, St. Louis, MO) diluted (5%) inphosphate-buffered saline (PBS) (0.01 M, pH 7.4) weremade by pressure (0.32–0.5 µl) in different sites of thestriatum in relation to the CA-CP system of coordinates.The survival period of the monkeys was 3 days. Biotinedextran amine (BDA) diluted (10%) in PBS (0.01 M, pH7.4) was injected iontophoretically (6.8 µA current deliv-ered in 7-second pulses every 7 seconds over a 10-minuteperiod) in area A8 of experimental case CA8.

Before sacrifice, the animals were anesthetized as de-scribed above, and two vertical and two horizontal cannu-lae (one in each hemisphere) were introduced into thebrain, perpendicular and parallel to the ventricular CA-CPplane, respectively. This allowed these two planes to beidentified in order to analyze the brains post mortemaccording to the stereotaxic landmarks. The monkeys werethen perfused transcardially with 400 ml of saline (0.9% at37°C) followed by 5 liters of 4% paraformaldehyde (in0.1 M PBS, pH 7.4 at 4°C) and by 1 liter of PBS with 5%sucrose. The brains were removed from the skull, rinsed inPBS complemented with 10% sucrose during 1 day and20% sucrose during 1 day, and then frozen and cut into50-µm-thick sections on a freezing microtome. In order tocut the sections transverse to the CA-CP plane, the brainswere placed on the freezing microtome and oriented so thatthe marks of the two vertical cannulae were complete onthe first sections. On each transverse section, the holescorresponding to the horizontal cannulae, which wereplaced in the horizontal CA-CP plane, were used asreference for the dorsoventral position of the CA-CP plane.

Histological processing

Transverse sections of the brain of Macaca mulattaMM16, used as a reference for the cytoarchitectonic studyof the mesencephalon, were stained using cresyl violet.

TH immunohistochemistry was performed on free-floating sections taken 1 mm apart over the whole extent ofthe mesencephalon from the rostral substantia nigra tothe caudal part of A8. Sections were incubated with amouse monoclonal antibody raised against TH diluted to1:500 (INCstar, Stillwater, MN) for 48 hours at 4°C undergentle agitation. Adjacent sections were stained for Cbimmunoreactivity using a monoclonal antiserum raisedagainst Cb diluted to 1:1,000 (Sigma) for 48 hours at 4°Cunder gentle agitation. The primary antibodies were re-vealed using the ABC method (diluted 1:100; Vector,Burlingame, CA) using diaminobenzidine tetrahydrochlo-ride (DAB 0.05%) as peroxidase chromogen. A sequentialdouble-labeling procedure was applied on three sections atthe rostral, middle, and caudal levels of the mesencepha-lon. In brief, we first visualized TH, using the above-mentioned procedure but with DAB (0.05%)-nickel (0.2%)as chromogen, and then Cb as described above by usingDAB alone as chromogen. Control experiments in whichthe second primary antibody was omitted showed thatDAB alone did not result in staining associated with thefirst step of the immunohistochemical reaction.

For the WGA-HRP experimental cases, brains were cutinto 50-µm-thick transverse sections, and every tenthsection was processed using the tetramethylbenzidineprocedure to reveal WGA-HRP, as previously described(Mesulam, 1978). The reaction was stabilized (Rye et al.,1984), and the sections were counterstained with methylgreen or neutral red.

For revelation of BDA, all sections were pretreated with1% Triton (X-100) in PBS and then incubated using avidinbiotin complex staining (ABC, Elite, Vector) in PBS with1% Triton for 48 hours at 4°C. Sections were treated withnickel (0.2%)-DAB (0.05%) as peroxidase chromogen.

Mapping and counting of neurons

Computer-assisted microscope system. Tracing ofcontours of the anatomical regions and mapping of TH-positive (TH1), WGA-HRP-labeled and Nissl-stained neu-rons were performed on a computer-assisted microscopesystem (HistoRag, Biocom, France). This system com-prises a high-resolution camera that transfers the image ofthe section onto a video monitor. The different magnifica-tions provided by the objectives of the microscope or a lighttable were used as appropriate to visualize the contours ofthe entire section, the contours of a given anatomicalstructure, or the contours of individual cell bodies. What-ever the objective used, X and Y coordinates were perma-nently provided by two sensors attached to the stage of themicroscope. Contours, lines, or points were traced manu-ally with the aid of a computer pointing device and weredisplayed automatically on the image of the section at thesame magnification. We were thus able to draw theoutlines of the different catecholaminergic cell groups atlow magnification with the help of adjacent sections stainedfor Nissl stain and plot each positive neuron manually.This procedure was performed on adjacent fields of viewcovering the entire anatomical region analyzed. Since theimage analysis system allowed a mark to be placed on eachcounted cell, and since this mark moved with the micro-scope stage deplacement, any unwanted double countingwas avoided.

As soon as cell bodies were plotted and contours ofcerebral regions traced, counting of neurons was per-

CELL GROUP A8 AND ITS STRIATAL PROJECTIONS 335

formed automatically by the computer-assisted microscopesystem. The system compared the X and Y coordinates ofeach plotted cell body with the outlines of each contour anddetermined the number of cell bodies contained in eachanatomical region. The numbers of these neuronal profilesgiven by the computer system were corrected using Aber-crombie’s (1946) correction factor to estimate the numberof neurons. As section thickness was 50 µm and the meancell body size was 45 µm, the risk of superposition of twocell bodies was negligeable and could be avoided by ananalysis of the different focusing planes during the neuroncounting procedure.

Mapping of TH1 neurons and delimitation of dopa-

minergic areas. TH1 neurons were plotted in nineregularly spaced (1 mm apart) TH1 transverse sections ofthree Cercopithecus brains. These sections were matchedas closely as possible in the three brains so as to havesimilar mesencephalic regions. TH1 neurons were identi-fied by using alternately the 310 and the 340 objectives,the former to verify that all cell bodies has been plottedand the latter to verify that TH1 structures were actuallycell bodies and not thick dendrites. As the computer-assistant microscope allowed the plotted neurons and theactual section to be visualized simultaneously, each stainedneuron was plotted only once. The overall contour of thesection was traced as well as the hole produced by thehorizontal cannulae.

As TH1 neurons constitute a continuous band from therostral to the caudal part of the mesencephalon, the A8,A9, and A10 areas were delineated according to arbitraryoutlines defined with reference to the contours of neighbor-ing anatomical structures: the third cranial nerve, the rednucleus, the medial lemniscus, and the substantia nigrapars reticulata. The same procedure has already been usedin humans (Hirsch et al., 1988). The contours of neighbor-ing anatomical structures and of dopaminergic areas weretraced in the Cb-stained (Cb1) sections adjacent to thesections in which mapping of neurons was done. Cb1sections were precisely aligned with TH1 sections bysuperimposing the contour of the section and the holesproduced in each section by the horizontal cannulae.

Numbers of TH1 neurons were estimated by multiply-ing the mean of the neurons counted in two examinedsections by the number of sections separating these twosections. The total number of TH1 neurons present ineach mesencephalic area was obtained by summing theresults for the nine sections examined.

Mapping of retrogradely labeled neurons. Retro-gradely WGA-HRP-labeled neurons present in each mesen-cephalic area were plotted with the same computer-assisted microscope system in three transverse sections ofeach experimental case. The rostrocaudal levels selectedwere defined with reference to the posterior commissure(CP13, CP, and CP-1). As it was not possible to comparethe absolute number of labeled neurons between animalssince injection sites varied from one experimental case toanother, we expressed the number of labeled neurons as apercentage of WGA-HRP-stained cells with reference tothe total number of neurons present in each area. Thistotal number was determined in Nissl-stained sections ofthe monkey MM16 using the same computer-assistedmicroscope system and the same transverse levels as forWGA-HRP experiments (CP13, CP, and CP-1).

RESULTS

Topographical distribution of dopaminergicneurons in cell groups A8, A9, and A10

Since catecholaminergic neurons constitute a continu-ous band from the rostral to the caudal part of themesencephalon without any clear subdivisions, the fourcatecholamine-containing cell groups analyzed in the pres-ent study were delineated according to arbitrary outlines(Fig. 1). The outlines chosen had the advantage of beingreproducible from one brain to another. The lateral limit ofA10 was a line parallel to the midline of the brain andseparating the red nucleus into two equal parts. This linecorresponded to the lateral border of the bundle of thethird cranial nerve. The dorsal limit of A10 correspondedto the inferior border of the nucleus of the third cranialnerve. Cell group A10 included neurons of the nucleusparanigralis, as well as neurons of the medial part of theretrorubral field and of their medial prolongation, thenucleus interfascicularis and the nucleus linearis (rostra-lis and centralis) according to the nomenclature of Halli-day and Tork (1986). The substantia nigra pars compacta(area A9) was delineated medially by the ventral tegmen-tal area, as previously described, dorsally by the mediallemniscus, and ventrolaterally by the pars reticulata. Thepars compacta was divided into a dorsal part (A9D or parsmixta [Francois et al., 1985]) characterized by scatteredcell bodies and a ventral densocellular part (A9V) made upof a horizontal zone rostrally and of ventral fringes descend-ing into the pars reticulata more caudally.All catecholamin-ergic neurons located inside or dorsomedial to the mediallemniscus were considered to correspond to cell group A8.The medial limit of the catecholaminergic cell group A8corresponded to the lateral limit of the third cranial nerverostrally and of the periaqueductal gray substance cau-dally. The caudal limit of A8 corresponded to the rostrallimit of the pedunculopontine nucleus, with some catechol-aminergic neurons being scattered among this latternucleus.

A rich Cb1 neuropil was observed in the substantianigra pars reticulata but not in the substantia nigra parscompacta. TH1 and Cb1 neurons of the mesencephalonwere plotted on a single series of regularly spaced sectionsalong the rostrocaudal axis of the mesencephalon (Fig. 2).The dopaminergic cell groups that extended from therostral periventricular gray substance to the caudal pon-tine central gray substance were not analyzed in thepresent study. Rostrally, and at mid-levels of the mesen-cephalon, TH1 neurons occupied the pars compacta (A9Vand A9D), the ventral tegmental area (A10), and the peri-and retrorubral area (A8), whereas Cb1 neurons wererestricted to A9D and to the whole extent of cell groups A10and A8. In the latter structures, Cb1 neurons were morenumerous dorsally than ventrally. More caudally, Cb1cells were observed over the entire dorsoventral extent ofarea A8. Nevertheless, on double-stained TH-Cb sections,Cb1 neurons that were not TH1 were present not onlydorsally but also ventrally to the brachium conjunctivum(Fig. 2, lower part).

Finally, mesencephalic TH1 neurons could be dividedinto two tiers, one located dorsally comprising cell groupsA10, A8, and A9D and containing Cb1 neurons, and theother located ventrally corresponding to cell group A9Vand containing Cb– neurons.

336 C. FRANCOIS ET AL.

Fig. 1. Cartography of area A8 in monkey MM16 based on Nisslmaterial. A: Photomicrograph showing the location of A8 in themesencephalon. B: Schematic drawings depicting the area on eightregularly interspaced transverse sections. The anteroposterior loca-tion of each section is indicated in reference to CP. BC, brachiumconjunctivum; CP, posterior commissure; DBC, decussation of the

brachium conjunctivum; DR, dorsal raphe; III, third cranial nerve;LM, medial lemniscus; MLF, medial longitudinal fasciculus; NCS,nucleus centralis superior; n III, third cranial nucleus; n IV, fourthcranial nucleus; Pn, nucleus paranigralis; PPN, pedunculopontinenucleus; Ru, red nucleus; SN, substantia nigra; STN, subthalamicnucleus; ZI, zona incerta. Scale bars 5 2 mm.


Fig. 2. A: Topographic distribution of tyrosine hydroxylase (TH)-positive neurons (stars) and calbindin (Cb)-positive neurons (dots)represented on eight transverse levels from the anterior (ant) toposterior (post) mesencephalon. B and C: Photomicrographs showing

two adjacent sections stained for Cb and TH. D: Cell bodies immuno-stained for TH are indicated by the black (DAB-nickel) color and thoseimmunostained by calbindin (Cb) are indicated by the brown (DAB)color. Scale bars 5 2 mm in A, B and C; 50 µm in D.

Number of TH1 neurons in A8 comparedwith the other mesencephalic regions

The total number of TH1 neurons was determined inthe different mesencephalic regions of three African greenmonkeys (CA1, CA4, and CA8) and then corrected by usingAbercrombie’s correction factor (see Materials and Meth-ods) with a section thickness of 50 µm and a maximumdiameter of TH1 cell bodies of 45 µm (mean 6 SD 5 45.2 65.2 µm).

The results were very similar in the three brains studied(Table 1). The mean number of TH1 neurons in the fourmesencephalic regions considered was 92,380 6 4,820(mean 6 SD). More than two-thirds of the TH1 neurons(72%) were located in the ventral tier represented by theA9V cell group, whereas only 10% of TH1 mesencephalicneurons were located in A8. The dorsal tier of the mesen-cephalon was thus constituted of A10 (14%), A9D (4%), andA8 (10%), which represented about one-third (28%) of theentire population of mesencephalic TH1 neurons.

Topography of the striatal projectionof A8 neurons

The main projection of dopaminergic cell group A8 wasrevealed in experimental case MI49, in which the WGA-HRP injection site was centered in the ventrocaudal part ofthe putamen (Fig. 3A). Numerous retrogradely labeledneurons were found in cell group A8 (Fig. 3B,C). However,other mesencephalic neurons, located in A10, A9D andA9V and also in the raphe nuclei, were also retrogradelylabeled. To determine whether A8 neurons project primar-ily to the ventrocaudal part of the striatum, an injection ofthe anterograde tracer BDA was centered in A8 in experi-mental case CA8 (Fig. 4). The injection site was very smalland did not involve adjacent dopaminergic areas (Fig.4A,B). Numerous anterogradely labeled axons were foundin the ipsilateral striatum, mainly in the ventral andcaudal parts of the striatum but also in all the other parts,namely, in the caudate nucleus, the nucleus accumbens,and the sensorimotor putamen (Fig. 4C).

Striatal projections of dopaminergicmesencephalic neurons: Quantitative data

The striatal projection from area A8 was compared withthat originating from A9V, A9D, and A10. For this purpose,WGA-HRP was injected into various parts of the striatumof five experimental cases, either in the associative or inthe sensorimotor striatal part, as previously determined inour laboratory (Francois et al., 1994). The topography ofthese territories is depicted in Figure 5A. The associativestriatum comprises the main part of the caudate nucleus(head and tail), the fundus striati or nucleus accumbens,and also the part of the putamen that is medially located atrostral levels and medioventrally located at more caudallevels. The sensorimotor striatum occupies the remainingdorsolateral part of the putamen, and a more restrictedlateral part of the caudate nucleus. Examples of injectionsin the associative caudate nucleus (MI38) and sensorimo-tor putamen (MI42) are illustrated in Figure 5B.

Retrogradely labeled cell bodies are shown in threerostrocaudal levels of the mesencephalon of five differentexperimental cases (Fig. 6). Results of the quantitativeanalysis (Table 2) show the number and percentage ofretrogradely labeled neurons. These percentages werecalculated with reference to the number of Nissl-stained

cell bodies counted in the same three rostrocaudal levels ofthe mesencephalon. These numbers were found to be 800in A8, 850 in A10, 400 in A9D, and 2,500 in A9V.

In experimental case MI49 (injection into the ventraland posterior part of the putamen) most the retrogradelylabeled neurons were located in A8. Besides this mainprojection to an associative part of the striatum, therewere also more restricted projections of cell group A8 to thenucleus accumbens (MM27), the caudate nucleus (MI38),and the sensorimotor putamen (MI42). In comparison,while A10 neurons projected mainly to the nucleus accum-bens (MM27), they also projected, albeit to a lesser degree,to the ventrocaudal part of the putamen (MI49), althoughthis projection was less important. Only a few neurons incell group A10 were retrogradely labeled after injectionsinto the caudate nucleus (MI38) or the sensorimotorputamen (MI42). A similar organization was observed forA9D, which projected to both the nucleus accumbens(MM27) and the ventrocaudal part of the putamen (MI49),and only weakly to the caudate nucleus (MI38) and thesensorimotor putamen (MI42). In summary, the dorsal tierof mesencephalic neurons (A8, A9D, and A10) mainlyprojected to the ventral part of the associative striatum(nucleus accumbens and its caudal extension in the ventro-caudal part of the putamen), with preferential projectionsof A8 to the ventrocaudal putamen, of A10 to the nucleusaccumbens, and of A9D to both. Besides these mainprojections, each mesencephalic region also participated inthe innervation of the remaining parts of the striatum, thecaudate nucleus and the sensorimotor putamen.

Cell group A9V provided a complementary projection toboth the sensorimotor putamen (MI42, MI34) and thecaudate nucleus (MI38). More precisely, the main target ofthe ventral fringes of A9V was the sensorimotor putamenwhereas the dorsal tier of A9V innervated essentially thecaudate nucleus. Scattered retrogradely labeled neuronswere also found throughout A9V after injection of a tracerinto the ventrocaudal putamen (MI49) and the nucleusaccumbens (MM27).

DISCUSSION

Quantification of cell numbers

Tyrosine hydroxylase-positive neurons as well as WGA-HRP-labeled neurons were counted with the aid of acomputer-assisted microscope system. The results of count-ing were considered to be reliable, since labeled neuronswere identified through the high-resolution objectives ofthe microscope, neurons were counted once and once only,and superimposition of cell bodies in the thickness of thesection was detected.

In the second part of this study, we determined therelative participation of each mesencephalic area to the

TABLE 1. Number of TH-Positive Neurons in the Four Different Regionsof the Mesencephalon (A8, A9V, A9D, and A10) in Three Monkeys

(CA1, CA4, and CA8)

Mesencephalicregion

Monkey TH1 neurons

CA1 CA4 CA8 Mean 6 SD %

A8 7,880 9,420 9,940 9,080 6 1,070 10A9V 65,200 72,140 63,400 66,920 6 4,620 72A9D 6,090 2,460 2,180 3,580 6 2,180 4A9 71,290 74,600 65,590 70,490 6 4,560 76A10 10,880 13,900 13,620 12,800 6 1,670 14Total 90,050 97,920 89,160 92,380 6 4,820 100


projection to different parts of the striatum. To this end,WGA-HRP injections were made in different parts of thestriatum in different experimental cases. As the size of WGA-HRP injection sites differed from one case to another, it wasnecessary to express the numbers of labeled neurons aspercentages. We therefore divided the number of neuronslabeled in each mesencephalic area by the total number ofneurons labeled in each experimental case and assumed

that the total number of labeled neurons was proportionalto the size of the injection. The main projection of eachmesencephalic area was simply defined as the one corre-sponding to the highest percentage given in Table 2.

Cartographic definition of area A8

The precise borders of A8, anteriorly with A9, mediallywith A10, and posteriorly with A6 noradrenergic neurons

Fig. 3. A: Photomicrograph of the WGA-HRP injection site in theventrocaudal part of the putamen (Pu) of experimental case MI49.GPe and GPi indicate the external and internal segments of the globuspallidus. B: Examples of retrogradely labeled neurons in A8. C: Distribu-tion of retrogradely labeled neurons shown on regularly interspaced

transverse sections from the anterior (CP14.3) to posterior (CP-2.7)mesencephalon. Numerous retrogradely labeled neurons were foundin A8 but also in other mesencephalic regions (A10, A9D, A9V, and theraphe nucleus). Scale bars 5 1 mm in A and C; 100 µm in B.


Fig. 4. A: Photomicrograph of the biotine dextran amine injectionsite in A8 in experimental case CA8. B: Drawing of the injection site.C: Distribution of anterogradely labeled axonal endings shown on

regularly interspaced transverse sections from the anterior (ant) toposterior (post) striatum. DBC, decussation of the brachium conjonc-tivum; LM, medial lemniscus; Ru, red nucleus. Scale bars 5 2 mm.


Fig. 5. A: Drawings of transverse sections mapped in relation tothe ventricular system of coordinates (CA-CP plane) showing thedelineation of the associative (stippled area) and of the sensorimotorterritories of the striatum. The sensorimotor territory occupies thedorsolateral part of the putamen (Pu) and of the head of the caudatenucleus (Cd), and the associative territory occupies the remaining

striatal parts. The ventral striatum is represented by the nucleusaccumbens (acc). B: Photomicrographs of injection site in the associa-tive caudate nucleus (MI38) and in the sensorimotor putamen (MI34).The caudate nucleus and the putamen are demarcated by dashedlines. Scale bar 5 5 mm.


Fig. 6. A–E: WGA-HRP injections (hatched area) in different partsof the striatum in five experimental cases. For each experimental case,three rostrocaudal levels of transverse sections, in relation to the

posterior commissure (CP13, CP, and CP-1) were considered and werematched as closely as possible across brains. Retrogradely labeled cellbodies are shown as dots. Scale bar 5 2 mm.


(locus cœruleus), are difficult to draw, even though A8neurons display more intense TH immunostaining (Pear-son et al., 1983; Kastner et al., 1993) and may have smallersomata and more branched dendrites than nigral A9neurons (Arsenault et al., 1988). Cell group A8 corre-sponds to the peri- and retrorubral area, whose main partis located at the level of the decussation of the brachiumconjunctivum. This location corresponds to that alreadydescribed in macaques (Herrero et al., 1993a) and owlmonkeys (Gaspar et al., 1992) using different histochemi-cal techniques. In humans, MacRitchie et al. (1996) de-scribed A8 not only in the retrorubral area but also moreanteriorly in the «midbrain reticular field» which is locatedlaterally to the parabrachial pigmented nucleus and corre-sponds to the nucleus peripeduncularis of Olszewski andBaxter (1954). According to our findings in the monkey thisregion is located laterally to the medial lemniscus, and wehave therefore considered that it belongs to A9D. The totalnumber of TH-positive neurons that we counted in themesencephalon of African green monkey (92,380 neurons)is somewhat higher than that reported in Macaca fascicu-laris (81,680 neurons [German et al., 1988] and 80,000[Herrero et al., 1993b]). This may be due to a difference inmonkey species. Our laboratory records show that theCA-CP length in 6 Cercopithecus aethiops was 10.5 6 0.4mm and in 43 Macaca fascicularis it was 10.5 6 0.6 mm.The brain dimensions of African green monkeys andmacaques are thus relatively similar in the anteroposte-rior dimension but are larger in the mediolateral dimen-sion. The difference in number of TH1 neurons may alsobe due to differences in estimating the total number ofneurons, and more especially to differences in determiningthe limits of A8 as we counted all TH1 neurons in this areaup to its caudal end in the pedunculopontine nucleus.

In another study, made in Nissl-stained material inmacaques (Poirier et al., 1983), the number of pars com-pacta-type neurons in the whole substantia nigra andassociated structures was estimated to be 62,624. This

figure, obtained from material in which only cell bodieswith a distinct nucleolus were counted, may hardly becompared with TH-stained material in which all TH1 cellbodies were counted. Indeed, neurons with a morphologydifferent from that of pars compacta neurons, such asintermediary-type or globular-type neurons observed inNissl-stained material may be TH1 neurons.

It is interesting to note that, in a study made in humansin which the delineation of the three mesencephalic re-gions was similar to that of the present study in themonkey, 75% of TH1 neurons were counted in A9, 18% inA10, and 11% in A8 (Hirsch et al., 1992), which is verysimilar to the present data.

Numerous Cb1 and TH1, which are less vulnerablethan other TH1 neurons in Parkinson’s disease (Yamadaet al., 1990; Hirsch et al., 1992) and in MPTP-treatedmonkeys (Lavoie and Parent, 1991; Iacopino et al., 1992),were observed in A8 as well as in the other mesencephalicareas studied. These Cb1 catecholaminergic neurons havebeen described as more abundant dorsally than ventrallyin the mesencephalon taken as a whole (Gaspar et al.,1993), which is confirmed in our material. We also notedthat caudally in A8, Cb1 and TH– neurons are especiallyabundant over the whole dorsoventral part of A8, anarrangement that corresponds to that reported in humans(MacRitchie et al., 1996).

In summary, mesencephalic dopaminergic neurons havebeen subdivided into two tiers, a ventral tier formed byA9V neurons (the densocellular nigral part) and a dorsaltier including A10 and A9D neurons (Lynd-Balta andHaber, 1994b). As already suggested (Feigenbaum Langeret al., 1991), cell group A8 should also be included in thisdorsal tier, which represented about one-third (28%) of themesencephalic TH1 neurons as observed in the presentstudy and thus constitutes a continuous rostrocaudal bandof TH1 and Cb1 neurons.

Striatal projections of the dorsal tier of themesencephalon

The present study demonstrates that A8 neurons projectprimarily to the ventrocaudal part of the putamen, whichis also laterally located. As A8 represents the caudolateralgroup of mesencephalic dopaminergic neurons, the mesen-cephalostriatal projection seems to be topographicallyorganized, confirming previous data obtained in monkeys(Szabo, 1980; Hedreen and Delong, 1991). The ventrocau-dal part of the putamen is considered, with the tail of thecaudate nucleus, as a «visuomotor» striatum receivingcortical inputs from the «visual» inferior temporal andposterior parietal cortex (Saint-Cyr et al., 1990). However,A8 neurons also participate, albeit to a minor extent, in theinnervation of all other parts of the striatum, whetherassociative (caudate nucleus and accumbens) or sensorimo-tor. This is clearly demonstrated by our anterograde tracerinjection of cell group A8, which did not extend into theother mesencephalic regions. Thus, in primates, the A8-striatal projection is both specific to the ventrocaudalputamen and widespread throughout the entire striatum.This innervation of the whole extent of the striatum fromA8 neurons has already been reported in rats (Fallon andMoore, 1978; Gerfen et al., 1987; Brog et al., 1993) and cats(Vandermaelen et al., 1978; Jimenez-Castellanos and Gray-biel, 1987). Furthermore, this striatal innervation hasmainly been observed in the matrix of the striatum

TABLE 2. Number of Labeled Neurons Counted in Areas A8, A9V, A9D,and A10 After WGA-HRP Injection Into the Striatum (Striatal Injections)

in Five Experimental Cases

Experimentalcases

Striatalinjections

Mesencephalicregions

Labeledneurons

No. %

MI49 Pu V A8 198 24.7A9V 70 2.8A9D 33 8.3A10 138 16.2Total 439 52

MM27 Ny acc A8 54 6.7A9V 76 3A9D 16 4A10 211 24.8Total 357 38.5

MI38 Ny Cd A8 10 1.2A9V 83 3.4A9D 1 0.2A10 5 0.5Total 99 5.3

MI42 Pu A8 20 2.5A9V 149 6A9D 3 0.7A10 15 1.7Total 187 10.9

MI34 Pu A8 0 0A9V 4 0.2A9D 0 0A10 0 0Total 4 0.2


(Jimenez-Castellanos and Graybiel, 1987; FeigenbaumLanger and Graybiel, 1989; Feigenbaum Langer et al.,1991; Brog et al., 1993).

In contrast to A8 neurons, A10 neurons (the rostrome-dial group of mesencephalic catecholaminergic neurons)mainly innervates the rostromedially located ventral stria-tum. Interestingly, neurons ofA10 have a reciprocal connec-tion with the ventral striatum (Haber et al., 1990), whichis known to receive cortical information from limbic andparalimbic cortical areas (Kunishio and Haber, 1994;Haber et al., 1995). However, the striatonigral projectiondoes not support a precise point-to-point topography butrather a widespread projection to the whole extent of thedorsal tier neurons. The ventral part of the striatal fibresthus terminates on dopaminergic neurons that projectback to the same striatal region, but it can also beconnected with other dopaminergic neurons innervatingother striatal regions, such as the putamen or the caudatenucleus. It is likely that a similar pattern holds for A8 andthe ventrocaudal, «visuomotor», part of the putamen.

Other projections of the dorsal tier

The fact that in our study several injection sites cen-tered in the striatum included the internal capsule mayaccount for the labeling of mesencephalocortical neurons.It has been reported in monkeys that the dopaminergicinnervation of the motor and premotor cortex, supplemen-tary motor area, and prefrontal cortex (Lewis et al., 1987;Maeda et al., 1995) takes its origin in the dorsal part ofareas A8, A9D, and A10 (Porrino and Goldman-Rakic,1982; Gaspar et al., 1992; 1993), i.e., in the dorsal tier ofthe mesencephalic areas as defined in the present study. Intwo experimental cases in our study, the injection sitecentered in the striatum included a small part of theadjacent internal capsule. Some retrogradely labeled neu-rons might thus be mesencephalocortical neurons. How-ever, such neurons would be very few in number incomparison with mesencephalostriatal neurons. Moreover,the possibility that individual dopaminergic axons collater-alize into both striatal and cortical structures cannot beruled out. Should that be the case, all labeled cell bodieswould then represent mecencephalostriatal and mecen-cephalocortical neurons. Since dopaminergic degenerationin Parkinson’s disease or MPTP intoxication is less markedin the cortex than in the striatum (Di Paolo et al., 1986;Schultz et al., 1989), the cortical target of dopaminergicneurons dorsally located in the mesencephalon could ex-plain their resistance to degeneration.

The mesencephalopallidal dopaminergic projection,known to innervate the pallidum profusely, mainly itsmedial segment (Lavoie et al., 1989), has been demon-strated to arise mostly from neurons that are dorsallylocated to the substantia nigra pars compacta and that aredistinct from those projecting to the striatum (Smith et al.,1989; Charara and Parent, 1994). The possibility that inour experimental case MI49, in which the injection siteinvolved a part of the external pallidum, some retro-gradely labeled cell bodies could be interpreted as mesen-cephalopallidal neurons should also be taken into account.However, the number of such neurons would be very smalldue to the very restricted pallidal region involved in theinjection site.

Striatal projections of the ventral tier of themesencephalon

The ventral tier of mesencephalic neurons is made up oftwo parts, the ventral fringes, also known as cell columns(Lynd-Balta and Haber, 1994b), or ventrally extendingfingers (Feigenbaum Langer and Graybiel, 1989), and thehorizontal zone, both made up of TH1 Cb– neurons. Nocortical projection of these neurons has been described,suggesting that the ventral tier of the substantia nigraexclusively innervates the striatum. In the present studythe ventral fringes were shown to constitute one-third(36%) of the mesencephalic dopaminergic neurons, project-ing mainly to the sensorimotor putamen (Lynd-Balta andHaber, 1994b), and to a lesser extent to the caudatenucleus (Smith and Parent, 1986; Jimenez Castellanosand Graybiel, 1989). The few neurons observed in theventral fringes in cases with ventrocaudal putaminal andnucleus accumbens injections (MI49 and MM27) may beexplained by the extension of the injection site into theadjacent sensorimotor putamen and caudate nucleus, re-spectively. However, a projection of A9V to the nucleusaccumbens and the ventrocaudal striatum cannot be ruledout and would confirm data recently obtained in monkeys(Haber and Fudge, 1997). The horizontal zone also consti-tutes one-third (36%) of the mesencephalic dopaminergicneurons; it projects mainly to the caudate nucleus but also,as with the other subdivisions, to the other striatal re-gions, namely, either the associative (nucleus accumbensand ventrocaudal putamen) or sensorimotor putamen.

As a whole, the ventral tier thus chiefly innervates thesensorimotor putamen and the associative caudate nucleus.These ventral tier neurons are in a position to receive backinputs from the same parts of the striatum as they havelong dendrites extending ventrally into the pars reticulata(Yelnik et al., 1987). There is thus a clear nigro-striato-nigral loop. However, as dopaminergic neurons located inthe ventral tier can also project to the ventral and ventro-caudal parts of the striatum, the ventral tier of themesencephalon can modulate the whole extent of thestriatum.

Functional implications

In the brains of monkeys rendered parkinsonian byMPTP administration, the most prominent cell loss isobserved in the ventral tier. The most ventrally locatedneurons (i.e., in the ventral fringes) project mainly to thesensorimotor putamen, which receives inputs from thesensorimotor cortex, whereas the dorsally located neurons(i.e., in the horizontal band) project primarily to theassociative caudate nucleus, which receives inputs fromthe associative cortex. These two striatal regions are alsodepleted of dopamine in Parkinson’s disease, a factor thatmay be related to the motor symptoms as well as to thecognitive dysfunction often seen in Parkinsonian patients.In contrast, the surviving dopaminergic neurons are mainlyfound in the dorsal tier. These neurons project primarily tothe ventral parts of the striatum, represented by thenucleus accumbens and the ventrocaudal part of theputamen, striatal regions that are relatively spared fromdopaminergic degeneration. However, a more restrictedprojection to the putamen and caudate nucleus also exists.These surviving neurons might play a role in the func-tional recovery often seen in MPTP-treated monkeys.


LITERATURE CITED

Abercrombie M. 1946. Estimation of nuclear population from microtomesections. Anat Rec 94:239–247.

Arsenault MY, Parent A, Seguela P, Descarries L. 1988. Distribution andmorphological characteristics of dopamine-immunoreactive neurons inthe midbrain of the squirrel monkey (Saimiri sciureus). J Comp Neurol267:489–506.

Brog JS, Salyapongse A, Deutch AY, Zham DS. 1993. The patterns ofafferent innervation of the core and shell in the ‘‘accumbens’’ part of therat ventral striatum: immunohistochemical detection of retrogradelytransported FluoroGold. J Comp Neurol 338:255–278.

Charara A, Parent A. 1994. Brainstem dopaminergic, cholinergic andserotoninergic afferents to the pallidum in the squirrel monkey. BrainRes 640:55–170.

Dahlstrom A, Fuxe K. 1964. Evidence for the existence of monoamine-containing neurons in the central nervous system. Acta Physiol Scand232:5–55.

Di Carlo V, Hubbard JE, Pate P. 1973. Fluorescence histochemistry ofmonoamine-containing cell bodies in the brain stem of the squirrelmonkey (Saimiri sciureus). IV. An atlas. J Comp Neurol 152:347–372.

Di Paolo T, Bedard P, Dajgle M, Boucher R. 1986. Long-term effects ofMPTP on central and peripheral catecholamine and indolamine concen-trations in monkeys. Brain Res 379:286–295.

Fallon JH, Moore RY. 1978. Catecholamine innervation of the basalforebrain. IV. Topography of the dopamine projection to the basalforebrain and neostriatum. J Comp Neurol 180:545–580.

Feigenbaum Langer L, Graybiel AM. 1989. Distinct nigrostriatal projectionsystems innervate striosomes and matrix in the primate striatum.Brain Res 498:344–350.

Feigenbaum Langer L, Jimenez-Castellanos J, Graybiel AM. 1991. Thesubstantia nigra and its relations with the striatum in the monkey.Prog Brain Res 87:81–99.

Felten DL, Sladek JR. 1983. Monoamine distribution in primate brain. V.Monoaminergic nuclei: anatomy, pathways and local organization.Brain Res Bull 10:171–284.

Felten DL, Laties AM, Carpenter MB. 1974. Monoamine-containing cellbodies in the squirrel monkey brain. Am J Anat 139:153–166.

Francois C, Percheron G, Yelnik J, Heyner S. 1985. A histological atlas ofthe macaque (Macaca mulatta) substantia nigra in ventricular coordi-nates. Brain Res Bull 14:349–367.

Francois C, Yelnik J, Percheron G, Fenelon G. 1994. Topographic distribu-tion of the axonal endings from the sensorimotor and associativestriatum in the macaque pallidum and substantia nigra. Exp Brain Res102:305–318.

Garver DL, Sladek JR. 1975. Monoamine distribution in primate brain. I.Catecholamine-containing perikarya in the brain stem of Macacaspeciosa. J Comp Neurol 159:289–304.

Gaspar P, Stepniewska I, Kaas JH. 1992. Topography and collateralizationof the dopamine projection to motor and lateral prefrontal cortex in owlmonkey. J Comp Neurol 325:1–25.

Gaspar P, Heizmann CW, Kass JH. 1993. Calbindin-D28K in the dopaminer-gic mesocortical projection of a monkey (Aotus trivirgatus). Brain Res603:166–172.

Gerfen CR, Herkenham M, Thibault J. 1987. The neostriatal mosaic: II.Patch- and matrix-directed mesostriatal dopaminergic and non-dopaminergic systems. J Neurosci 7:3915–3934.

German DC, Dubach M, Askari S, Speciale SG, Bowden DM. 1988.1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced parkinsoniansyndrome in Macaca fascicularis: which midbrain dopaminergic neu-rons are lost? Neuroscience 24:161–174.

Haber SN, Fudge JL. 1997. The primate substantia nigra and VTA:integrative circuitry and function. Crit Rev Neurobiol 11:323–342.

Haber SN, Lynd E, Klein C, Groenewegen HJ. 1990. Topographic organiza-tion of the ventral striatal efferent projections in the rhesus monkey: ananterograde tracing study. J Comp Neurol 293:282–298.

Haber SN, Kunishio K, Mizobuchi M, Lynd-Balta E. 1995. The orbital andmedial prefrontal circuit through the primate basal ganglia. J Neurosci15:4851–4867.

Halliday GM, Tork I. 1986. Comparative anatomy of the ventromedialmesencephalic tegmentum in the rat, cat, monkey, and human. J CompNeurol 252:423–445.

Hedreen JC, DeLong MR. 1991. Organization of striatopallidal, striatoni-gral, and nigrostriatal projections in the macaque. J Comp Neurol304:569–595.

Herrero MT, Hirsch EC, Kastner A, Luquin MR, Javoy-Agid F, Gonzalo LM,Obeso JA, Agid Y. 1993a. Neuromelanin accumulation with age incatecholaminergic neurons from Macaca fascicularis brainstem. DevNeurosci 15:37–48.

Herrero MT, Hirsch EC, Kastner A, Ruberg M, Luquin MR, Laguna J,Javoy-Agid F, Obeso JA, Agid Y. 1993b. Does neuromelanin contributeto the vulnerability of catecholaminergic neurons in monkeys intoxi-cated with MPTP? Neuroscience 56:499–511.

Hirsch EC, Graybiel AM, Agid Y.1988. Melanized dopaminergic neurons aredifferentially susceptible to degeneration in Parkinson’s disease. Na-ture 334:345–348.

Hirsch EC, Mouatt A, Thomasset M, Javoy-Agid F, Agid Y, Graybiel AM.1992. Expression of calbindin-D28K-like immunoreactivy in catecholamin-ergic cell groups of the human midbrain: normal distribution anddistribution in Parkinson’s disease. Neurodegeneration 1:83–93.

Iacopino A, Christakos S, German D, Sonsalla PK, Altar CA. 1992.Calbindin-D28K-containing neurons in animal models of neurodegenera-tion: possible protection from excitotoxicity. Mol Brain Res 13:251–261.

Jimenez-Castellanos J, Graybiel AM. 1987. Subdivisions of the dopamine-containing A8-A9-A10 complex identified by their differential mesostria-tal innervation of striosomes and extrastriosomal matrix. Neuroscience23:223–242.

Jimenez-Castellanos J, Graybiel AM. 1989. Compartmental origins ofstriatal efferent projections in the cat. Neuroscience 32:297–321.

Kastner A, Hirsch EC, Herrero MT, Javoy-Agid F, Agid Y. 1993. Immunocy-tochemical quantification of tyrosine hydroxylase at a cellular level inthe mesencephalon of control subjects and patients with Parkinson’sand Alzheimer’s disease. J Neurochem 61:1024–1034.

Kastner A, Herrero MT, Hirsch EC, Guillen J, Luquin MR, Javoy-Agid F,Obeso JA, Agid Y. 1994. Decreased tyrosine hydroxylase content in thedopaminergic neurons of MPTP-intoxicated monkeys: effect of levodopaand GM1 ganglioside therapy. Ann Neurol 36:206–214.

Kunishio K, Haber SN. 1994. Primate cingulostriatal projection: limbicstriatal versus sensorimotor striatal input. J Comp Neurol 350:337–356.

Lavoie B, Parent A. 1991. Dopaminergic neurons expressing calbindin innormal and parkinsonian monkeys. Neuroreport 2:601–604.

Lavoie B, Smith Y, Parent A. 1989. Dopaminergic innervation of the basalganglia in the squirrel monkey as revealed by tyrosine hydroxylaseimmunohistochemistry. J Comp Neurol 289:36–52.

Lewis DA, Campbell MJ, Foote SL, Goldstein M, Morrison JH. 1987. Thedistribution of tyrosine hydroxylase immunoreactive fibers in primateneocortex is widespread but regionally specific. J Neurosci 7:279–290.

Lynd-Balta E, Haber SN. 1994a. The organization of midbrain projectionsto the ventral striatum in the primate. Neuroscience 59:609–623.

Lynd-Balta E, Haber SN. 1994b. The organization of midbrain projectionsto the striatum in the primate: sensorimotor-related striatum versusventral striatum. Neuroscience 59:625–640.

Maeda T, Ikemoto K, Satoh K, Kitahama K, Geffard M. 1995. Dopaminergicinnervation of primate cerebral cortex. An immunohistochemical studyin the Japanese macaque. In: Segawa M, Nomura Y, editors. Age-related dopamine-dependent disorders. Basel: Karger. p 147–159.

MacRitchie DA, Hardman CD, Halliday GM. 1996. Cytoarchitecturaldistribution of calcium binding proteins in midbrain dopaminergicregions of rats and humans. J Comp Neurol 364:121–150.

Mesulam MM. 1978. Tetramethylbenzidine for horseradish peroxidaseneurohistochemistry: a non-carcinogenic blue reaction product withsuperior sensitivity for visualizing neural afferents and efferents. JHistochem Cytochem 26:106–117.

Nobin A, Bjorklund A. 1973. Topography of the monoamine neuron systemsin the human brain stem of tree shrew (Tupaia). Brain Res Bull9:205–216.

Olszewski J, Baxter D. 1954. Cytoarchitecture of the human brain stem.New York: Karger.

Parent A, Mackey A, De Bellefeuille L. 1983. The subcortical afferents tocaudate nucleus and putamen in primate: a fluorescence retrogradedouble labeling study. Neuroscience 10:1137–1150.

Pearson J, Goldstein M, Markey K, Brandeis L. 1983. Human brainstemcatecholamine neuronal anatomy as indicated by immunocytochemis-try with antibodies to tyrosine hydroxylase. Neuroscience 8:3–32.

Percheron G, Francois C, Yelnik J. 1986. Instruments and techniques forthe stereotactic surgery based on the CA-CP system of coordinates inmonkeys. J Neurosci Methods 17:89–99.

Poirier LJ, Giguere M, Marchand R. 1983. Comparative morphology of thesubstantia nigra and ventral tegmental area in the monkey, cat and rat.Brain Res Bull 11:371–397.


Porrino LJ, Goldman-Rakic PS. 1982. Brainstem innervation of prefrontaland anterior cingulate cortex in the rhesus monkey revealed byretrograde transport of HRP. J Comp Neurol 205:63–76.

Rye DB, Saper CB, Wainer BH. 1984. Stabilization of the tetramethylbenzi-dine (TMB) reaction product: application for retrograde and antero-grade tracing, and combination with immunohistochemistry. J Histo-chem Cytochem 32:1145–1153.

Saint-Cyr JA, Ungerleider LG, Desimone R. 1990. Organization of visualcortical inputs to the striatum and subsequent outputs to the pallido-nigral complex in the monkey. J Comp Neurol 298:129–156.

Schultz W, Studer A, Romo R, Sundstrom E, Jonsson G, Scarnati E. 1989.Deficits in reaction times and movement times as correlates of hypoki-nesia in monkeys with MPTP-induced striatal dopamine depletion. JNeurophysiol 61:651–668.

Smith Y, Lavoie B, Dumas J, Parent A. 1989. Evidence for a distinctnigropallidal dopaminergic projection in the squirrel monkey. Brain Res482:381–386.

Smith Y, Parent A. 1986. Differential connections of caudate nucleus andputamen in the squirrel monkey (Saimiri sciureus). Neuroscience 18:347–371.

Szabo J. 1980. Organization of the ascending striatal afferents in monkeys.J Comp Neurol 189:307–321.

Tanaka C, Ishikawa M, Shimada S. 1982. Histochemical mapping ofcatecholaminergic neurons and their ascending fiber pathways in therhesus monkey brain. Brain Res Bull 9:255–270.

Vandermaelen CP, Kocsis JD, Kitaı ST. 1978. Caudate afferents from theretrorubral nucleus and other midbrain areas in the cat. Brain Res Bull3:639–644.

Yamada T, McGeer PL, Baimbridge KG, McGeer EG. 1990. Relative sparingin Parkinson’s disease of substantia nigra dopamine neurons contain-ing calbindin-D28K. Brain Res 526:303–307.

Yelnik J, Francois C, Percheron G, Heyner S. 1987. Golgi study of theprimate substantia nigra. I. Quantitative morphology and typology ofnigral neurons. J Comp Neurol 265:455–472.


Dopaminergic cell group A8 in the monkey: Anatomical organization and projections to the striatum

Documents

Transcript of Dopaminergic cell group A8 in the monkey: Anatomical organization and projections to the striatum