~pergamon Neurosc/ence Vu!. 86, No. 2, pp. 153·387, 199R

Copyright c' 1998 !BRO. Published b) FIsevier Science Ltd

PII: S0306-4S22(98)00004-9

COMMENTARY

Printed in Great Britalll. All rights reservcu 0306 4)22/98 $19,00+000

MICROCIRCUITRY OF THE DIRECT AND INDIRECT PATHWAYS OF THE BASAL GANGLIA

Y. SMITH,*t M. D. BEVAN,t E. SHINK*t and J. P. BOLAM'I *Yerkes Regional Primate Research ('enter and Department of l\eurology. Emory University. Atlanta,

GA 30321. l.S.A.

tCentre de Recherche en Ncurohiologic. H()pital de I'Enfant-Jesus. Universite Lava!. Quehec City. Quebec. Canada

tUniversity Department of Pharmacology, Mansfield Road, Oxford OXI 3QT. U.K.

'IMRC Anatomical Neuropharmacology linlt, Mansfleld Road, Oxford OXI 3TH, lJ K.

Abstract Our understanding "I' the organi/ation of the has,,1 gangha has advanced markedly over the last 10 years, mainly due to increased knowledge of their anatomical, neurochemical and physiological organization. These developments have led to a unifying model of the functional organization of the basal ganglia in both health and disease. The hypothesis is based on the so-called "direct" and "indirect" pathways of the flow of cortical infclrmation through the hasal ganglia and has profoundly influenced the field of basal ganglia research, providing Cl framework for anatomical. physiological and clinical studies. The recent introduction of powerful techniques for the analysis of neuronal networks has led to further developments in our understanding of the basal ganglia. The ohjective of this commentary is to build upon the established model of the basal ganglia connectivity and review new anatomical findings that lead to the refinement of SClme aspects of the lllodel. Four issue, will be discussed. (I) The existence of several routes for the flow of cortical information along "indirect" pathways. (2) The synaptic cllnv~rgence of information flowing through thc'direct" and "indirect" pathways at the single-cell level in the hasal ganglia output structures. (31 Th,: convergence of functionally diverse information frOl11 the globus pallidus and the ventral pallidulll at different levels of the basal ganglia. (4) The interconnections hetween the two divisions of the pallidal comple, and the suhthalamic nucleus and the charactcri/atioll of the neuronal network underlying the indirect pathways.

The findings summarized in this COllll11ent<Jl'Y confirm and elahorate the models of the direct and indirect pathways of informatillll flow thrnugh the hdsal ganglia and provide a morphological framework for future studies. ( 19lJ8 I BRO. Puhlished hy Elsc\ ier Science Ltd.

Ke\' l\'(Irds: globus pallidus, suhtlialamic llucleUS, suh,tantia nigra, entopeduncular nucleus. striatum, synaptic organiLation.

('O'VIT\TS

I. INTRODUCTION 354 1.1. Terminology 356 1.2. The direct and indirect pathways of information flow through the basal ganglia 356 1,3 Technical developments in the elucidation of neuronal networks 357 lA. Characteristics of synaptic terminals underlying the direct and indirect pathway, of

information flow through the basal ganglia 358 lA.I. Axon terminals of projection neurons of the striatum 358 lA.2. Axon terminals of neurons of the globus pallidus ,~5lJ

IA.3. Axon terminals of neurons of the subthalamic nucleus 35'i 2. SYNAPTOLOGY OF THE DIRECT AND INDIRECT PATHWAYS 35lJ

2.1. Cortical inputs to striatal neurons giving rise to the direct and indirect pathways 35lJ 2.2. Synaptic connections hetween striatal neurons gi\ ing risc to the direct and indirect pathways 361 2.3. Synaptic organization of the direct pathway 361 2A. Synaptic organization of the indirect pathways 364

Correspondence should be addressed to Y.S. or to J.P.B. Abhreriatiol1s: BDA, biotinylated dextran amine; El', entopeduncular nucleus; GP, globus pallidus: (IPe, external segment

of the globus pallidus: GPi, internal segment of the globus pallidus; NADPH, reduced nicotinamide adenine dinucleotide phosphate; PHA-L, Phaseolus I'ulgari" leucoagglutinin; PPN, pedum:ulopontine nucleus; RTN, reticular nucleus of the thalamus: SN, substantia nigra; SNc, suhstantia nigra pars compacta: SNr. substantia nigra pars reticulata; STN. suhthalamic nucleus: VP, ventral pallidur11.

354 Y. Smith ('/ al.

2.4.1. The projection Crom the striatum to the globus pallidus 364 2.4.2. The projection from the globus pallidus to the subthalamic nucleus 366 2.4.3. The projection from the subthalamic nucleus to basal ganglia output nuclei 366 2.4.4. The projection from the globus pallidus to the entopeduncular nuclcuslinternal

pallidum 367 2.4.5. The projection j'rom the globu, pallidus to the substantia nigra 367 2.4.6. The projection from the globus pallidus to the reticular nucleus nf the thalamus 367 2.4.7. Intrinsic axon ,ollateral> of globus pallidus neurons 3611 2.4.B. Other efferent projections of the globus pallidus 36~

2.5. Synaptic convergence of direct and indirect pathway, on basal ganglia output ncurons 36x 2.5.1. Convergence 01 subthalamic and striatal terminals on individual basal ganglia output

neurons 36H 2.5.2. Convergence 01' pallidal and striatal terminah on individual basal ganglia output

neurons 368 2.5.3. Convergence of ,ubthalamic, pallidal and striatal terminals on individu.JI basal

ganglia output neurons 36~ 2.6. Synaptic convergence of descending functionally diverse information arising from the

globus pallidus and the ventral pallidum 369 2.7. The corticosubthalaI1lic prnjection: an additional indirect pathway 369

1. NEURONAL NETWORK UI\OERLYING THE INDIRECT PATHWAYS 37(J 3.1. Basic circuit underlyillg the indirect pathways 37(J 3.2. Functional specificity nf the indirect network 374

4. AN CPOATEO VERSION OF THE SCHEME OF THE BASAL GANGLIA CIRCUITRY 376 ACKNOWLEDGE M EN IS 37(, REFERENCES 376

I. INTRODtl(TIO"

The basal ganglia are a group \)f subcortical nuclei of the vertebrate brain that are intimately involved in the control of movement. The basal ganglia include the striatum (or caudate-putamen), the globus pal­lidus (GP) and its equivalent in primates, the external segment of the globus pallidus «(iPe), the entopedun­cular nucleus (EP) and its equivalent in primates. the internal segment 01" the globus pallidus (GPi). the subthalamic nucleus (STN) and the substantia nigra (SN). They are a complex and highly interconnected group of nuclei that have been the subject of intensive study over many decades, primanly because of their clear involvement in neurological disorders that arc associated with abnormal motor activities. Indeed. one of the first descriptions of the basal ganglia by Willis in the 17th Century intimated a role of the basal ganglia in the control of mOvement and in neurological disorders: "To the corpw, callosum are attached the corpora striata connecting the cerebrum to the legs of the medulla oblongata. In these corpora there are some striae passing upwards and others downwards and through them tIll' spirits and images of sensible things pass from the medulla oblongata into the cerebrum, while spirits initiating movement descend into the medulla oblongata. In those who suffer or have died from paralysis. I have often observed that these corpora dre affected: they became flaccid and their striae ;lrc almost obliter­ated" (Willis, c. 1664, from lecture notes by Locke translated by Dewhurst""'j.

The role of the basal ganglia in the control of movement is more subtle and complex than simply a direct influence on muscle contraction. On the basis of extensive anatomical studies, Nauta proposed that the basal ganglia act as an interf;lce between limbic

and motor systems, i.e. the basal ganglia subserve an integrative role in the manifestation of motor behav­iour."" Since that time, many functional analyses, as well as anatomical studies, have expanded this con­cept and it is now clear that the basal ganglia arc involved in a variety of cognitive and mnemonic functions in the generation and execution of context­dependent behaviours (see, for instance, ReI's 123, 273, 274 and 339). Despite intensive studies of the anatomical and functional organization of the basal ganglia and the large amount of data gathered about the pathophysiology of motor disorders associated with neurodegenerative diseases that alfect thc basal ganglia (e.g., Parkinson's disease. Huntington's dis­ease. hemiballismus), unifying hypotheses of basal ganglia function that take into account data derived from different disciplines remained elusive for many years (sce review by DeLong and Georgopoulos7

<).

However, several key advances in the knowledge of the anatomical, neurochemical and physiological organization, as well as data from post morrem studies, led Albin et al." to formulate their unifying model of the functional organization of the basal ganglia that accounts for both normal and abnormal function. This model, which has been expanded and elaborated by other groupS.7.6S 74 7(,.11' 11'.11S is

based on the so-called "direct" and "indirect" path­ways of the flow of cortical information through the basal ganglia (Fig. I). According to this model. cortical information impinging on the striatum is processed and transmitted to the output nuclei of the basal ganglia via two routes: either directly from the striatum to the output nuclei or indirectly via the GP and STI'i (Fig. I). The consequences of activation of the direct and indirect pathways are functionally opposite in the target regions of the basal ganglia. 7.76

Thus, activation of the direct pathway leads to a

'vlicrocircuitry of the basal ganglia

CEREBRAL CORTEX

Brainstem Spinal cord

Direct Pathway

(DA)

SNc Thalamus

Feedback or output

Fig. I. The circuitry of the basal ganglia in primates as propo,ed in 1'i90. Oh Inhibitory projections are shown as filkd arrows. excitatory projection, a.s open arrows. According to this model. cortical infor­mation that reaches the striatum i, conveyed le' the basal ganglia output structures IGPi/SNr) via two pathways. a direct inhibitory projectIOn from the striatum to the GPi/SNr and an indirect pathway. which involves an inhibitory projection from the striatum to the GPe. an inhihitory projection from the GPc to the STN and an excitatory projection from the STN to the GPi/S"Jr. The information is then transmitted back to the cerebral cortex via a relay in the th,ilamus llI" conveyed to various brain stem struclUres. The GPi projects to the pedunculopontine nuclew, (PPN) and the latent! habenular nucleus (!-IB"J I. whereas the SNr innerv,ltes the PPN. the superi,)r colliculus (Se) and the parvicellular rcticu"'r formation I RI) The direct and indirect pathways largely arise from ditl"crent populations of striatal spiny neurons that contain ditferent peptides and preferentially expre~, different ,ubdasses of dopamine rcceptors. The dopaminergic ncuml1s of the oubstal1tia nigra pars compacta (S"Ic) exert a 1](;t excitatory elfect on spiny neurons giving rise to the direct pathway by the activation or D, receptor,. whereds they nnt a net inhibitory dfect on spiny neurom giving rise to the indirect p,ttllllay by activation of D., ,"eccptors. Cortical information can al,o reach the basal ganglia via the corticosubthalamic projection. Other abht"Cviati(lns: DA. dopamine: cn~. enkephalin: subst 1'. substance P. Mll(\lilcd from Fig. ~ in Alexander and Crutchcr.;

disinhibition or neuron, in the target regions of the

basal ganglia, whereas activation 01 the indirect pathway leads to an inhibition of neurons in the

target regions (see below). Thc devdopment or this concept has had a proround int1ucnce nn basal gan­

glia research, providing a stimulus and rationale ror

anatomical, functional and clinical studies and. in­deed, has led to the development nf new therapies

and the resurgence of surgical approaches (see Laitinen et al. '0',,) for the treatment of Parkinson's disease. 16.1 8.22.2 ;.2.K.:N.5.5.12:'>.lhlJ, 195.2()().2{)~', 2,'<1, I J.' 1 l,d. '~') ",11)

The introduction of powerful techniques I"or the analysis of neuronal networks has led to many

advances in our knowledge and understanding of the

anatomical and synaptic organization of the basal ganglia. Tbe objective of this commentary is to

review tbese new anatomical data concerning the connections. synaptic organization and neurochemis­

try of the neurons in the basal ganglia that underlie

the direct and indirect pathways. Our aim is to

illustrate how these new data support and expand the concept of the direct and indirect pathways and how they provide clues tt) tbe t"uncti()nal organiz­

ation of the basal ganglia. For more details about

the overall organization of the basal ganglia, the reader is referred to recent comprehensive

356 Y. Smith eI al.

review's. 7.27a.41,h5,h7. 11_1,.114.11 x. I .:.~.I 27.121<.1 1().1 "i7a.l (lCl I (lX,

:>04.2!7a.2.'S242.2R).:n:> The discussion will be almost

exclusively confined to the "dorsal" aspects of thc basal ganglia, except for some of the connections of the ventral pallidum (Section 2.6). The n:adl:r is referred to recent review;, dealing with the cir­cuitry of the ventral components or the basal ganglia,I).<Ja.1 ::'7, Il,(),l )().1';;7a.J~4

In order to provide a basic framework for the interpretation of the new data within the functional organization of the basal ganglia. wc will begin with a brief discussion of the concept ()f direct and indirect pathways as introduced by Albin ('I £I/o' and elab­orated by DeLong and colleagues 7.7(, (Fig. I). This will be followed by a brief description of the technical developments that have led to tlie elucidation of the pathways and synapses that mediate the interaction between different ncurons and dilferent nuclei of the basal ganglia. We will then summarize reccnt data relating to the synaptology of the direct and indirect pathways and present a revised version of the circuitry of the basal ganglia.

1.1. Termin%gl'

The terminology applied to the divisions of the basal ganglia is particularly confusing because the nomenclature is based on the anatomical location and gross appearance of individual nuclei. and because of differences in the gross anatomy of primate and rodent brains, For the purposes of this commentary. we will endeavour to w,e the simplest terminology. Thus, the term "basal ganglia output nuclei" will refer to the entopeduncular nuclcus or the primate equivalent, the intcrnal segment ut' the globus pallidus (EP/GPi), and the substantia nigra pars reticulata (SNr), In using the term "globu,; pallidus" (GP), wc will not ilnly ret'cr to that structurc in non-primates but IIlclude the primate equivalent, the external segmcnt of the globus pal­lidus (GPe), Only when referring to particular cxper­iments in a single species will we use the terms GP and EP or GPe and GPi. The t,Tm .. targets of the basal ganglia" refers to the mall! structures inner­vated by the basal ganglia, i,e. the vcntral tier of the thalamus. the lateral habenula. t he superior collicLl­Ius. the mesopontine tegmenturll and the reticula I' formation.

1.2. The direct and indirect parh'fal'S 0/ ill/ormalioll !fOH' through the hasld gang/ill

The direct and indirect pathways of information flow through the basal ganglia, as originally intro­duced. are summarized in Fig. 1.·7

.2k

76 Virtually all regions of the cerebral cortex prllvide a topographi­cal projection to the striatum and. indeed. the conical input imposes functionality upon different tcrritorie, of the striatum. The cortical intormation. together with informati(ll1 from local neurons and other

extrinsic afferents, is integrated within the striatum primarily by the spiny projection neurons. These neurons account for up to 90"i(, of neurons in the striatum. they are recipients of most of the afferent synaptie input to the striat um and they are the main output neurons, 11 X.I.'2.1 71 17'.2H5 Once "pro-

cessed", the cortical information is transmitted to the output nuclei of the basal ganglia either by a sub­population of spiny neurons that projects directly to the output nuclei, or a separate population of spiny neurons that conveys the "proccssed information" to the output nuclei by an indirect route, The neurons that give rise to the indircct pathway project to the GP,cl.99.ln.It'.tt'l.200.2(l1 which. in turn. projects to

the STN and then to output nuclei of the basal ganglia (Fig, Il. The subpopulations of spiny neurons that give rise to the direct and indirect pathways arc further characterized by their selective exprcssion of neuropeptidcs and dopamine receptor subtypcs, Thus. although all striatal spiny neurons use GABA as their main neurotransmitter. the subpopulation that gives rise to the direct pathway contains the neuropeptides substance P and dynorphin, and pref­erentially expresses the D I subtypc of dopamine reccplors, and the subpopulation that gives rise to the indirect rathway contains enkcphalin and pre­ferentially expresses the D2 subtype of dopamine receplOrs,'· I I.'. J 15. I IX. I J ,'-"(" 1.20 I A small pop ula-

tion of striatal neurons express both DJ and I),

receptors315iL.h It has been shown in the rat that singk spiny neurons in the c;triatum do not exclu­sively innervate the GP or the output nuclei. but the density of the axonal arbor is greater in only one of the targets. 169 Thus. neurons that arborize profusely in the GP give rise to minor axon collaterab with only few terminals in the EP and S"Jr. whereas neurons that project massively to the EP and SNr emit more sparse axon collaterals in the GP."'" These features have recently been contirmed in monkcys.2'"

By virtue of the neurotra nsmitters and basal activity of neurons in these networks, activation of the direct and indirect pathways produces function­ally opposite effects in neuruns of the target nuclei of the basal ganglia. Corticostriatal neurons and neurons of the STl\ are cxcitatory, utilizing gluta­mate as Cl neurotransmitter. All other neurons in thc network. including ncurons of the output nuclei, arc GARAergic. l'nder resting conditions, the activity or the spiny output neurons is low compared to that of the tonically active neurons in the GP and the STN, Activation of the corticostriatal pathway leads to increased firing of striatal neurons. Increased activity of neurons that give rise to the direct patbway leads. by virtue of their GABAergic nature. to the inhi­bition of neurons in the output nuclei. A reduction in the tonic activity of neurons in the output nuclei leads 10 a reduction in the inhibition of. or a disinhi­bition of, neurons in the tarl!et nuclei of the basal ganglia 77

(' The phenomenon' of reduced inhibition nr disinhibitioll of the targets of the basal ganglia i,

!'vi icrocircllit ry 01' thL' hasal g:lI1glia ~57

A B c o

'¥ , I ,I * J

Fig. 2. 'VIultimodal transport (If 11c'lIronal traet-tracns Diagr:llll illustrating the multim')lLtI Ir:lllsport of som~ neuronal tract-tracers that arc commonly considered as .:xclusivdy anterograde tracns (biocytin. PHA-L BDAI. In addition to hcing transported in an 'II1terogradc fashion lA). many anterograde tracers arc ab" transported rctrograddy. i.c. from the terminallicld 01' a neuron hack tL) its LTII body (B). Tracers that have heen retrogradcly transported may suhsequently be transported in an allterogralk Lhhion ,tlong aXOll collaterab (Cl. In some cases. trael'l's may he retrogradcly tr<lllsported to the branch p')lI1t of "ll ;l.\(lll and then preferentially transported :don~ the collaterab with only minim:tlbheliing "flhc ptTikarVoll (DI.

cl?ntral to thc physil)logy of the has;d ganglia and may underlie many basal ganglia-associated runc­tionsf'7J'~.su") In contrast to this, actIvation ofthm,e

spiny neurons that project to thl' (JP, i.e. neurons that give rise to the indirect pathvva\" leads tll the opposite functional clfect in the targL'ls of the basal ganglia. This is brought about In the followins manner. Activation or corticostriatal libres leads to

increased activity of striatal neuroIls which, in turn, inhibit the tonically active neurons in the (JP, Inhi­bition of these neurons disinhibih IIcurnns in the ST:"J. Since neurons in the STl'\ ,11',' e\citatory, their increased activity kads to inereased fit ing DJ' neurnlb in the output nuclei and, hence, bc,'allse Ih.:urOlh in the output nuclei an.: GABAergic. leads to a greater

inhibition of neurons in the target nucki. The increased inhibition 'If neurons in the larget nuclei is likely 10 be associated with the ce"atlon lll' ,e!t.:cted movements and possibly the supprl',sion nf n()n­selected movements'"?(' The tonic acti\ ity llJ' neumns

in the GP and STN in the resting animal may alsp

shape the tonic firing patterns of basal ganglia output neurons and thus the inhibition of neurons in the

targets of the basal ganglia. The model also serves as a basis for understanding

the pathophysiology of disorder, Df movement associated with diseases of the basal ganglia. '.7'7'LCS7(,

Since the increased activity or the direct pathway is associated with f~lcilitation of nH>VL'menl and in­creased activity or the indirect pathw"y is dssociatcd with inhibition of movement, it h,IS heen suggested that akinetic motor disorders. of IV hi,'h Parkimon's

disease is the archetype. are the result of an imbal­ance in the activity of the direct and indirect path­ways in favour of the indirect palhwav.'~7(' On

the other hand. dyskinetic or hyperkinetic nwtor disorders, ofwhieh HUlltingtoll's chor,'a is the arche­type, are associated with an imhahlnce in favllllr of the direet pathway. In keepil1,!2: vlith these

suggestillns, data obtained from experimental ani­n1al..;17.:?..;.2q.~"'i."17.l)~.11~ l"t··LI·I, .. )j"l.1 1

,) have in1plicated

~I relative over-activity llf the indirect pathways in Parkinson's disease and a 1'I:lati\e under-aclivit:­in 1I11ntinston', disease. Furthernwre. pharmaeo­I'lgicai manipUlation or surgical ll1tenentions that r,'stllre the balance between the two pathways ~t!leviatc the abnormal motor activity,I("".:".I>lo',

The value of the nwdcl IS further c,empliiied by the appliC<ltion 01' this type of intcrvcntion to Ihe treatment of Parkinson's diseas,'.' '.:' '.')-t.I '''.'''<>.:''''. '"

1.3. 'j'c('illlim! det'c!oJ!!I1CIII.I ill /iI(' e!ucida/ioll of

IICUI'OIlIl!I1I'/II·or/,.1

The elucidation of the neuronal networks of the basal ganglia at both light and electron microscopic levels has posed particular problems because or the complex nature of the interconnections between thesc nuclei. Several technical advances havc been import­,Int in the elucidation of these neuronal networks.

hrs!' the availability of new sensitive anterograde tracer, thal result in a high resolution of labelling of axons and terminal fields has helped our ability to trace connections between populations of neurons and hetween individual neurons in the eNS, The Ilrst nf Ihese tracers to be introduced \Ias the lectin, 1'/1iI.IL'IJ!U.I l'lilgari.l' leucoagglutinin !PHA-Ll.117 Two

further markers have also proved tll he valuable tools in tracing neuronal connections al both light and electron microscopic levels, biocytin Llr biotinylaled Iysincli,"I and biotinylated dextran amine (BDAl.,!,1 ~1 The availability of more than onc

hish-resolution neuronal tracer ;Ind the ability to perform double peroxidase staining for light w;.;n ,Ind electrnn microscopy-'''l.'''; has allc)Vved us to

develop double anterograde tracing techniques for the elucidation of convergence Ill' dilTerent path­vlays at the synaptie leveL'S!."""H The combined

Y. Smith £'/ ,,/.

anatomical approaches to the study of synaptic inter­actions, especially the ability to characterize neuronal structures postsynaptic to anterogradely labelled tcr­minals on the basis of connectivity and thc ability to identify the presence of amino "cid transmitters in individual anterogradely labelled terminals. ha,,? been particularly important in the c1ueidation of neuronal lnicrocircuils. 30,.1, I "L:'.-1/'./(/, 111,t,! (I.'-.:!(j). ~,,\').~H) I

2'J 1..2 l l-1- .. IO, .. 1,()..:!.32...J

The application of these techniques has led to major advances in our knowledge and understanding or the neuronal networks of the basal ganglia. Hm\­

ever. these technical advances hme not been without their drawbaeb. The main dnlwback is that the anterograde tract-tracers. although being trans­ported preferenti,lIly in the ant,:rograde direction. may alsl) be transported retrngradcly (hg. 2A .. B)."2.'"l, .. qJAd.:'l).1.\.).177.:-,·n.2,,)7.~-,q"_"?~, '::-X2. '~-1-."d.~'X rur-

thermore. retrogradely transpnrlc'd tracc'rs may then be transported anterogradelv along a\on collatc'rals (Fig. 2e see. for instance. Rer:; h·la. XL), 117.2)7.25') and 277) The factors that dictate whether an "ankro­grade" tracer will be transported retmgradel) ar,' unknown, but may rclate to. the lknsitv ()fthl' a\()nal arborizatinn, the activity or till' neuron I 10,1 e)1' 11ll' c:lfcct of damage caused at the injecti()n site. The retrograde transport of antero~r;lde tracers is a par­ticular problem in the basal gan>!lia. The interpret­ation nf data from anterograde tracing studies is complicated because the basal ,l';mglia arc heavil) interconnected and individual Ileurons I'requentl) give rise to axon collaterals Ihat inncrvatL' multipic target areas. Thus. in the use pi' anterograde' tracers it is necessary to incubate and analyse' sect inns. n\)1 only from the prnposed region 01 anterograde label­ling. but also from any region nf the hrain that lI1a\

have retrogradely transported the tracers and then anterogradely transported them \ ia <[\()n collaterals. Data from tracing studies may :,oll1etill1es he even more ditlieult to assess as traeel's may be retrognlllel:­transported to the branch point (li';ll1 aXLln and then ho: preferentially transported alon~~ the collateral with only minimal retrograde Iabellinl' of the perikarynn (Fig. 2D).""·L:"7

The phenomenon of retrograde' and then antero, grade transport of tracers. which can be' referred to as l1lultimodal transport. is best illustrated with an namplc. In analyses of the synal'tic organi/<ltioll of the projections of the STI\i tll the output nuclet of the basal ganglia in rats and primate..;. ',' '1 .. ")'.")'1

deposits ut' either PI'IA-I.. "r biuc).tin were made in the STN. As predicted frolll the kllllwn projections of the STN. both the !·P/(jPi and the SNr were rich in populations elf anterogradely labelled termitwls. However. light microscop> in primates. " " and combined light and electron microscopy in rats and primates. ". '4'%"1') revealed that the anterogradely labelled termin;lls were hctcrogeneow; in their morphnlogl'. In each nf these experiments. two population, (if 1crminals \,erl'

labelled. Electron microscopy in the rat revealed that the major type of terminal possessed the typical characteristics of terminals from the STN (sec Sec­tion 1.4.3). i,e. they were medium-sized boutons that contained round synaptic vesicles and formed asymmetric synapses with perikarya and den­drites. \2. '42'1X,299 The same class of terminals. antern­gradely labelled from the STN. has been shown to be enriched in immunoreactivity for glutamate. 2h

' The sccnnd class of terminals. in contrast. were large. contained pleomorphic vesicles that congregated at the active lono:. usually eontallled several mitoc:hon­dria. femm:d symmetric synapses and were immulw­reacti\e for GABA. Furthermore, the distribution of this second class of terminals on the postsynaptic neurons was different to that of the major type. i.e. they v,ere predominantly located on the cell body and proximal dendrites. Since all neurons of the STN arc believed to be glutamatergie. L2')7 it is unlikely that the ..;econd class l)f terminals were labelled by direct anterograde transport from the STN. The morpho­logical characteristics. the presence of GABA and the pattern of innervation of the postsynaptic neurons arc leatures typical of terminals derived from the (iP I sec Section IA.2.). Furthermore, retrogra(kl). labelled neurons were observed in the GP. It can be concluded. tho:refore. that in addition to being an­terog.rddeiy transported by subthalamofugal neurons. the tracers were also retrogradely transported along the aXLlns of neurons elf the (JP that project to the STN and then anterogradel; lI'an~ported along thl?ir axon (ollaterab to the output nuclei (Fig.. 2C sce discussions in ReI's )2. )4. 29:-1 and 299).

fhe multimodal transport 1)1' neuronal tracer~ in experiments designo:d t() elucidate neuronal networks mean:-. that the data obtained require careful interpretation. It is essential to have a thorough kIlllwlcdge of the connections between the regioll'i under investigation and the findings must be sup­ported by ultrastructural anah·sis and the character­ization of the endogenous transmitters of the antero­gradel\' labelled boutons. Howevt.:r. the ability of tnlcer:- to be transported in a t1lultimodal fashion can have advantages in the study of neuronal networks, since the collatendizatilln ofaxons and topographical reiatiLlnships can be identilied hee below; Figs 9 11,.

lA. C/wracteristies oj Sl'lIl1pliC INmillills ullder/rillg thc dirc('/ IIncl indirec/ !J(/t/Il1'{/I'.I' of in(imlwtioll j!oll through the hasa/ ganglia

1.4.1. AxolI termilla!I' of projcctioll ncurolls (It the ItrlUtUJII. The first data relating to the ultrastructural features and synaptic organization of striatal aner­cnts 1\) thc pallidal complc" and the SN were obtained by means of anterograde degeneration methods. 1.1 Q.I·ll.17(UO' '.'7. '.\ I Thesc observations

have since been conlirmed and extended in dinerent species using modern tract-tracing methods. intracellular labelling or immunohistochemical

localization of peptides known tll be present in striatal neurons. ~2,:1.4A6 4S.6.~.64.K(1.2()') 2' L2')_~. 1(l(1.1()7 ~24

In each of the targets of the striatum. i.e. the GP. the output nuclei of the basal ganglia and the sub­stantia nigra pars compacta (SNc). terminals of striatal neurons have a similar morphl1logy, Further­more, the terminals of the local axon collaterals or striatal neurons identified by intracellular label­ling."4 Golgi impregnation.")1 ur b\ immuno­cytochemistry for substance P. ellkephalin or glutamate decarboxylaseI1AOA1.44.'~'.'I' '"f! ,1(1.'·1" ~""

are indistinguishable from terminals in the targets of the striatum.

The terminals of striatal neurons arc sl11all- to medium-sized (0.51.5 /.1m in diameter). the) arc densely packed with ovoid, electron-lucent vesicles and contain only an occasional mitl1chlll1dril1ll. Thcy form symmetrical synaptic contact> "it h tlKir largets (Figs 3A, 4A, B, SA Cl. In somL' st1 <tins ()f rdL a proportion of striatal boutuns in basal.",anglia l111tl'llt nuclei have an irregular shape and ,Ire pierced. or interdigitated. hy unmyelinated a\()J1S and terminals (Fig. 4B).32.34.lhO The combinatiPIl ",I' Ihe 'lIlterll­grade labelling with post-embedding immunogold labelling utilizing antibodies against (jABA has demonstrated that striatal terminals in thc' EP/CiPi and SNr are GABAergic (Figs :1;\. :'lA. 13).'" .,.) ,"

IA,2. Axol1 Icnnil1uls of I1Cllrow ()f Ihe g/nllll,1

pallidus. Following deposits L)f tracers in the (iP. the morphology. the ultrastructural fl:ature:s and the neurochemistry of anterogradcl~ Iahe:lled pal­lidal terminals have been charactL'I'i/ed In tIll: EP/GPi,4KA~.c')k2'J') the STN" "'I "11 <lnd the SN.l6.2S~.2~1.:2'!"24 In each region, terll1inals derived rrom the GP have a characteristic n1<lrplllllogy and neurochemistry (Figs 3B. C, SA C. 7) that i, ulllf(ll'm across species. The terminals are large /1.0 .t.) pm in diameter), contain small pleomorphic :'Yll<Iplic ves­icles that form clusters close to the: active I.lllleS and usually contain several mitochondria (Figs :113. c. SA C 7). They form short symmetrical synaptic contacts most frequently with the proximal regions of their postsynaptic neuron .. j<)·2~1 IndiVidual bOllll)nS often possess more than onc act I\'e /OllL' making multiple synaptic contach with a single pllstsynaptic structure. Post-embedding immunogold labelling has revealed that anterogradel;. lahelled pallidal outons 11.4K.4'!,2k'l.2'! 1.2').<.''''1.:'24 or boutl )ns \\ ith simi-

lar ultrastructural katures"UI.7'1 '"I arL' st1'llngl: immunoreaetiw for GABA (Figs 3( '. ~A. H)

IA.3. Axon lamill({/.I ()/I1Clll'Oll.1 uf 1/'(' ,llIhlhal(//lIh

1111c/(,US. The morphology and ultr.htrUL'\ural katures of terminals anterogradely labelled I'rom neurons III the: STN ha vc been characterized III t hL' GPe.277.2RO.2'N III the EP/GPi q,.'".2'J'1 and In the SI\i.'2.IK2.:',,2 As with terminals delived from the striatum and the GP, the morl'lwlog\ and type 01' synaptic specialization are similar ill each l)1 the

targets of the STN and in different species. They arc of medi UIl1 size (0.7 2.5 pm in diamcter), often contain Iwo or three mitochondria and numerous rulllld or slightly pleomorphic vesicles, The most characteristic feature of terminals derived from the STl\ is that they form asymmetric synapses associ­ated with .1 thick postsynaptic dl'nsity and some­times 'iubjunctiol1al dense bodies (Figs :ID F. 4). ".1-1. I' ' . .'c(>.cr':'.:277 .. 2"'.2')" The use of anterograde

transport methods eomhined with post-embedding immunllgold labelling has revealed that subthalamic terminals'!" or terminals with similar ultrastructural featul'C'c"c'" arc enriched in glutamate immul1o­react ivity.

2. SY'\,\I'TOLO(;\ OF THE DIRHI \'\IlI'\()(RHI PATIl\\\ \ S

2.1. Conic(/I il1/!lI1.1 10 .Ilrilllu/llellrolll gi,'illg ri.l(, lu Iht'

rilrel'l Will illriir('cl IJ(/lhll'lll'l

In primates. the somall1SenSlH\, Illotor and pre­motllr c()rtices project somatl1tl)picall~ 10 the' post­commissural region of thl' putamcn.''' '''''I''L .. I')' ,"'" the' associative cortical area:, pl'l)Jel'1 to the caudate nucleus and the I'l)stral putamcn,' 'I.,''',.q, q' and the limhic cortices. the amygdala and hippo­CdmjlUS. lerlll1l1alc preferentially In the ventral striatum,'!'!"·' ".1"1 ,(,' This fUllctillllal segregation of the L:llrtical inputs in the strialulll i, ab() maintained in rats ,me! cats.">.I':.1 'I "1,1·,'"."1 The ncurons that

give risc' tu the corticostrialal projc'ction arc divi(kd into al leasl three major type, hased on their intracorticdl Cllnnect iom. laminar origin and IXlttern of striatal ab()rinltioll, "'.'" Striatal neurolls arc believed to rc'ceivl' inputs from a large number pr cortical fibres, sllggeslil1g that a striatal neuron may increase its firing rate (lnl~ ii' there is aL'livatil\ll uf c()n'vergent input i'r(l111 many different cortical ncurons'"; '1' n'"

(\lrtic,d terminab form aSYl1lmetric synapses primarily with dendritic spines I: I 'n.'x' 3"1 of the l1ledium-:,i/cd densely spiny projection neurons and also with the dendrites of interncurolls. 412s

' In the rat. it has been shown that striatal projection neurons giving ri:,e tll the direct I ,-/ '''1 and thl1se giving rise to the indlrcct' pathways both receivc svnaptic input fn1111 nwtor cortical areas.

Striawl projection neurlll1S <11\' also the malor recipient of other afll:rents nf the striatllm, including the dopaminergic inpul from the SNc.'I"11I4.I'JlI,,'" the sel'lllonergic input from the dorsal raphe. '011 and the excilatory. probably glut'llnalcrgic. inputs from the thalamus')!.1I1S.I"';.'!II."') ", "Ill and amy-gdala,'''' 1",.:,' . .'13 Furtherlllllre. the\, arc also the major recipients or termin,t1s dcri\nl from local (j!\ BAcrgic interneurons. I' "I' "".''''' cholinergiC internellrons'-I·I', 1.2' I,'",' a nd soma Illsta tin-positive interneurons.'" 17 Each of Ihese allcrcnts gives rise t" a specilic pattern of innen'atloll of the spiny

360 y'. Smith ('/ Id.

GABA." ". ··ol ~,·(.b2 Wl •·• ••

.~

• I,. .. . .. '.

, .. '~

'",,' ;.

. den

IIg . .\.

.' . -" .. . ··E·,·:~ ft

F

,

." -; ~, . ~

: '

\'licrocircuitry ()f the h,,,al ganglia 361

neurons~1.:'X5 and contribute to the modulation of the e.xcitatory cortical input to these neurlll1S. '~.5').:' H:'71

Although it is clear that the majority of cortical terminals form synapses with spiny ncurons, ana­tomical data indicate that striatal interncurons immunoreactive for parvalbumin (i.e, GAI3A interneuronsfs,:'9dYJ7,246d or neuropeptide V"~' also

receive cortical input. Although anatomical evidence has not been forthcoming,l% electrophysiological and pharmacological evidence suggesh that choliner­gic neurons also reccive cortical atlt:renh, 71.33' but this input is likely to be sparse and terminate on the distal dendrite,;, Each of these cla~se~ of neurons is likely to feed-forward the cortical lI1formation to spiny projection neurons, 2:"A1. I (<I 11,', I ,

" ,)~\'naptic connectiolls hetll'een stria/ul neurons

gil'illg rise [() the dir{'(t and indircc/ {illl/lll'lll'S

Evidence from morphological studics, including the intracellular filling of neurom'N,{, 1.1 (,<).1 xx. "~ and

Golgi impregnation .. '47,1()1 has shown that spiny

neurons give rise to extensive local a.xon collaterals that arborize within, or close to, their dendritic i1eld and form symmetric synapses with dendrites and spines,1()1."4 Evidence from immun(lhistochel1lical data suggests that spiny neurons th .. lt ~i\e risc ([\ the direct pathways arc synaptically Interconnected. as arc those that give rise to the indirect path­way, 11.~4.:"().".S7.2"3,:"','()7 Furtherl1lure, evidence

from striatal tissue double imlllunostall1ed with markers of the neurons giving risc to the direct and indirect pathways indicates that the t\Vo popuiati'lns are synapticalIy interconnected. I Iq, Since all spiny neurons are GABAergic, these intercllnnections have been traditi()nally ascribed as the substrate for

mutual inhibition between spiny neurons; 115 how­ever. little evidence has been found for surround inhihition arising from their collaterals, I ('2 One possi­bility, therefore. is that the interactions between spiny neurons are mediated predominantly by neuro­peptide transmission and that GAI3A interneurons arc the main source of inhibitory influences on spiny neuron~. 2";.167.1. 17H. 1 X(,

2,), Synaplic orgal1i:::aliol1 of the dll'eer palhll'ul'

The terminals of striatal neurons that give rise to the direct pathway account for the majority of boutons in contact with neurons in the EP/GPi and SNr. and it has been suggested that individual ,triatal axons establish multiple C,)J1tacts with their targets, although there i, still debate over this issue,"-u 11 I I Lc. 1"111.1 0" In the GPi ofsljuirrel monkeys,

it has been estimated that striatal terminals aecollnt fur more than RO'/' , 01' the afferent input to dendrites and 32'~;, of the input to perikarya (Fig, R),'xfI and Cl

similar pattern of innervation is likely to occur in both the Er and SN of rats,~".-l'I"I")·"!)2

Comhined tracing and immunocytochemical studies have shown that striatal terminals in the EP and SNr are immunoreactive for GABA,4"AX,lc~ and

make symmetrical synaptic contacts with EP neurons that project to the thalamus, q,~.'" and with neurons in the S\Jr that project tLl the tilalamus"e.,," the superior c()liiculus."'):', '"I the region of the mesopon­tllle tegmentum 'I' and the reticular formation, ,24

There is likely to be a high degree of convergence in the direct projections from the striatum to neurons in the llutput nuclei, as it has been estimated that the FP and SNr of the rat contain .'2()() and 26100 ncurons respectively, whereas the striatum contains

Fig. ~, Characteristic katurb ui synaptlc boutons (ll' the direct and indirect pathway" Micrographs illustrating typical ultrastructund features. synaptic specialinl1ions dnd neurochemistry of synaptic terminals derived from the ncostri.lIum (A). the glohus pallidus (B, C) and the subthalamic nucleus iD F), The sections illustrated in A, C and F were lahelled hy the post-embedding immunogold method tu reveal GABA immunoreactivity. and the seclilln illustrated in E was processed to reveal glutamate immunore­activity (A) A striatal bouton in the (;Pi anterogradcly lahelled following an injection of BDA in the putamen of a squirrel monkey The bouton is in symmetric synaptlc contact (arrow) with ,j dendrite (den) and i, immunoreactive f()r (JABA, Tw() neighhouring bouton, (bl and h21, which posse", the morphological features of striatalterminab. arc also immut1<lrcactive for GABA, In contras\. the bouton b3 forms an asymmetric synap,e (;IITowhead) and does not display GABA immunoreactivity. This houton possesses morphological features "I' a terminal derived from the STN, (8. C) Terminals derJIed from the GP fl)rming symmetrical synapti, contacts larrows) with a dendritic shaft (den) in B and a perikaryon (peri) in C The bouton in B I' ll'\ the El' :Jnd was labelled after an injection of I'HA-L in the GP of the rat (revealed llsing henzidine dih)drochloride). The houton in C i, in the STN and was lahdkd after an injection of BDA in the GPe 01 the s'luirrcllllonkey, This labelled houton displays a high le\cl 01' CjABA immunoreactivity, 'Jote the similarity 1li the morphological characteristics of the pallidal b(lutOllS. despite the fact that they arc 1'1'0111 ditkrcllt species and in dilrerelll nuclei, (D);\ terminal derived frnnl the STI\, This tLTtllinal i, in the rat Sl\ I ,\lId Ivas 'Intcl'llgradely lahelled I()llowing the mjectiun of biocytin in the STN. It forms an asymmetric s\ napse (arrl'whead) with a dendrite (den) that contailh retrogradely transported h(lrseradish per(lXilLt", (HRP) frnm the \entmmedlal thalamic nucleus. (L I) Adiacent sectiom of the same STN hou1<\I1 In the (;Pe that forms an asymmetric synapSe (arrow headsl. The h'uuton was labelled by tllultin1lldal transport 1'"llowing injection of BD;\ in the GPi of the squirrel nHlnke) , The BDA was transported retrogLldch to neuron, in the STN and thell anterograddy, via axoll C\)IJatcrals. to the GPc, The houton is enriched In glutamate (F), bUl i, not immunoreactive for (jABA it·), \'\ote the similarity in the morphologiul fc,.lturcs of the subthabmic terminals ill dilferent specie, and in ditferent

nllcI- i, SCCllc h<lr in A=II,~ rllll (valid for B I'i,

Y Smith cl uf.

Fig. 4. Synaptic convergence of direct and indirect pathways. These micrographs illustrate synaptic convergence of striatal and subthalamic terminals at the level of single dendrites (den) ill the El' (A) and the S;\Ir (B) of the rat. In these experiments, double anterograde tracing '>'as performed by the injections of PHA-L in the STN (IocaliLed with benzidine dihydrochloride) and biocytin (Bio) in the striatum (STR) (localized with diaminobenzidine). The terminals derived from the STI\ form asymmetric synaptic contacts (arrowheads) with the dendrites, whereas the terminals derived from the stri,ilum establish symmetric synapses (arrows). Note that the striatal bUlIton in B has an irregular shape and is pierced by an unlabelled veside-iilkd proce". Scale bar ill A=O.5 ~lIn (valid ror H). Data derived from

Bevan ,'I Ill. '.'.11

'.k'"!:' , .-.. ~,

c

den

'~~ {Erlo~, ',-I'

"'~ .. ' .... ' ......... '., :~

Fig. 5. Synaptic convergence: of direct and indirect pathways. These micrographs illustrate the synaptic convergence of terminals derived from the striatum (STR) and the GP at the level of individual dendrite, (den) in the El' (A, BI and the S:-.Jr (C) of thc rat. In these experiments, bincytin (Rio) was injected in the striatum and localized \\"nlt diaminobenzidine. whereas PHA-L was deposited in the GP and localized with benzidine dihydrochlorid~. A and B arc adjacent sections that have been immunolabelled to reveal GABA by the post-embedding illlmullogold method. Both the striatal terminal and thc GP terminal form symmetric synapses (aITOIY>I with the dendrite and display GABA immunoreactivity. The dendrite is also postsynaptic to an unlabelled bouton (asterisk) that forms an asymmetric synapse (arrowheads) and is not immunoreactive for GABA. The features of this terminal are typical of those derived from the STN. Scale:

bar in C=O.5 fllll (,,!lid ((l!' A, B). Data derived fwm Bolam and Smith4" and Smith and Bolam. 2

')2

364 Y. Smith 1'/ of.

EP

I.C,

\

Le.

~ L',P·

hg. 6. Convergence (,I' fUllctionall: diverse p,tllidal etJerents in the El' and the STi'-. Schel11atic representations of the mstrocaudal extent of the injection sites of PHA- L in the ventral pallidul11 (VI'; blue (h)ts, left column) and BJ)A in the GP (red dots, left column). The middle and right c"lumns show the resulting anterograde labelling (blue and red stippling) in the El' and ST:--J ,Lt two ditferent rostrocaudal levels. The green dots identif\ neurons that were apposed by \ <ll'lcllsities dcrinxl fl'll111 ollth the VI' and the (jP. Other abbreviations: a." , 'Interior c,)J11l11issure; i.c., internal c<lp:.;uic; c.p" cerebral peduncle. Data

derived I'mm Bev'ln er of."

2.79 x 10" neurons. c.'" Assuming that 90"~, ut' neurons

in the striatum arc spiny neurons I 'c and 50".;, of spiny

neurons give rise to the direct pathway to the EP/ SNr. II ' then 1.26 x ]0" striatal neurons din:ctl y innervate the output nuclei, This gives a ratill or .19:' striatal neurons to one EP neUI\)lJ and 4X stri,ltal

neurons to one SNr neuron, Sincc' it is likely that an

individual striatal neuron makcs synaptic cuntact

with many neurons in the EP and S)\ r. 1(,'1.' ") thcn the

degree of convergence of the direct pathway at the

level of the output nuclei is likely to hl~ much highcr.

However. it remains to be establishcd whether thL:

converging striatal input to ,In individual neurun in

the output nuclei arises frLJtll functiunally related

neurons in the striatum or whdhl:r this convergence

represents a mechanism for the integration of functiunally diverse informati,lll.',s--'-+<J.:''i''

2.4. S1'I1(/ptic urg(/l1i::(/lioll 011/1(' il/(/ircCi flUt/III'Il).1

2.4,1. The !,mjecliolljrOlIl Ihe slriUlI/lII1O Ihe glo/Ju,1

!'ol/idus, The tirst neuronal link in the indirect path­

way is the projection from the striatum to the GP,

Three i'eatures charactcrizc this pro.iection: the dual

pattcrn of arborization, thc high dcgree of specificit)

and thc high density ut' innervatiuJ1. In the ral. aXlln,;

of single or groups of striatall'elb that enter the GP

arhori/e profusely and form two distinct bands llf

anterograde labelling that arc interconnected by thick varico,;e axons,(,-+·llc.,<, There is an indicatilln that

----- -.-- ._-----_ .. _---- ------.. ----..

Fig. 7. Synaptic convergence of taminals derived from different functional dom'lins of the pallidal complex in the EP (A) and the STN (B DJ. lA) Electron micrograph of part of a proxilllal dendrite of a neuron in the cntopcduncular nucleus (EPn). The neurun i, apposed oy three anlerogradely labelled boutons, each of which fornh symmetric synapscs with the neuron (arrows). Two of the boutons (VP) Cllntain the benzidine dihydrochloride reaction product that was used tll localize PHA·1. dnterogradely transported from the vcntral pallidull1 I VP). The third bouton (GP) contains the dlaminobenzidine reaction product that was USc'd to localize the BDA anterograddy transported from the Cip. 'JOle that the benzidine dihydrochloride reaction product has an irregular appearance and occupics only part of the labelled terminals. In contl'a'r. the di'1l11illllbenzidinc reaL·tion product i, ammphoLh and ()ccupic, the whole of the labelled structures. I B D) Part of:1 ncuronal perikaryon in the subth,ilal1lic nllcleu, (STi'-n) that is apposed by three 'Illtl'l'ogradcly labelled terminals (VI', GP). Two of them an: ,llllwn at higher magnification in C and D In tillS animal. the injectiom ' .... ere rewrsed, i.c. thl' I'll "-I (i,)caitzcd with benzidine dihydrochloride) WdS injected in, ,md ankrogradely transported from, thc' (jp and the BOA (localized with diaminobenzidine) wa, injccted in, and anterogradely transported I'rom, thl' VP One of the boutons (C) contains the aiTlOrphou, diaminobel17idim: re,lction product, identifying it ,IS arising I'rolll the VI', whereas the other two boutons arc strongly labelled with the cryslalline benzidine diilydrochloride reaction product, indicating Ihat they ari,e from the GP Ithe one on the Idt is illustrated 'It high magnification ill D). The thll'(' I<lbelll'd terminal> form symmetric synaptic contacts with the neuron

(arrows). Scale bar.s= I plll 11\). :2 pm (H). I 1.1111 (D: valid '<'r C). Oat,! derived fl'lllll Be\an er (If."

\11icrDcircuitry t)f the ba~al ganglia 365

Fig 7

Y. Smith 1'1 ul.

GPi / SNr

Fig. 8. Diagrams summarizing the ovnall pattern of inner­vation of projection neurons in the GPe and the GPi. These diagrams are based on data obtained in the 'ljuirrd monkel­by means of anterograde tracing and post-em~e~I~\~1~!Xi~,;~ munogold labellmg for GABA or glutamate.- ... . Evidem:e indicates that it is likelv that neuron, of the GP and the SNr of non-primates als,; relTlve " similar pattern of innervation (see text for more ddails). The relative ,i~e, and proportions of each category 01' tcrnllnal are repre­sented in the diagrams. The major difl'crcncc between the innervation of neurons of the GP" and GPi j, that the I"ller receive a high proportion of their input at the level [If the perikaryon from the GPe, wherea', tennimlis derived 1'1'<1111 the striatum and the STN are relativelv ewnlv distributed on GPe and GPi neurons. Although I{Ot indi~ated ill thi, diagram, terminals derived ti-om the (;Pe "ho ma~c synap­tic contact with pr'Jximal dendrite', and. <1 I1x'it to a le"er extent. distal dendrites. For the sake ul' clarity, the b, well characterized inputs from the raphe, I'PN. SNc and thala­mus have not been included. Data dCIIVed from Shink and

Smith.'""

this is also the case in primates, 23~ Although it appears to be more complex, a similar pattern of organization has been observed in the SNr. 1 L',ltX The high degree of specificity of the ,triatofugal projec­tions has been demonstrated in experiments that involved small injections of two anterograde tracers in close, but non-overlapping, regions of the stria­tum,112,15' The anterogradely labelled libres that

arise from these injections form dense bands of staining that are largely segregated in the GP and also in the output nuclei of the b,lsal ganglia. These findings suggest that the information arising from small pools of striatal neUllJ11S is transferred with a high degree of specifiL-ity to restricted parts of the GP. However, there is probably a high degree of synaptic convergence in the GP_ as the ratio of striatal neurons to neurons of the GP is

about 27:1.216 Striatal terminals form symmetrical synaptic con­

tacts with all parts of neurons in the GP, as shown by immunostaining for enkephalin, and account for the majority of boutons in contact with them,'7,107 In the

GPe of the squirrel monkey, striatal terminals have been estimated to represent over 80'/'" of terminals in contact with perikarya and dendrites2KO (Fig, 8), The ultrastructural features of the striatal terminals in the GP are typical of those in other nuclei (see above): they are GABA immunoreactive46 and have been shown in the rat to make synaptic contact with pallidonigral neurons. 319

2.4,2. The projection /i-ol/1 rhe glohus pallidus 10 the suhthalamic l1ucleus. The projection from the GP to the STN represents part of the "classical" indirect pathway_ Both the GP and the ventral pallid urn (VP) give rise to massive topographically organized pro­jections that terminate throughout the entire extent of the STN. In the rat the terminals arising fr0111 neurons in the GP are distributed according to a mediolateral and rostrocaudal topography?94 On the other hand, the dorsolateral part of the VP projects to the dorsomedial part of the STN, whereas the ventral part of the VP is connectcd with the adjacent lateral hypo thalamic area, 126, I_~') Similar relationships have been described in monkeys. D6 The pallidosub­thalamic fibres characteristically possess large vari­cosities, which are sometimes grouped to ensheath the perikarya and dendrites of STN neurons. 13.294

Single GP axons may give rise to several varicositics apposed to the surface of a single neuron in the STN.2"4 Pallidosubthalamic varicosities have thc typical ultrastructural appearance of pallidal termi­nals (see abovc), are GABA positive and form syn­apses with all parts of STN neurons,,3,2Xl,294 In the

rat, it has been estimated that ~I';-;J of pallidal termi­nals form synapses with perikarya, 39% with large dendrites and 30'/;, with small dendrites,294 Prelimi­nary findings indicate that terminals arising from the GPe in the squirrel monkey display a similar pattern of distribution in the STN.2HI Some of the GPe terminals form synapses with \'esicle-containing pro­mes in monkeys281 and cats,225 but this type of synapse has not been observcd in the ra1. 3o,294 Many of the STN neurons that receive pallidal inputs project back to the GP_ m .l2 '.:!]] indicating that the

relationship between neurons of the STN and the GP is, at least in part. reciprocal (see Section 3), Conver­gence and divergence is likely to exist in the system as in the rat, the ratio of the number of neurons in the GP to the number in the STN is approximately 3: I :'11> and an individual neuron may contact multiple subthalamic neurons.'),IX)

2A.3 The projection from the subthalamic nucleus to ha.wl Kal1Kliu output nuclei. The major projection sites of the STN are to the two output nuclei of thc basal ganglia, i.e. the EP/GPi and the SNr, as well as the GP. Additional projections to the stria­tun1. 20. I X2,24,~.29~,2')() the SNc. I ;or). I H2.221.264,286,:?9:" the-

pedullculopontine nucleus (PPN)14A.I,2,244 and the

spinal cord,'I(, have also been described, but will not be con,idered further here.

V1icrocircuitry of the basal ganglia 367

In the rat. STN neurons are highly collatcral­ized.x2.'47.'Hu:,:, Intracellular labelling,'47"s, electro­

physiological analyses82 ,'46 and tracing experiments in which the tracers were transported in a multimodal fashion32.14.48.w indicate that single ST'-J neurons send axon collaterals to the GP. EP and SNr. The situation has been proposed to he different in pri­mates, primarily on the basis of retrograde double labelling methods.241.244.24) Thus, neurons projecting

to the GPe and those projecting to the SN were found to be spatially separate populations within the STN of squirrel monkeys.244 Similarly, ST'-J neurons pro­jecting to the GPe have been proposed to he segre­gated from those projecting to the GPi.241.24' However, in the latter case the conclusion was based on injections of fluorescent tracers in different func­tional domains of the GPe and GPi which would result in the retrograde labelling of different regions of the STl\. Indeed, the results of tract-tracing exper­iments, in which the multimodal tran,port of HDA was utilized (see Section 1.3), indicate that in pri­mates as welL single neurons in the STN project to both the GPe and GPi, and do so primarily to related functional domains:'77 (see Section 3). It remains to be established whether neurons in the primate STN project to both the GPe and SNr.

Axon terminals in the basal ganglia output nuclei and the GP that are derived from the STN display common ultrastructural features (Fig. 3D-F). arc enriched in glutamate immunoreactivity and form asymmetrical synaptic contacts (sec abovc). In pri­mates, they account for approximately 10';'1> of the total popUlation of terminals in the GPe and GPi, and arc evenly spread over perikarya and den­drites2XIl (Fig. 8); a similar distribution has been observed in the rat. 1:', 14 Combined tracing studies

have demonstrated that they make direct synaptic contact with neurons in the EP and Sl\ r that project to the thalam liS. 12,34

2.4.4. The projl'Ction from rhl' g/ohu.I pallidus to rhl' I'ntopeduncu/ar nuc/ellslintl'rna/ pallidwlI. In addition to the "classical" indirect pathway, consisting of projections from the striatum to the (;P, the GP to the STN and then the STN to output nuclei, cortical information may also influence the output of the basal ganglia by the projection directly from the GP to the output nuclei. A direct projection from the GP to the EP or GPi has been des\.ribcd in both rat4X .4Y.I74, I X5,29(1 and monkey. I 54.:r.',2"'.2%.2'J" In the

monkey, this projection is organi;:ed according to a strict dorsoventral and rostrocaudal topogra­phy.277.299 In the rostrocaudal plane. the GPe cells

are located 0.5-1.0 mm more rostral than their ter­mination area in the GPi. 277 The principles of organi­zation of the projection from the (JP to the EP/GPi arc discussed in Section 3 (Fig. 11).

Terminals from the GP that make synaptic contact with EP/GPi neurons display the typical ultrastruc­tural features of pallidal boutons, forming sym-

metrical synaptic contacts and dIsplaying GABA immunoreactivity. In the monkey, they form short symmetric synapses predominantly with the proximal part of GPi neurons,277.2XO,299 and have been esti-

mated to account for 48'j';, of the total number of terminals in contact with the perikarya of GPi cells and 5'~/" of the axodendritic synapses2HO (Fig. 8). In the rat, the v are more evenly distributed on neurons of the EP~4H.4'J Single ne~ronal perikarya in the EP/GPi are tightly surrounded by dense aggregates of pallidal terminals that often arise from single pallidal axons.·+',15429'1 It is clear from single cell labelling

studies that individual GP neurons may contact multiple neurons in the EP."·' HS Small neurons in the GPi of monkeys, which arc presumed to be inkr­neurons .. '~' I(JI do not appear to receive input from the (iPe.:'XIl

2.4.5. The projcction ji-OIl1 Ihl' glo/Ju.\· pallidus ro Ihe .I'uhslallliil Iligra. Analogous to the projection from the GP to the EP/GPi, the existence of a projection frum the GP (or GPe) to the SN has been demonstrated in various species by means of both retrograde 1'7.1) 1.24(U7.',,1()~,' 11.11 'J and anterogradt; tracing.'6., '''.2K'J,291.2'12,324 Filling of single neurons in

the (JP of the rat has shown that the axons reaching the SN arc collaterals of the pallidosubthalamic projection. i5.1 K5 Anterograde tracing studies ha vc revealed that the pallidonigral projection IS organized according to an inverted dorsoventral topogra­phy .4'112'), I '7,2X'I,2'112'J2,124 and cell-filling studies indi-

cate that individual GP cells terminate over a large rostroc<ludal extent of the SN. ".I~·

Pallidonigral terminals display ultrastructural fea­tures typical of boutons derived from the GP, they form symmetrical synapses and are rich in GABA immunoreactivity. They make contact predominantly \\ ith the perikarya (59'Y.,) and proximal dendrites cn'~/;,) of SNr neurons, but much less frequently (4'Y.,) with distal dendrites 4 'I:'K".'J)' They display a

basket-like innervation of their target neurons, with a single axon sometimes forming tllany contacts with the cell body and proximal dendrites of individ­ual SNR neurons. The neurons postsynaptic to the pallidal terminals have been characterized as project­ing to the thalamw" tectum, PPN and reticular formation. 1'),:"11 ,:'4

2.4.6. The projection from rhl' gl()hu.I pallidus to rhe reticular IJUclcus of'lhe rlw/a/l1us. The existence of a projection from the GP to the reticular nucleus of the thalamus (RTN) was first proposed in cats on the basis of the anterograde transport of tritiated amino acids from the GP. :'32 More recent findings obtained by llleans of retrograde and anterograde tracing techniques conflrmed that the R TN n:ceivcs an input from the GP in rat,12,1).72,11I'),2 7(. catY! and mon-

key11,14152 The projection is organized according to a rostrocaudal topography'-I.I:u772 and uses GAHA as a neurotransmitter. 13, I 5,.17 Anterogradely labelled

Y Smith Cl !I/.

pallidoreticular boutons display the typical ullra­structural features of pallidal terminals, form sym­metric synapses with the perikarya and proximal dendrites of RTN neurons,I'.I"'· and an: immuno­

reactive for GABA. I"'7 A smlll propllrtion of labelled terminals form asymmetric synapses with distal dendrites. 15 These termin~tls probably arise from the cholincrgic neurons of the basal forebrain which, in lhe rat and cat, ~trl: intermixed with the GABAergic neurons of the GP. 17.'1' Indeed. the

ultrastructure of these terminals i, similar tll that of cholinergic boutons described ill other ';ludies. II

'

These findings suggest that the information I'rom the basal ganglia can reach thalamocortical cells, not only via the EP/Gpi and SNr. but also via the pallidoreticular projection. Whether or not the information flowing through the F.p/GPi dorsal thalamus and GP RTN thalamus pathways C·.)Jl­

verges on common populatilllls ,,1' dorsal thalamic neurons remains to be established

2.4.7. IllIril1.1'ic aXIJn col/alerll/I of g/ohu.I !lldlidu.1 ncurons. The majority of neurons in the GP possess local axon collaterals. '5.<)1.10'.1~' '.'().:~" The axons

may innervate widespread or more restricted regions of the nucleus and form dense clusters of terminals on the proximal regions of a small number or neurons."·IS5 Boutons presumed tu be derived from local collaterals display ultraslructural features or pallidal terminals and have been cstimatcd to repre­sent ]()'/';, of the terminals in contact with the perikarya of GPe neurons in the squirrel monkey"" (Fig. R)

2.4K Olher ,jjcrml projectiolls of liIe glohll.1 {la/fidus. The existence of a topogr~jphically organized GABAergic projection from the GP to the dorsal striatum or from the VI' to the wntral striatum has been described in retrograde and anterograde tracll1g studies in rat.,)4;1.69.1~l).2~X.2k~.'.j()."() catl')l)~.I(l' and

monkey. I'U40 .. '<J61OS Some of the pallidal cells pro­

jecting to the striatum send axon collatcrals tu the Sl\.'5.'11 the STN" 1,5 or the cerebral eortex.'n

Houtons in the striatum that arc dnived from the VP have been shown to mainly form S\l1lmdric synapses predominantly with dendrites alld less frequcntly with somata of projection neumllS in the rat. 1,,-1 In

line with these findings. light microscopic obser­vations 129 '5X.2% and electrophy,iological data 11.'

suggest that striatopallidal and rallidostriatal projec­tions are reciprocal. Preliminary findings indicate that the NADPH-diaphorasc-colltaining interneu­rons as well as spiny neurons receive pallidal inputs in the rat. '·lAU 12 Furthermor,:, a single cell-filling

study suggests lhat GP terminal" in the striatum preferentially innervate the parvalbull1in-positive and nitric oxide synthase-positive interneurons."

Although the bulk of basal ganglia afferents to the mesopontine tegmentum arises f'r0111 the EP/Gpi and SNr (Fig. I L a minor projectionl'rol11 the GP has also

been described ."24.27.' I n the ra t, this projection is

GABAergic and arises from the caudal part of the Gp.c2.1 276 Those GP neurons that project to the PPN

send axon collaterals to the STN and the SNr. but du not project to the auditory cortex'.'··I..'72

2.5. ,'hIlOplic COl11'ergellce of direCI £111£1 indirecl flu/fI­ll'lll'l Oil hasal gallglia '1l1/pUI lI"uro/l,\

The response of output neurons of the basal gan­glia to striatal stimulation is not simply decreased firing due to activati()L1 or the direct pathway or increased tiring due tu activation of the indirect pathway. but ralher individual neurons respond with increased and/or decreased liring depending on the site of stimulation in the striatum or e<)r­lex."!,I"""".:'(,!.",X.l.'" Indeed, in behaving animak

output neurons exhibit complex palkrns of increased and decreased tiring. 'I, 111l.' I' :.'2 These findings.

together with observations cllncerning the tnpo­graphical organization of thl' direct and indirect pathway." raise the possibtlity that individual neurons in the output nuclei receive convergent synaptic input fl'om both the direct and indirect pathways.

2.5.1. Convergellcc or SlIhllllllamic alld l'lriawl lermilluls (Ill illdividual ha.\"({1 gUlIglia out/JUI I1(,UI"OIlS.

Doubk anterognlde tracing has demonstrated that lleUrLlllS of the striatulll (direct pathway) and STN (indirect pathway) innervate common regions of thc EP/CiPi or SI\r.,.'q·I" Electr()n microscopic analy­

ses (Fig. 4) havc demonstrated that the terminals deri\L~d from the striatum and the ST"J form conver­gent synaptic contacts with individual dendrite, and perikarya in both the El' and the SNr, and at least some of these neurllns have becn identified as pr01ecting to the ventral medial nucleus of the thalamll'. \2.'4

2.5.2. COl/vergcncc of pallidal und slrialallermina/l Oil im/iridzwl hawil ganglia ()Ulplilll('urOl1s. In addition lo the indirect pathway that includes the STN, syn­aptic convergence between the direct and indirect pathways mediated by the projection from the GP to the output nuclei has beell demonstrated in the ral.-H-I"2'".3~'4 Thus, deposits of tracers in the stria­

tum and GP lead to largely merlapping fields of anterograde labelling in the El' and SNr. Electron microscopic analysis has demonstrated that both striatal and pallidal terminals make convergent syn­aptic C,lntact with the perikarya and dendrites ut' individual neurons in the El' and SNr4~A~2,),.'21

(Fig. 5). Some of the postsynaptic neurons in the SNr have been further characterized as projecting to the superior colliculus or the reticular J"ormation.:H

,-,. l1.!

2.5.3. COli vergence o( suhllwlalllic. pallidal and slriallll lerminals Oil indil'itiulll ha.lal ganglia OUlpUI IICUroIlS. In simple ultrastructural analyses of basal

Microcircuitry oj' the basal ganglia

ganglia output neurons in the EP/Gpi or SNr. individual neurons are seen to receive synaptic input from terminals that have the morphological features of all three classes of terrninab that mediate the direct and indirect pathways. i.c. striataL sub­thalamic and pallidal terminals. On the basis of data from double anterograde tracing studies in which the multimodal transport ot' tracers injected in the GP or the STN has occurred (sce Sectilln ~). it is evident that individual output neUHllh in the El' or SNr that receive synaptic input frolll the striatum also receive synaptie input from tnminals derived from the STN and the Gp':>·l.\Ak.-1·) H)·.12·~ (Figs 4.5).

These findings indicate that groups Ill' Ileurons. in the GP. STN and output nuclei, arc Iib:ly to he reciprocally connected.

2.6. Sl'l1apfic COI1Vf!rr;CI1CC 0/ df!SCCllilillg jllllcfiOlllll/.1'

divc!'se injimllation IIrising jrum rhe gIll/mol pa/fiill/.I

(/nd 1'Cl/lra/ p(/I!idum

It has been suggested that fUllctinnally diverse information arising from thc cCTcbral cortex is processed in thc basal ganglia bv parallel and segregated cortical basal ganglia thalamocortical 100ps."·'·12,.I".II,I,.11>7 However. it is clear that the

basal ganglia integrate function;llly diverse infor­mation derived from dilferent cortical regiom !ll

genera te con tex t -dependen t. gll;d -cl i Icded pa t terns of behaviour. ' (··'2.;.:,c'.'7,u 1

<J Anatomical ,1l1alyscs llr

the basal ganglia have identified s\:vcnil neuronal elements or systems which could provide the morphological basis or such illtq!ratillll. rhese include the local circuit neurons ut the ncostria­t um:~ 1."1>.1 I 1.1 "k.1911 the ascending prnjl:ctions of mid­brain dopamine neurons,III,.I"'_-·".".,.,,(' the C;Pi

()utPLlt to the PP'J'7X'7'J and open-interconnected cortico-basal ganglia thalamocortical loop,_' (,',11,7

It has recently been demonstrated" 'I, that the descending projections of the VI'. which largely receives limbic cortical aflerents via the nucleus aecumbens.6"~x and the GP, which receives Illostly

sensorimotor and associative alfcren t'i vi,1 the neo­striatum",·s."2.'2k.'5'.Ii,,,.,,,7 may prllvide a mor-

phological basis for the synaptic integration of runctionally diverse information in thc' ha,;tl ganglia. Thus. double anterograde tracing from the two divi­sions of the pallidal complex in individual animals revealed, in addition to the well estahlished topo­graphically segregated fields of anterogradely lahelled terminals in the El'. STN and SN, /llnc'S of overlap of the two projections (Fig. 6), Electr,lll microscop) demonstrated that in the regions \11' overlap in each nucleus the proximal parts of many nCUfllllS. includ­ing tyrosine hydroxylase-immunoposltive neuron, in the SNc, received convergent svnaptic input from hoth the VP and Gp,3'I, (Fig. 7).

Another way by which EP, ST'J and SN neurons may integrate functionally diversl~ inl'l)rmation from

the pallidal complex is via their dendrites, as they also receive pallidal inputs'" '''AK_~'') .. '')I and are often

oriented to cross the functional houndaries defined by pallidal inputs. 1 i.I11.1 k 1:'2').:" I

In monkeys, projections arising from the associa­tive and limbic territories of the GPi converge on common regions of the thalamus. lateral habenular nucleus and pPN,c7f; .. ~7".'X1 This Illay also underlie a

mcehalllsm for the synaptic convergence of function­ally diverse information ill the output regions of the basal ganglia.

2.7. The ('()!'lico.llIhr1i(/lallli( prujcclioll: 'Ill aJdiliollill

illdireef pil/fllm.\'

Although tht: striatum is comlllllnly seen as the main entrance of cortical information to the circuitry of the basal ganglia, the STN ab" receives excitator) glutamatergic projections from the cerebral cor­tex.'II.\'''; Anatomical evidence indicates that the conicosubthalamic projection is exclusively ipsilat­eral. '.<01 ','.1.\') In contrast to the eorticostriatal prolec­

tion which arises from the entire cllrtical mantle. the corticosubthalamic projection is largely derived fmm the primary motor cortex. with a minor contribution from the prefrontal and premotor cllrtices,'·I';').I')1 '11

hut not somatosensory or visual ((lrtical areas. '.1'\" In both rat and monkey_ the corticllsubthalamic projec­tion is topographically organized. sn that afferents from the primary motor cortex arc confined tll the dorsolateral part of thc STN: the prl't1lotor area, the supplementary motor area ,lIld adjacent frontal c'ortical arcas innervate mainly tlie medial third of the nucleus, whereas the prefrllntal limbic cortices project to its medial-nll)st tip.' '7 I~').' '1 Like tIlt:

cortical input to the striatum. the corticosubthalamic projection from the primary motor cortex is somatll­topically organized: the face area lies laterally, the ,Irm area centrally and the leg area medially.'.\":'" In line with these anatomical findings. neurons in the dorsolateral part uf the STN rc'spond somatotopi­cally, with increasl.'s in discharge tll sensory stimu­latillI1 or active movements llf dilkrent blldy parh. \-:0]n contrast nCllr()n~ lucatcd 1110re rnedl­,illy arc not alfeeted by somatosensory stimulation ;lnLl skeletal muvcments, but sOllle respond to vi suo­oculomotor tasks, which implies that they may be involved ill the control of visual saccades.:'11

The exact cellular origin and degree of collateral­ization llf the corticosubthalamic projection arc still poorly understood, Double retrograde labelling in the rat''' has shown that the l'orticosubthalamic neurons are mainly located in layer V and that many of them send axon collaterals to the striatum. Other findings in cats suggest that the eortieosub­thalamic axons detach from the pyramidal tract. I 'Il which indicates that the S TN. as is the case for the striatum,' ")fI.7f1' is directly intlucnced by copie,;

of cortical signals descending to the spinal motor centres.

370 Y Smith ('/ "I.

Corticosubthalamic terminals arc small boutons packed with round electron-lucent vesicles, and form asymmetric synapses with thc distal dendrites and spines of STN neurons. 3

1.:'61 In primates:''' '.2"1 and cats,2:'5 but not in rats,'1 about 100;;;i of the cortical terminals form synapses with vesicle-Illled structures. The corticosubthalamic terminals arc enriched in glutamate immunoreactivity.' 1 The same postsynap­tic structures that receive cortical input also receive synaptic afferents from boutons that have the morphological and neurochemical characteristics of pallidal terminals. 3 I

The intralaminar nuclei of the thala-mus, 31.93.127.22H.269.31' the dorsal raphe, I '9. I'm the mesopontine tegmentum''')' I 9'):' I (, .'2 >.' I~. "" and the dopaminergic cells in the Sl\,C(,j)·h I I 'ii. I S'Ja.:'<>I also

innervate the STN. The projection sites of STl\, neurons that receive

cortical input still remain to be establishcd. although it is likely that in the rat. hoth 'iuhthalarnopallidal and subthalamonigral neurons receive common cor­tical inputs, since single STN lIcurons send axon collateral, to the GP. EP and S:--.Jr (sce Section 2.4.3.). In line with these anatomical ohscnations. stimu­lation of the sensorimotor cortex induces short­latency exeitatory postsynaptic potentials in the different targets of ST\I neurons in this species. IKO A characteristic of the corticosubthalamie projection in the rat is the widespread excitatol'y influence gener­ated in the STN following stimul~ltion <)1' a single site in the sensorimotor cortex. Hie' Although it is dear that inputs from different cortic,t1 areas arc largel) segregated in the STN, >. 14') the existence <)1' intra­n udear axon eollaterals I x I and thl' large extent ()f the dendritic tree of single STN neuronsc," 117 I x 1."'<, arc

features that mav account for the l!eneralized d'fcct of cortical excitati~n. I07,IX(J Whethe'r similar respollses occur in primates remains to he established (sce below). The recent data sh,)win;.>: that single ST:--.J neurons innervate interconnected territories of' the GPe and GPi277 suggest that common cortical inputs may be conveyed to hoth pallidal segments I see Section 31.

3. "ifTRONAL NETWORK 1I"'DERLYI1'I<G THE INDIRECT PATHWA'S

3.1. Basic circuit under/1'ing the indirect par/l\\'ar"

The synaptology and tract-tracing data sum­marized above conllrm the existence of the "indirect pathway" of information flow through the basal ganglia and. furthermore, demonstrate its existence at the synaptic level. The data also indicate that there are several routes hy which c()rtieal information ma) he transmitted through the hasal ganglia which, on a hypothetical hasis, may give rise to increased liring or hasal gangJia output neurons and hence to inhihitioll of the targets of the hasal ganglia. It is dear from the extensive studies or the synapt(llogy of this system that each indirect pathway cOllverges. at the synaptic level. on to individual output neurons of the ba,.;al ganglia and that terminals or striatal neurons that give rise to the direct pathway make convergent synaptic contact with the samc output neurons. Thus, individual output neurons of the GPi or EP and S:--.Jr arc the common target, of the direct and indirect pathways.

The existence of IDultiplt: indirect pathways through the basal ganglia. however, does not imply the existence of multiple, unrelated, parallel path­ways hut. rather, the findings sUlllmarizt:d above indicate that the lllultipk indirect pathways are inti­mately interlinked. Data derived from the tracing and synaptology studies in tbe rat (sce above for refer­ences) and the squirrel monkey''" kad to the con­clusion that the multiple indirect pathways arc in fact component'; of a highly interconnected system and should he considered as an ""indirect network". The findings in the rat that lead to this conclusion are a, follows. (I) Two components of the indirect path­ways, namely neurons of the (iP and neurons of the ST'\!, make convergent synaptic contact with hasal ganglia output ncuroll'i in the EP and SNr. (2) The multimodal transport of the tracer, has demonstrated that the groups of neurons in the GP and STl\, that give rise to the convergent projection in the output nucki arc themsclve'i recipn)L'<llly interconnected.

Fig. 9, Neuronal network underlying the interconnections between the- STN and the two segments of the GP in monkeys. Schematic drawings of the GPe and GPi (AD) and the STN lE F) of the squirrel monkey illustrating the distrihution of labelled fibres (sinuous lines) and perikarya Ired dots) following injections of BOA in interconnected regions of the sensorimotor territory in the GPi lA. C. E) and GPe­(B. 0, F). The deposits of BOA in the GPi (e) led to the retrograde labelling of cell bodies in both the GPe (A) and STN lE) by retrograde transport of the BOA and. by multimodal tran,sport, led to the labelling of terminal 11elds in both regions. Thus. the terminal 11eld in the GPe was derived from ncurom in the STN that had retrogradely transported the tracer and then anterogradely transported it, and the terminal licld in the STN was derived fnlm retrogradely labelled neurons in the GPe. The dep"sits of BOA in the GPe (B) led to retrograde and anterograde labelling in the ST1\ IF). and to lahelling of termmal 11elds in the GPi (D) by anterograde and multimodal transport. The location of the injection ,ite in the GPe corresponds to the position where the rctrogradcly labelled celb arc found after injecLion in the GPi (compare A and B). As predicted from functional topography, the labelling in the GPi (D) after injection in the GPe (B) occurred in th,' same region as the injection site in the GPi (C). Similarly. the rdrograde and anterograde labelling that resulted from injection, in the GPi and GPe are in register in cOITc>ponding regions of the STN IF F) Isec for dC'tails). The anteroposterior coordinates for each ,,((inn are ll1dicated

in parcnlheses, Data derived from Shink ('/11;,·'7'

A (A 11,0) B (A 11,0)

C (A 10,0) o (A 10,0)

E (A 7,5) F (A 7,5)

le

'"',,"' ...... STN

A-

, .~'1

,,....<..;.,,... . . (

GASA

. ;.

"

. '

SN

li" .

Y. Smith cl Ill.

~-.. -

.' .. .... ,. • ~i(, '

., ,

.. I '~, .,' III ,

~ jIo ,1

..... , •• ..-••. 1 • • '

t I, " ,. :rlI! '"

.......

fig Ill.

Microcircuitry of the basal ganglia 373

Fig, 11, Neuronal network underlying the interconnection> between the STN and the two segments of the GP in monkeys, Summary of the relationships netwecn the GPe, STN and the basal ganglia output nucleus, the GPi, as revealed by injections of BDA in fUllc\lon,tlly rcla\cd re­giom of the GPi and GPe ill squirrel monkeys,"" (iroups of neurons ill homologous functional wnes (If the ClPe 'lI1d STN are reciprncally connected and innervate, via axon collaterals, common, functionally hom"lo~()us regions in the GPi, In addition to this system, there is also evidence for connections between functionally non-hon1l'logolls regions of the pallidal complex and the STN hee text) lurther­more, when considering topographical relationships it shlmld be remembered that the dendrites 01 nellr()ns in the pallidal complex and STN arc very long and often oriented to cross functional boundaries. The bldck .lIT"VI indicates the inhibitory cOllnections of the GPe and the white arnlV> indicates the excitatorv connections of the '-iTN. Redr,lwn

f'n;t11 Shink Cl ,,/.-'--

The findings in the squirrel monkey that support the notion of an indirect network are derived from the tracing study of Shink et al,,277 in which thc connec­tions between the two segments or the pallidal com­plex and the STN were examined, The kcy findings are as follows, (I) Tracer deposits in 1 he GPi led to clusters of retrogradely labelled neurolls in hoth the GPe and the STN (Figs 9A, C. E. lOA, B, 0, E), (2) The retrogradely labelled nCl1fl>ns were <':0-

distributed with clusters of labelkd terminals (Figs 9A, E, 10), (3) Electron microscllpy and post­embedding immunocytochemistry identified the majority of terminals in the GPe as having arisen, by multimodal transport, from neurons or the STN (Fig, lOF), whereas the majority of labelled terminals in the STN were derived from neUl'lln, in the (iPe

(Fig, IOC), (4) Tracer deposits in the GPe led to retrograde labelling of neurons in the STN that were co-distributed with anterogradely labelled terminals derived from the same region of the GPe (Fig. 9B, 0, F), (5) The same deposits of tracer in the GPe gave rise to a cluster of terminals in the GPi (Fig. 90) that were derived from both the GPe and, by multimodal transport. from the STN (Fig, 9), Thus, in the squirrel monkey, as in the rat, reciprocally inter­connected regions of the GPe and STN converge on the same region (and probably the same neurons) in thc GPi, Furthermore, this organizational principle largely maintains the functional topography of both segments of the pallidal complex and the STN (Fig, 11). Thus, groups of neurons of the GPe are reciprocally connected to functionally related groups or neurons in the STN and both sets of neurons innervate common groups of functionally related neurons in the output nuclei of the basal ganglia.

Although there is clearly much to learn about the intrinsic physiological properties of cells in the GPe, STJ\ and output nuclei and their responses to aifer­ent synapti<.: activity, these data may partly provide the anatomical substrate for the complex sequences or inhibition and excitation that are observed in individual GPe, ST.\I and output neurons fol­lowing electrical or pharmacological stimulation of the cortex or striatum and normal movement he ha vio UL (l7, 77 .7N.J·m. I O(),! 07.1 7'J. 1 RA-. 1 ~! .:266.2() 7. 1:20. 1:2X,3~~q

Studies by several groups have: demonstrated that the first response of GPe, STN and output neurons to cortical stimulation or stimulation or coni<.:ofugal fibres is a brief period of exci­tation,l"I.,l()7,t79,lo7,266.2(,7. D ) This effect appears to

be mediated by the corticosubthalamic pathway, which excites subthalamic neurons, and these, in turn, excite GP/GPe neurons and neurons in the output nuclei,llJ6,)U7,l79.lK7,c(,6,2"7,'2o The conduction

speeds of this system are faster than those of the pathways 110wing from the eortex through the stria­tum, t06.11l7,17'J.tk7,2(,6,2(,7,'20 This brief period of exci-

tation is terminated and followed by a longer period or inhibition, which is mediated in part, by the

Fig, 10, Neuronal network underl)lng the interconnectill!1s between the STN and the two segments of the GP in monkeys, Retrograde clnd ,mterngrade labelling in the STN (A -C) and GPc (D F) following injections of BDA in the sensorimotor territory of the GPi, (A) Cluster otlabelling in the dorsoi<lteral part of the STN, At higher magnification (B), this cluster is seen to contain both labelled (am1ws) and unlabelled (arrowhead) neurons in a field of varieosities which became lanellcd by retrograde transport of the tracer to the GPe and then anterograde transport tp the STN, (C) An example of the major type of terminal that was labelled in the STN following injection of BDA in the GPi, The bouton display, the ultrastructural tCatures of terminals derived from the GPe (see Fig, 3B. C), it is in symmetrical synaptic contact (arrows) with a dendrite (dl) and displays GABA immunoreactivity, The terminal labelled G+ is also immunoreactive for GAB/>., vvllereas the terminal indicated ny (J-- and the dendritic shafts Id) do not display GA.BA immunoreactiv·ity. l l), E) Cluster of labelling in the central part of the GPe thal occurred following the tracer deposit in the GPi, The cluster contains both rdrogradely labelled perikarya and a population of varicositics thal bt'came labellcd f()lloVl ing retrograde transport to the STl'< and then anterograde transport to the GPe, I F) I:::lcctr'lll micn)graph of the major type of terminal labelled in the GPe after injection of BDA in tire GPi, The bouton displays lhe ultrastructural features tvplcal of termin'lb derived from the ST),; (sec Fig, ."\D F) and fnrms an asymmetric synapse with ~l dendrite (d), Scale bars= I ,n mm (A), 100 fll1l (Iq, (J,) .Ul11 (C: v~Jlid f,)r F), 250 ,lm (D), 20,1l11 (F) Data derived from

Shin!" e/ <le

374 ''t'. Smith <'I ill.

activated population of GP/GPe neurons that pro­vide feedback inhibition to the activated population of subthalamic neurons, in turn leading to reduced excitation of neurons of the GP/GPe and the output nuclei.l06.107.179.1H7,266.267.320 Since the activated GP/

GPe neurons that provide feedback inhibition to the STN also project to the population of activated neurons in the output nuclei, they may also contrib­ute to the inhibition of neurons in the output nuclei.

Of course, the major route of cortical influence on the basal ganglia is through the ~triatum, and it has been shown that the long periods of inhibition of the GP/GPe and neurons in the output nuclei that occur following corticostriatal activation and follow the initial period of excitation (see above) are a result of striatal-mediated inhibition.",,106.17g,='''7Y'O Synchro-

nous inhibition of GP/GPe and output neurons would hypothetically result in a period of decreased tiring of GP/GPe and neurons in the output nuclei. This period of inhibition of output neuron tiring is associated with the disinhibition of basal ganglia targets and movement. o.7.f>7,<,H 76.:- U39 Since the in-

direct pathways are likely to tcrminak on function­ally homologous populations of output neurons that are targeted by the direct pathway'23HH.2"2 and an.: likely to exert their effects aftcr thc direct path­way."7,1()".1"7.1~4.266.267,320 then the final period of

facilitation of firing that is observed in the STN and output neurons following cortical activation might be mediated by inhibition of GP/GPe neurons (scc above; indirect pathway), This inhibition would act to disinhibit neurons in the output nuclei and STN neurons. Presumably, disinhibition of the STN would further supplement the facilitation of basal ganglia output neurons by increased excitatory drive. The increased tiring of neurons in the output nuclei. and the consequent inhibition of basal ganglia targets, may then act to terminate or inhibit the behaviour associated with the activation of the direct pathway. The restoration of firing pattern, and rates in the GP/GPe, STN and output nuclei that are associated with rcsting animals are likely to result from the reciprocal interaction of populations of GP/GPe and STN neurons, which may lend towards equilib­rium following the perturbation caused by cortical activation.

3.2. Functional specificily of the indirecl IIctwork

The degree to which the interconnections of the STN and pallidal complex respect the functional divisions of these regions is critical to our under­standing of the indirect network and of the functional organization of the basal ganglia, It has rccently been proposed. "4:1 on the basis of doubk retrograde fluor­escent labelling,24' that neurons of thc STN that project to the GPi are distinct from those neurons that project to the GPe. Furthermore. it has been suggested. on the basis of anterograde labelling, that the GPe innervCltes mainly the d(,rsolalcral part of

the STN, i,e. that region of the STN that is proposed to provide a reciprocal innervation of the GPe. 24

'

These suggestions raisc questions about the position of the STN in the functional organization of the basal ganglia and call into question the existence of the indirect pathway. However. the tracer deposits that led to this interpretation wcre located in different functional territories of the GPe and GPi, and it is likely that the positions of the retrogradely labelled neurons and anterograde labelling in the STN simply respected the known topographical relationships of this system. From the observations of Shink et (/1.,:' 7

it appears that (i) all regions of the STN project to both the GPc and GPi in a topographical manner, (ii) that the GPe innervates all regions of the STN in a topographical manner. and (iii) that interconnected rcgions of thc ST1\ and GPe innervate common. functionally related, regions l1f the GPi, Further­more. many of the individual neurons that contribute to the reciprocal connections between the STN and GPe also project, via axon collaterals, to a common region of the GPi. Thus. the indirect pathway. as originally proposed,'7.76 is supported by the exper­imental data and. indeed, exhibits a high degree of specifIcity,

The interconnections between the GPe. the STN and output neurons of the: basal ganglia in the GPi are thus capable of a greater degree of speei­licity than suggested previously, ,41.243 However. in addition to this highly specific organization in which functionally homologolls zoncs of the GPe. STN and GPi are interconnected, .loci and Weiner ' (" have suggested, on the basis of topographical studies, that an <ldditional component of the GPeSTN pro­jection terminates in a functionally non-homologous region of the ST~, They proposed that the associative GPe projects mainly to the associative STN, but also to the motor and limbic territories of the nucleus. In addition, they raised the possibility that although the STN projects to functionally homologous regions of the GPe and GPi, it is also likely to innervate functionally non-homologous 70nes (a\so see ReI'. 139), Experimental data demon­strating both functionally homologous and non­homologous connections arise from the work of Shink et al. ,77 Thus, the deposits of BDA in the GPc or GPi, which gave rise to clusters of retrogradely labelled neurons in registcI with anterogradely labelled GPe terminals. also led to retrograde labelling of STN ncurons outside the tields of antero­gradely labelled GPe terminals. It is possible that these neurons are reciprocally connected with func­tionally non-corresponding regions of the GPe. Fur­thermore. in the same expcriments. it was noted that then: werc many STN neLLnlIlS within the antcro­gradely labelled GPe terminal fields that wcn.: not retrogradely labelled. The possibility that thc~L:

ncurolls project (0 functionally non-corresponding regions of the pallidal complex should be considered. However, they may also innervate only the GPe

Microcircuitry of the basal ganglia 375

CEREBRAL CORTEX

Brainstem Spinal cord

Feedback or output

Fig. 12. Updated model of the circuitry of th.: basal ganglia in the light of new anatomical data on the connectivity of the GPe. The major difference between this model and that outlined in Fig. I is the existence of mUltiple "indirect" pathways through the GPe. In addition to a massive projection to the STN. the GPe projects directly to the output structures of the basal ganglia (GPi/SNr) and 10 the RTN. In the basal ganglia output structures. the direct and indirect pathways thrnugh the GPe and the STN converge at the single-cell level. The transmitters used by the difl"erent pathways arc indicated in Fig. I. It should be noted that the diagram is still a simplification. as many connections have not been indicated.

Modified from Fig. 2 in Alexander and Crutcher. 7

or GPi, or may project to targets other than thc pallidal complex.

It should be noted that the findings of most topographical studies relate to the location of ncuronal perikarya. However, it is evident from work in both the rat and primate that the dcndrites or neurons in thc STN are oricnted in sllch a manner to traverse functionally heterogeneous regions defined by pallidal inputs D

.2K

I Thus. considerable convergence of functionally divers!: pallidal infor­mation is likely to occur at the level (11' dendrites in the STN. 3

.1

These data paint a confusing picture of the topo­graphical relationships of the GPe. GPi and STN. It is clear that these nuclei are not simply connected to each other with a point-to-point. functionally homologous organization. The projections are also distributed to such an extent that evcn different functional streams converge on to indi\idual nellrons

(for references, sec above). The precise details of the connectivity of neural networks in these nuclei remain to be determined, but one promising approach is likely to be the three-dimensional recon­struction and analysis of the connections of single tjlled neurons.

The functional implications of this system are apparent !i'om the responses of output neurons to the indirect and direct pathways that are engaged following stimulation of the cortex. Thus, individual neurons appear to respond with any combination of early excitation. late inhibition and late excitation depending on the site and intensity of cortical stimu­lation. 10(' The spatial arrangement Df output neurons responding in a similar manner to cortical stimu­lation is highly complex and does not appear to conform to any simple geometrical pattern. 10(, One pllssibility is that output neurons that only respond with excitation during behaviour (see Refs 219 and

1,76 Y. Smith 1'1 ill

321, and references therein), or to stimulation of a specific region of striatum or cortex,6X.Sl.lo6.no are

targeted by indirect pathways th'lt do not conform to functionally specific topographic rules. This system might act to excite and/or disinhibit output neurons that mediate non-selected motor programmes and thus prevent the execution of inappropriate motor behaviour. ~ 17a.220 Conversely. t he functionally ho­mologous component of the indirect network is likely to be more directly involved in t he motor behaviour by terminating it or by medi<lting a selective in­hibition of groups of muscles that is an integral component of the behaviour.

4. AN llPDATED VERSIO"li OF nu: SCHE."IE OF THE BASAL GANGLIA ClRCUITRV

Five major conclusions summarize the new ana­tomical findings presented in this commcntary. (I) There arc several routes I'm the flow of cortical information along functionally detined "indirect" pathways, i.e. those pathways that hypothetically result in increased firing of the output neurons (lf thc basal ganglia. Thus, informatioll carried by neurons in the GP can reach the output st ructures or the basal ganglia, not only via the STN .. hut also directly via massive inhibitory projection, that terminate on the proximal parts of EP/GPi and SNr neur(ll1s. Thc GP also innervates the RTN, \\hich provides a routc hy which a copy of the information flowing along the indirect pathways reaches thal~lmoc(lrtical neurons and, in view of the GABAergic nature llf neurons in the RTN. activation of this projection will produce the same effect on thalamocortical neurons as acti­vation of other indirect pathways. An updated ver­sion of the basal ganglia--thalalllocortical circuitry, which takes into account the connections of the GP, is presented in Fig. 12 (sec also Re!'. 65). (2) Infor-

mation flowing through the direct pathway and the indirect pathways interacts at several levels within the basal ganglia, including the output neurons in the EP/GPi and SNr. Thus. striatal neurons giving rise to the direct pathway are synaptically interconnected to neurons giving rise to the indircct pathways, and the direct and indirect pathways converge at the synaptic level on single output neurons of the basal ganglia. Furthermore, synaptic terminals derived from the GP and terminals derived from the cerebral cortex con­verge at the single-cell level in the STN. (J) Function­ally diverse information carried by the descending projections of the pallidal complex is synaptically integrated by individual neUfl)l1S in the EP, STN and SN. (4) A major component of the interconnections between the STN and the two divisions of the pallidal complex are highly specific and f()l1ow a strict func­tional topography in primaks. The basic circuit in both the rat and primates is such that reciprocally interconnected groups of neurons in the GPe and the ST~ innervate, via axon collaterals, the same popu­lation of neurons in the EP/GPi. (5) The interconnec­tiLlns between the GPe, GPi and STN arc also likely to exhibit additional levels of organization that facilitate the communication between functionally non-homologous regions.

Al'klll!l\·/edgeIllCI1I.1 Thc author, thank Louis.: Btrtrand. Isahellc D~audclin, Carolinc Francis, Liz Norman and Jcan·Fran,ois Pare for technical assistance. We also thank A. D. Smith for stimuhHing and helpful discussions on the hasal ganglia. and \lick Clarke and Jason Hanley for their Clllllmcnts on t hc manuscript. This research was supported by grants from the Mcdi<.:al Research Council of Canada (MT-II2.17 to Y. Smith) and U.K .. the l'iational Instituk of Health tRROOI(5). the Fonds de la Recherche en Santc du Quebec. the \Vcllcome Trust Im675511.5 to A. D. Smith) and l\ATO. M.D.B. is currently supported by a Wellcol1lc Trust .\dvanccd Training Fellowship. (46613/2/96/2).

I. Adinolfi A M. (1969) The fint' structure of neurons and synapses in the entopeduncular nucleus of the cat. 1. ('(ilJlp.

Neurol. 135. 225 248. 2. Afsharpour S. (1985) Lightmicnm:opic analysis of Ciolgi-imprcgnated rat subthalamic neurons. 1. COlllp. Nell/·ol. 236.

113. 3. Afsharpollr S. (1985) Topographical projcctions of the cerebral cortex to the subthalamic nucleus. J mlllf!. iVeul'O/

236, 14 28.

4. Albin R. L .. Aldri<.:h J. W .. Young A. B. ,1I1d Gilman S. (1989) Feline suhthalamic nucleus neurtlns contall1 glutamate-like but not GAHA-like or glycine-like immunoreactivity. Braill Res. 491, I R5 18~.

5. Albin R. 1... Young A. B. and Penncy .I. H. (19X9) The functional anatomy (If basal ~an~li~l disorders. '1'1'('11<1., Nellro.l<'i. 12, 366 375.

6. Alexander G. E., Crutcher Iv!. D. and DeLong 'v1. R. 1 I 99(J) Basal ganglia thalamocortical cir<.:uits -parallel suhstrates for motor oculomolor 'prel'rontaJ' and 'limhic' functions. In i'rl'li-lIl1lal Conn·. fr.1 Slruclure, FUl1cTioll alld Parliologr (eds Uylings H. B. M .. Vanedcn C. G .. Dcbruin .I. P. C .. C.~orncr M. A. and Feenstra M. G. P.). pp. 119 146. Progre.\·,1 ill Bl'llil1 RcsCilrch. VoL X5. E1sc\ier Scicn<.:c, Amsterdam.

7. Alexander Ci. E. and Crutcher M. I .. (1990) (Cunetional architecture of hasal C"anglia circuits: neural substratcs of parallel processing. Trend., .V('/(/'().\'ci. IJ, ~66 ~71. " "

8. Alex'"lder G. E., DcLonl! M. R. ,Ind Strick 1'. l.. 11986) Parallel organization of fUIlL'tionally segregated circuits linking basal ganglia and l'(lrln. A Rei Vellro.lcl. 9. 357 ,S I.

9. Alheid G. F. and Heimcr L. (19XS) New pcrspectives in ha sal lorebram organizatiol1 of special relevancc to neuropsychiatric disordcrs 111<' slriatopallidal amygdaloid and conicopctal components Ilfsuhstantia in nominata. Nellroscience 27. I 39.

9a. Alhcid G. I ., Heimcr L. and ~wit7cr R C. (I (J9Il) Basal ganglia. In The HUll1all S('/'l'OI/.l Srlle/JI (cd. Paxinos G.). pp. 4R.' 582. Acadcmic, S"11 Dicgo, CA

Microcircuitry of the basal ganglia

10. Aosaki T. Kimura M. and Graybicl A. M. (1995) Temporal and spatial characteristics of tonically active neurons of the primate's striatum. 1. Neuropli.l'sio/. 73, 1234 1252.

II Aronin N .. Chase K. and DiFiglia M. (1986) Glutamic acid decarboxylase and en kephalin immunoreactive axon terminals in the rat neostriatum synapse with striatonigral neurons. Brain Rn. 365, 151 158.

12. Asanuma C. (1989) Axonal arborizations of a magnocellular basal nucleus input and their relation lo the neurons in the thalamic reticular nucleus of rats. Proc Iwtll. Acac/. Sci. ('.S.A. 86,4746-4750.

13. Asanuma C. (1993) Fine structure of external pallidal tenninals within the monkey thalamic rdlcular nucleus. Soc. Neurosci. Ahstr. 19, 1435.

14. Asanuma C. (1994) GABAergic and pallidal terminab in the thalamic reticular nuc1cu, of sqLlirrel monkeys. E\pl Brain Res. 101,439-451.

15. Asanuma C. and Porter L. L. (llJ90) Light and electron microscopic evidence fnr a GABAergic projection from the caudal basal forebrain to the thalamic: reticular nucleus in rats. 1. l"OlIlp. Neurol. 302. 159 172.

16. Aziz T. Peggs D., Sambrook M. A. and ('rossman A. R. (1991) Lesion of the subthalamic nudel!:, for the alleviation of l-methyl-4-phenyl-I,2,J.6-tetrahydropyridine (MPTP)-induccd Parkinsonism in the primate. ,\forelllent Disord 6. 288-292.

17. Baik J.-H .. Picetti R .. Saiardi 1\ .. rhirid G .. Dierich A., [)epaulis A., Le Mcur \1. and Borrdli E. (llJ95) Parkinsonian-like locomotor imp,urmcnt in mice lacking dopamine D2 receptors. NUll/re 377, 424 42g.

18. Baron M. S., Vitek J. L., Bakay R. A. E.. Green J.. K,lIlcoke Y., Ha,himoto T .. Turner R. S. Woodard J. L.. Cole S. A., McDonald W. M. and DeI.ong M. R. (1997) Treatment of advanced Parkinson's disease by posterior GPi pallidotomy: I-year results ofa pilot slUd) . . 11111 .. Vmrol. 40,355 .,6(,.

19. Beckstead R. M. (1983) A pallidostncttal projection in the cat and monkey. Braill Res. Bull. 1 \, 629 6,,2. 20. Beckstead R. M. (1983) A reciprocal ,lxonal c(lnncctinl1 hetween the subthalamic nucleus and the neostriatum in the

cat. Brain Res. 275, \37 -142. 21. Beckstead R. M. and Cruz C . .I. (llJ~(l) Striatal awns to the globus pallidus. cntopeduncular nucleus and substantia

nigra come mainly from separate cell populations in cat. VellrOSclel1CC 19, 147 15S. 22. Benazzouz A., Boraud T. Fegcr 1 .. Burbaud P .. Bioulac B. and Gross C. (1996) Alleviation of experimental

hemiparkinsonism by high-frequcncy stimulation of the suhthalamic nucleus in primates: a comparison with L-Dopa treatment. Movement fJisord 11. (,27 6-'2.

21 Benazzouz A., Gross c.. Fegcr .1 .. Boraud T. and Bioulac B. ( 1993) Reversal of rigidity and improvement in motor performance by subthalamic high-fre'Iu<:ncy stimulation in \1PTP-trcated monkeys. Eur. J. :\'('I(/"O.lci. 5, 382 389.

::'4. Bennett B. D., Bacon S. and Bolam .I. P (llJ93) Idel1lified targeh of the pallidostriatal projectlon in the rat. Sue Neurosci. Ahstr. 19, 1432.

~5. Bennett B. D. and Bolam J. P. (1994) Synaptic input and output of parvalbumin-immunoreactlYe neurones in the neostriatum of the rat. /Veuril.\('Il'n( e 62, 7117 719

::'6. Bcrendse H. W., Galis-de-Graaf Y. and Groencwcgen H. J. (I ')92) Topographical organization and relationship with ventral striatal compartments of prefl"Onto-corticostriatal projections in the rat. J COIIlf!. Nellml. 316,314 347.

27. Berendse H. W. and Groenewegen H. J. (1989) The connections of the medial part of the subthalamic nucleus in the rat: evidence for a parallel organi/.ation. In T/I(' Bas(d Ganglia II (eds Bernardi Cl .. Carpenter \1. B .. Di Chiara G .. Morelli M. and Stanzione P.). pp. XC) 9S. Plenum. Ne\\ York.

27a. Bergman H., Feingold A., Nini A .. Ra:! A. Slovin 11 .. Abeles M. and Vaadia E. (19')8) Physiological aspects of information processing in the hasal ganglia of normal and parkinsonian primates. Trend.1 Ncur,'sci. 21,32 3S.

28. Bergman H .. Wichmann T. and DeLlmg M. (1990) Reversal pI' experimental parkinsonism by lesions of the subthalamic nucleus. Science 249. 14.'6- 143K

29. Bergman H., Wichmann T. Karl110n B. and DeLong M. R. 11994) The primate subthalamic nucleus. 11. Neuronal activity in the MPTP model of Parkinsonism. J Nellrol'hniol. 72, 507-520.

29a. Berretta S .. Parthasarathy B. and Gr"ybiei A. M. (1997) l.ocal release ofGABAergic inhibition in the motor cortex induces immediate-early gene expression in indirect pathway neuron, of the striatum. J. Neurl!.ld 17,4752 4763.

3D. Bevan M. D. and Bolam J. P. (1995) Cholinergic. GABAergic and glutamate-enriched inputs from the I11csopontine tegmentum to the subthalamic nucleus in monkeys. J. lliellrosci. 15, 7 \05 7120.

31. Bevan M. D., Francis C. M. and Bo"'m J. P. (1995) The glutamate-enriched cortical and thalamic input to neurons in the subthalamic nucleus of the rat. convergence with (jABA-ppsitive terminab. 1. COIII/! . .veulD/' 361,491-511.

32. Bevan M. D., Bolam J. P. and Crnssman A. R. (19lJ4) Convergent synaptic input from the neostriatum and the subthalamus on to identified nigwth,t\amic ncul"llns in the rat. Fill'. 1. ,VelltOsci. 6, 320 334.

31 Bevan M. D., Clarke "l. P. and Bo\alll J. P. (19lJ7) Synaptic integration of functionally diverse pallidal information in the entopeduncular nucleus and subthalamie nucleus in the rat. J. IVellrosci. 17, 30g 324.

34. Bevan M. D., Crossman A. R. anel Bol<ll11 J. P. 11')94) "leurons projecting from the entopeduncular nucleus to the thalamus receive convergcnl syllaptlc inputs from the subthalamic nucleus and the neostrialum. Braill Res. 659, 99-109.

35. Bevan M. D .. Eaton S. A. and B"lam .I. P. (1997) Synaptic targets of physiologIcally. ncurclchcmically and morphologically characterized neurons of the rat globm pallidus. SO\". Neurosci. Ahstr. 23, 196.

36. Bevan M. D .. Smith A. D. and Bolam J. P. (1996) The substantia nigra as a site of synaptic integration of functionally diverse information arising from t he ventral pallidum and the globus pallidus in the rat. Ncuro.l(·iel1ce 75, 5 12.

37. Bickford M. E., Gunluk A. E.. Van lIorn S. C and Sherman S. M. (llJ94) GABAergic pmjectioll from the basal forebrain to the visual sector of the thalamic rcticular nucleus ill the cat. J. comp. ,vel/ml. 348,481 -510.

38. Bishop G. A., Chang H. T and KJtai S. T (1982) Morphological and physiological properties of neostriatalneurons: an intracellular horseradish peroxid'hc study in the rat. Sellrosciellce 7, 179 191.

39. Blandini F .. Porter R. H. P. and C;rel'namyre 1. T. (llJlJ6) Glutamate and Parkinson's disease. :Ho/ec. ;VclIrohiol. 12, 73-94.

40. Bolam J. P. (1984) Synapses ofidcntilicd neurons in the ncostriatum. [n Funcliuns 0(1171' Ba.lo! (i{lllglia (eds Evercd D. and O'Connor M.). CIBA FOllnd,ltion Sympo,ium 10;. pp. 30 4~. Pitman, London.

41. Bolam J. P. and Bennett B. (llJ95) The microcircuitry of the ncostriatum. In Mo/ecular alld Cdllllar Mechanisms ot Neostriatal Functions (eds Arianc; M. and Surmeicr f) . .1.1. pp. 1 19. R. G. Landes. Austin. TX

378 Y. Smith cl (//.

42. Bolam J. P. and Ingham ('. A. (199lJ) Combined morphological and histochemical techniques for the study of neuronal microcircuits. In Handhook 0/ Chcmical Neuroanatomy, Vol. 8: Analn'is of Neuronal J1./icrocircuits and S},l1aptic Interactions (eds Bjorklund A .. Hokfelt T.. Wouterlood F. and van den Pol A.l. pp. 125-198. EIsevier Biomedical, Amsterdam.

43. Bolam J. P., Ingham C. A .. Izzo P N .. Levey A. l.. Rye D. B., Smith A. D. and Waincr B. H. (1986) Substance P-containing terminals make synaptic contact with cholinergic neurons in the basal forebrain and neostriatum: a double immunocytochemical study in the rat. Brain Res. 397, 279·289.

44. Bolam J. P. and Izzo P N. (1988) The postsynaptic targets of suhstance P-immunoreactive terminals in the rat neostriatum with particular reference to identified spiny striatonigral neurons. Expl Brain Res. 70,361- 377.

45. Bolam J. P., Powell J. P., \Vu J.-Y. and Smith A. D. (1985) Glutamate decarboxylase-immunoreactive structures in the rat neostriatum. /\ correlated light and electron microscopic study including a combination of Golgi­impregnation with immunocytochemistr). J ('(I/JIp. Neurol. 237, 1-20.

46. Bolam J. P. and Smith Y. (1990) The GARA and suhstance P input to dopamincrgic neurones in the suhstantia nigra of the rat. Brain Res. 529, 57 n.

47. Bolam J. P. and Smith Y. (1991) Characterinltion or the synaptic inputs to Jopamincrgic neurone, in the rat substantia nigra. In The Ba.l'al G£1I1y;/i1l III led, Bcrnardi G .. Carpenter \1. B .. Di Chiara G., Mordli M. and Stanzionc P.). pp. 117 1~9. Plenum. I'\cw York.

48. Bolam 1. P. and Smith Y. (1992} The ,triatum and the globus pallidus send convergent synaptic inputs onto single cells in the entopeduncular nucleus or the rat: a douhle anterograde laheling study comhined with post-embedding immunocytochemistry for GABA J (O/llp. ,\'cUI'III. 321, 456 476.

49. Bolam 1. P .. Smith Y., Ingh,lIn C. A .. von Krosigk \1. and Smith A. D. (1993) Convergence ofsynaptic terminals rrom the striatum and the glohus pallidus onlt) single neurones in the substantia nigra and the entopeduncular nucleus. In Chemical Signal/ing in /11" Ha.lal (jal1glia (eds Arbuthnott G. W. and Emson P. c.). pp. 73 88. I'rogr".I·.1 ill Brain Resear"h, Vol. 99. Flsevier Science. Amqerdam.

50. Bolam J. P., Somogvi P., Takaci H .. Fodor I. and Smith A. D. (19X~) Loc,di~ati()n nf sllbstance P-like immmunoreactivity i;" neUf<lns and nerve terminal> in the ncnstriatum \If the rat: a unrelated light and electron microscopic study. J. Nellm('ito/. 12, ~25 344.

51. Bouyn J. 1.. Jnh T. H. and Pickel V. M. (19K4) Ultrastructural localization Ill' tyrosine hydroxylase in rat nucleus accumbens. J. COll1jJ. Nellro/. 227, ()~ JIIJ.

52. Bouyer J. J.. Miller R. J and Pickel V. M. (1984} Utrastructural relation hctween cortical ellcrents and terminals containing en kephalin-like immunoreactivity ill rat neostriatum. Reglll. Pept. 8, 105 115.

53. Bouyer 1. L Park D. H .. Joh T. H. and Picke1 V. M. (1984) Chemical and structural an,dysis of the relation hetween cortical inputs and tyrosine hydroxylase-containing terminals in rat neostriatulll. Brllin Rc,\'. 302, 267 275.

54. Brandt H. M. and Apkarian i\.. V. (1992} Bintin-dextran: a sensitive anterogradc tracer tor neuroanatomic studies in rat and monkey. J. Neu)'(),\'('i /\4elh. 45, 35 411.

54a. Bmg 1. S., Salyapongse ;\, l>Cu1ch A. Y. and Zahm D. S. ( 1993} The patterns nr aiferent innervation of the core ,wd shell in the "accumhcns'" part of the ventral striatum: immunohistochemical detection or retrogradely transported fluoro-gold. J. comp. ,Vel/rol 338, 255 ~n.

55. Brotchie J. M., Mitchcll I. J., Samhrook M. i\. and Crossman A. R. (] 991) Alleviation of Parkinsonism by antagonism or excitatory amino acid tLlI1smission in the medial segment of the glohus p,1l1idus in rat and primatc. A/ovell1f!f1i Disord 6, I ~3 13K.

56. Brotchie P., lansek R. and Home M. K. (1991) Mntor function of the monkey globus pallidus. I. Neuronal discharge and parameters of movcmcn· .. Brain 114, 1(,67 16H:1.

57. Burbaud P .. Gross C, Bemuwuz A .. Cnussemacq M. and Bioulac B. (1995) Reduction of apomorphine-induced rotational hehaviour bv subthalamic lesion in 6,OHDA lesiollcd rats is associated with a 11llrmalizlltion of flrin~ rate ,lnd discharge pattern ~'f par'; reticulata neuron,. I':\/,I Brain RI'S. 105, 4H-58. ~

58. Calabresi P., De Murtas M. ;l1ld Bernardi G. (1997) The neostriatum beyond the motor function: experimental and clinical evidence. Neurosciu/,e 78, Y)(;(}.

59. C'alabresi P .. Pisani A .. Mercllri N. B. and Bernardi (j. (l996} The corticostnat,iI projection: ['rom synaptic plasticity to dysfunction, of the hasal ganglta. Trends !Vcl/I'osei. 19, 19 24.

60. CampbelI G. A., Eckart M. J. ,lOd Weight F. r. (1985) Dopaminergic mechllnislll s in the subthalamic nucleus of the rat: analysis using horseradish paoxidase and microiontoplHlresis. Brain Rn. 333, 261 270.

61. Canteras N. S., Shammah-l.agnado S L Silva B. A. and Ricardo .I. A. (1990) Alkrent conneclions or the suhthalamic nucleus: a combined retrograde and anterograde horseradish peroxidase study in the rat. Brain Res. 513, 43 59.

62. Carpenter M. B .. CarlelOn S. C .. Kelkr.l. 1'. and C\lnte P. (1981) Connections of the suhthalamic nucleus in the monkey. Brain RI'S. 224. I 21).

63. ('hang H. T. (1988) Suh.;tancc P dopamine rclation,hip in the rat suhstantia nigra: a light and electron microseopy study of double immunocytochemically labeled materials. Brain Res. 448.391 396.

64. ('hang HT., Wilson C. J. and Kitai S. T. (I n!) Single neostriatal efferent axons in thc globus pallidus: it light and electron microscopic study. ,\Ii{'IU'" 213. 915 918.

64a. Chen S. and Aston-Jones Ci. (1991') Axonal collateral-collateral transport of tract tracers in hrain neurons: fal,e anterograde labelling and usel'u] tool. :Vel/ro.l·cil'llc(' 82, 11:; I 1163 ..

65. Chesselet M.-F. and DcJj\ J. M. (1'196) Basal ganglia and movement disorden,: ,111 update. Trends Nelll'O.lci 19, 417422.

66. Chesselet M. 1-. and Graybicl 1\. \1. (19i\6} Striatal neurom expressing somatostatin-like immunoreactivity: evidence I'lli' a peptidergic interncurollClI syslel11 in the cat. 'vcul'O.\(·icl1ec 17, 547 571.

67. Chevalier G. and Deniau J. IVI. 119901 Disinhihition ,1S a IXlsic process in the cxpression "I' striatal functions. 7""".1.1 Ncul'Osci. 13, 277 280.

68. Chevalier G., Vacher S .. Delliau J. M. and Deshan M. (191'5) Disinhibition as a basil process in the expression or striatal functions. 1. The stnato-nigral influence on tecto-spinalltecto-dienccphalic' neurons. Brain Re.'. 3.14, 21 "226.

Micrllcircuitry of the basal ganglia 0,79

69. Churchill l. and Kalivas P. W. (1994) A topographically organized )'-aminobutyric acid projection from the ventral pallidum to the nucleus accumbens in the rat. 1. mmI'. Neurol. 345, 579-595.

70. Clarke N. P., Bolam J. P. and Bevan M. D. (1996) Glutamate-enriched inputs from the mesopontine tegmentum to the entopeduncular nucleus in the rat. ElIr. J. Nellrosci. 8, 1363- 1376.

71. Consolo S., Baldi G .. Giorgi S. and Nannini L. (1996) The cerebral cortex and parafascicular thalamic nucleus facilitate in vivo acetylcholine release in the rat striatum through distinct glutamate receptor subtypes. ElIr. J Neurosci. 8,2702 -2710.

n. Cornwall .I., Cooper 1. D. and Phillipson () T. (\ 990) Projections to the rostral reticular thalanllc nucleus in the rat. £Xl'! Brain Res. 80, 157 171.

73. Cowan R. L. and Wilson C. J. 1.1994) Spontaneous firing patterns and axonal projections (If Single corticostriatal neurons in the rat medial agranular L'nrtex . .J. /'·('/lwl'iI),sio/. 71, 17 .1~.

74. Crossman A. R. (1989) Neuralll1echanisms in disorders of movement. Comp. BiociJelll P!n·.lio! 93A, 141 149. 75. Crossman A. R. (1990) A hypothesis on the pathophysiological mechanisms that underlie levodopa- or dopamine

agonist-induced dyskinesia in Pmkin"m\ disease: implications for future strategies in treatment .'HU1'e!l1ent Dis()rd 5, IOO-IOX.

75a. Davis K. 0 .. Taub E .. Houlc S .. Ling A. 10 .. Dostmvsky J 0 .. Taskcr R. R. and lozano A \1. (1997) Globus pallidus stimulation activates the cortical 111otor system during alleviation of parkilbonian symptoms. ,Vature Med 3,671-674.

76. De long VI. R. (199()) Primate models of 1110vement disorders of basal ganglia origin. h,'Ild.1 Neurost'i 13. ~81-285.

77. Dclong M. R .. Crutcher M. D. alld Georgopoulos A. P. (19X,i) Relations between movement and single cdl discharge in the substantia nigra of the behaving monkey. J Nel/ro.I·,i. 3, 1599 1606.

n. De long M. R .. Crutcher M. D. and Georgopoulos A. P. (19851 Primate globus pallidus and subthalamic nucleus: functional organization. J Neuropil] lio/. 53. 530 54:\.

79. DeLong M. R. and Gcorgopnul,lS A. P. (1981) Motor functinns of the basal ganglia. In HlIlldho(!k of Phrsi%gy (eds Brookhart J. M .. Mountcastle V B and Geiger S. R.L Vol. 11, pp. 1017 1061. Amcrican Physiological Society, Bethesda, MD.

~(). DeLong M. R., Georgopoulos A. P. and Crutcher M. D. (198.i) Cortico-basal ganglia relations and coding of motor perfonnance. £.v»! Bwin RI'.I .. Suppl 7,,0 40.

81. Deniau.l. M. and Chevalier G. 11 %5) Disinhibition as a basic process in the expression of striatal functions. 11. Nigral inl1uencc on thalamocortical cells of the ventromedial thalamic nucleus. Brain Rcs. 334, 227 133.

8~. Deniau J. M., Hammond c., ('hey alil'r G. and Hger .I. ( 1978) Evidence for branched suhthalamic nCUl'l'n projections to substantia nigra, entopedullcular llUCleUS and globus pallidus. Ncul'Osci. Let!. 9, 117 1~1.

R3 Dcwhurst K. (1nl) Thomas Willl', and the foundations of British neurology. In l/i.I/O//(II! A.I{Jccts of rhe /'ieurosciclICes (eds Rose F. C. and Bynum W 1-'.1. pp. 327 0,46. Raven, :'-Iew York.

X4 DiFiglia M (1987) Synaptic Ol'!1anilati"n "I' c'll()linergic neuron, in the 1110nkey striatum . .I t'l!1II!,. Neurot 255, ~45-258.

X5. DiFiglia VI. and Aronin 1\. (10~2) Litra,tructural feature, of immunoreaetive somatoslatin neurons in the rat caudate nucleus . .1. ,".·('/I}'osei. 2, I ~(,7 127~

86. DiFiglia M., Aronin 1\. and Leeman S. E. (19~1) Immunoreactive substance P in the substantia nigra of the monkey: light and electron microscopic Imali/;ltlOn. Hl'llill Rcs. 233, 3X I '~8.

87. DiFiglia M .. Aronin N. and Martin .I. B. (I ')~~) Light and electron microscopic localil<ltion of immunoreactive leu-enkephalin in the monkey hasal !'angli;l..I NCl/},()I·ci. 2. 30.1 .120.

X~. DiFiglia M., Pasik P. and Pasik T (I '18~J !\ (Jolgi and ultrastructural study of the monkey globus pallidus. J. ((imp NCl/J'o/. 212. 53 7'.

89. Dolleman-Van der Wed M. Wouterlood 1-. (j. and Witter M. P. (1994) Multiple anterograde tracing combining Pilos('o/us w!gar/,I icucoagglutinin with rhodall1l11e- ;Ind hiotin-conjugated dextran amine. 1. ;Vel/rosei. M('/17. 51,9 21.

90. Donoghue.l. P. and Kitai S. T. (19KI) A wllateral pathway to the neostriatum frn111 corticofug<ll neurons of the rat sensory-motor cortex: an intracellular HRI' study 1. ('Oll/!'. Neurot 201, I 13.

91. Dubt' L .. Smith A. D. and Bolam .I. P. (19881 Identification of synaptic terminals of thalamic ,Ir cortical origin in contact witll distinct medium si/e spiny nCLHons in the rat neostriatum. 1. ('limp. Neuw! 267,4'5 471

9~. Falls W. M., Park \1. R. and Kitai S T. (19H.') An intr,Lccllular HRI' study of' the rat globus pallidus. 11. Fine structural characteristics and synapt;c Cllllneetions pI' medially located I,lrge GP neurons . .I. [(Imp. Ne/lrn!. 221, 229 245.

93. Feger J., Bevan \-1. and Crossnwll .\. R. (1994) The projections from the parafascieular th,ilamic nucleus to the subthalamic nucleus and the stri<ltum drisc from separate neuronal populatilHls: a comparison Iv·ith the corticostriatal and corticosubthalamic efTerent, in ;1 retrograde l1uorescent double-labelling study. Nel/l'oseil'llt'e 60, 1~5 13~.

94. Fernandel P. M. and Dujovny M (1')971 Pallid(ltomy: editorial review. NCl/m/. Rn. 19. ~5 :14 l)), Filion M. and Trcmhlay L. (19') I1 ,\bnonnal spontaneous actiY'ity llf gl(lblh pallidus neur[li1' 111 monkeys with

MPTP-induced Parkinsonism. 81'11ill Rn. 547, 1421'1. 96 Fink-Jensen A. and Mikkelsen J. D. 11989} The striato-ent(lpeduncular path\\ay in the rat. A retrugrade transport

study with wheatgerm-agglutinin ilorseradi,h peroxidase. Bl'oill Rn. 476, 194 IYx. 97. Fisher R. S .. Bovlan M. K., Hull (. D._ Buchw;lld N. A. and l.evine M. S. (I9X:i) Branched projections of

pallidal and peripallidal neurons ltl lleocorte.\ and nellstriatum: a double-Iabding stud v in the cat. Brain RI'S. 326, 156 159.

9~. Flaherty A. W. and (jraybicl A. M. (19'11} CorticostllCltal transformations in the primate ,omaltlsenslll'Y system. Projections from physilllogically mapped I""I)-part representations . .I. NeurujlilYl'io/. 66, 1249 1~63

9'-). Flaherty A. W. and Graybiel A. M. 11993) Output architcL'lllre of the primate putamen . .I. ,VCl/I'(!Ici. 13, 3~2232.i7. lOO. Flaherty A. W. and Graybiel A. vI. (1993) T\\o Input systems for hod\' representations in the primate striatal matrix:

experimental evidence in the squirrel l11onkey. J Nel//'()I('i 13, 1120 1137.

101. Fox C. A., Andrade A. N., Lu Qui I .I. and R"fols J. A. 119741 The primate globus pallidus: a Ciolgi and electron microscopic study. J lIimjill's('/i \5, 7) 'I.'

380 Y. Smith ('( al.

102. Fram;ois c., Percheron G .. Yclnik J. and Heyner S. (1984) A Golgi analysis of the primate globus pallidus.!. Inconstant processes of large neurons. other neuronal types and afferent axons . .f. COII/p. Neurol. 227, 182 199.

103. Freund T. F. (1993) Anterograde PHA-L tracing combined with pre- and post-embedding immunocytochemistry. In Immunohistochemistry 11 (ed. Cuello A. C.). pp. 329-·348. John WiIey. Chichester.

104. Freund T. F .. Powell l. and Smith A. D. (1984) Tyrosine hydroxylase-immunoreactive boutons in synaptic contact with identified striatonigral neurons with particular reference to dendritic spines. Neuroscience 13, 1189-1215.

105. Freund T. F. and Somogyi P. (1989) Synaptic relationships of Golgi-impregnated neurons as identified hy dectrophysiological or immunocytochemical techniques. In Neuroanatomicai Trucl-tracing Methods 11 (eds Heimer L. and Zaborszky L.). pp. 201238. Plenum. I\ew York.

106. Fujimoto K. and Kita H. (1992) Responses of ral substantia nigra pars reticulata umts to cortical stimulation. Nl'urosci. Lett. 142, 105 1119.

107. Fujimoto K. and Kita H. (1993) Response characteristics of subthalamic neurons to the stimulation of the sensorimotor Cllrtex in the rat. Brain Res. 609, 185192.

108. Fuller T. A .. Russchen F. T. and Price J. L. (1987) Sources of presumptive glutamatergic/aspartergi(: afferents to the rat ventral striatopallidal region . ./. mmp. ,vel/m!. 258, 31733R.

109. Gandia l. A., Delasheras S., Garcia M. and Gimencz-Amaya J. M. (1993) AflCrent projections to the reticular thalamic nucleus from the glohus pallidw, and the substantia nigra in the rat. Brain Rcs Bull. 32, 351 35R.

110. Georgopoulos A. P., DcLong M. R. and Crut(:hn M. D. (19R3) Rdations betwccn p'1r<lmcters of step-tracking movements and single cell discharge in the globus pallidus and subthalamic nudeus of the behaving monkey . ./. Nel/rosei. 3, 1586- 159X.

Ill. Gerfen C. R. (1984) The ncostriatal mosaic: compartmcntali"'ltion of corticostriatal input dnd striatonigral output systems. Narurc 311, 461464.

112. Gerfen C. R. (1985) The neostriatal mosai(:. I. Compartmcntal organization of projections from the striatum t() the substantia nigra in the rat. J. COII/J'. i\'c1mJi. 236, 454 476

113. Gerfen C. R. (1992) The nco-;triatal mosaic: Illultiple levels of compartmental organiLation. Trends NeuYOsci. 15, 133-139.

114. Gerfen C. R. (1992) The neostriatal mosaic: multiple Ieveb (11' eompartmental organiLation in the basal ganglia. A. Rev. Neurosci. 15, 285 120

I 15. Gerfen C. R., Engber T. M .. Ivlahan L. ( .. Suscl L. Chase T. N .. Monsma F. J. and Siblcy D. R. (1990) 01 and D2 dopamine re(:eptor regulated gene expression or striatonigral and striatopallidalneurons. Science 250, 1429 1432.

116. Gerfen C. R., Herkenham M. and Thibault J. (19X7) The neostriata 1 mosaic: 11. Patch- and matrix-dire(:ted mesostriatal dopaminergic and non-dopaminergic systems. J Vel/msci. 7, 3915 W34.

117. Gerfen C. R. and Sawchenko P. E. (1984) An anterograde ncuroanatomical tracing method that shows thc detailed morphology of neurons. their axons and terminals: immunohistochemical Incalizatinn (If an axonally tramportcd plant lectin. PIU/sea!us ni/go,.,', lcucnagglutinin (PIIA-L>. Braill Res. 290,219 231\.

118. Gerfen C. R. and Wilson C. .J. 11996) The hasal ganglia. In ffwulnoo,{ or Chelllim! .VCl/mUliu/om!'. Vo!. 12: fl1legm/eri Sr.ltems of rhe (,NS, Pdrt III leds Bjiirklund '\ .. Hiikfclt T. and Swanson I.), pp. 169-466. Elsevier Science. Amsterdam.

119. Gcrfen C. R. and Young W. S. (19XX) Distribution of striatonigral and striatopallidal pcptidcrgic ncurons in both patch and matrix compartments: an ill silll hyhridilation histochemistry and fluoresccnt retrograde tracing study. Brain Res. 460, 161 167.

120. Giulfrida R .. Li Volsi G .. \1augeri G. and Pereia\ alle V. 119~5) IniluelKC'i pf pyramidal tra\:! on the subthalamic nucleus in the cat. Ne1Ho.1( I 1./'11. 54, 231 235

121. Goldman P. S. and l'iallta \\ .J. H. (1977) An intricately patterned prefronto-caudat,' projection in the rhcsus monkey . ./. COII/p. Neurol. 17L 36,} .174.

In. Graybiel A. M. (1990) Neurotransmitter'i and neuromodulators in the basal ganglia. Trl'lIds Neurosci. 13,244 254 123. Graybiel A. M., Aosaki T" Haherty A. W. and Kimura M. (1994) The basal ganglia and adaptive motor control.

Science 265, 1826 1831. 125. Greenamyre J. '1' .• Eller R V .. ll1d Zhang Z. (1991) Antiparkinsonian effects ofremacide hydmchloride, a glutamate

antagonist in rodents and primate models of Parkinson's disease. Anl1. Neum!. 48, 977 981. 126. Groencwegen H. l. and Berendse H. W. (1990) Connections of the subthalamic nucleus with ventral striatopallidal

parts of Ihe basal ganglia in the rat. J millp. Neuro!. 294, 607 6n. 127. Grocnewegen H. J. and BercnLlsc H. W. ( 1994) Anatomical relationships betwecn the prdrontal cortex and the bas<i1

ganglia in the rat. In AI%r (Ill" C{lgllili\'c FlIIlI'ti{ll/.l' or Ihe Prcfrol1wf COr/C.I· led, Thierry A'-:'v1 .. Glowinski .l .. Goldman-Rakic P. S. and Christen Y). pp. 52 76. Springer. Berlin

128. Grocnewegen H. J. and Bcrcndse H. W.II,}94) The specificity "fthe 'nonspecific' midline and intralaminar thalamic nuclei. Trelldl' Nl'urosci. 17, 5:: 57

129. Groenewegcn H. J .• Bcrcndse 11. W. and Haber S. N. (199:1) Organization of the outpUI ,,1' the ventral striatopallidal system in the rat ventral pallidal etferents. Nellrll.lciel1l'c 57, 113 -142.

DO. Groenewegen H. l .. Berendse 11. W .. Mercdith G. I., Haber S. 1\., Yoorn P .. Woltcrs J. G. and Lohman A. 1-1. M. (1991) Functional anatomy of the ventral limbic system-innenated striatum. In n1l' Mcs{lIiJllnic [)opamin(' Srslml Fron1 iY/otil'lltioll to /lctioil led, Willncr P. and Scheel-Kruger .I.). pp. 19 59. John Wiley, Chi(:hestcr.

131. Groenewegcn H. l .. Room 1' .. Witter M. P. L. ,1Ild Lohman A. H. M. (1982) Cortical afferents of the Iludeus accumbcns in the cat studicd with antcrl'gradc and retrognlde transport techniques. NClIro.l'ci<'l1(·c 7, 977 -995.

132. Groenewegcn H. J. and W(Hltcrlood F. (i. (1990) Light and electron microsCllpic tracini! of neuronal connections with Phaseoi".1 vuigaris-lcu,:oagglutinll1 I PHA-l) and combinations with olher ncuroan<ltomical technique,. In Handbook of Chemical Nellr!hll/(/llJlJlr, Vol. H: Ani/irsis of ,Vcurol1a! AIicrocirclIils and Sl'lIal'lic In/<'I'ac/iolls (eds Bjlirklund A., H6kfeit T., WO\ltcrltl(ld 1-. and van den Pol A.I. pp. 47 124. Ebevier Bic1mcdical. Amsterdam.

133. Grofov,i L, Dcniau J. M. and Kit"i S. T. (19B2) Morpholo!!y of the substalltia nigra pars reticulata prnjection neurons intracellularly lahelcd with HRI'. J. "!!/IIp.Vcl/rol 208, 352 36~.

134. Grofoya I. and Rinvik E. (I (17111 An experimental eleelroll mlcruscopic study on the striatolllgral projection in the cat. E.lfll Brain Res. 11, 2492(,:'.

M icrocircuitry of the basal ganglia 381

135. Groves P. M. (1983) A theory of the functional organization of the neostriatum and the neostriatal control of voluntary movement. Brain Res. Rev. 5, 109--132.

136. Haber S. N., Lynd-Balta E. and Mitchdl S. J. (1993) The organization of the descending ventral pallidal projections in the monkey. 1. comp. Neurol. 329, 111-128.

137. Haber S. N., Groenewegen H. J., Grove E. A. and Nauta W. J. H. (1985) Efferent connections of the ventral pallidum: evidence of a dual striato-pallidofugal pathway. 1. comf'. Neurol. 235,322--335.

138 Haber S. N., Kunishio K" Mizobuchi M. and Lynd-Balta E (1995) The orbital and medial prefrontal circuit through the primate basal ganglia. 1. Neurosci. 15, 4851-4867.

139. Haber S. N" Lynd-Balta E. and Mitchell S. J. (1994) Integrative aspects of basal ganglia circuitry. In The Basal Ganglia IV: New Ideas and Data on .)tructure and Function (eds Percheron G., McKenzie J. S. and Feger J.), pp. 71-80. Plenum, New York.

140. Haber S. N. and Nauta J. H. (191'3) Ramifications of the globus pallidus in the rat as indicated by patterns of immunohistochemistry. Neuroscience 9, 245--260.

141 Hajdu F., Hassler R. and Bak I. J. (\973) Electron microscopic study of the substantia nigra and the strio-nigral projection in the rat. Z. Zell/arsch. 46, 207 221.

142. Hakan R. L., Berg G. I. and Henriksen S. J. (1992) Electrophysiological evidence for reciprocal connectivity between the nucleus accumbens septi and ventral pallidal region. Brain Res. 581, 344-350.

143. Hallanger A. E. and Wainer B. H. (\\189) The ultrastructure of ChAT-immunoreactive terminals in the thalamic reticular nucleus of the rat. J. comp. i''ieuro/ 278, 486 497.

144. Hamada I. and DeLong M. R. (1992) Excitotoxic lesions of the primate subthalamic nucleus result in reduced pallidal neuronal activity during active holding. 1. Neuropilysio/. 68, 1859 1866.

145. Hamada I. and DeLong M. R. (I \1921 Excitotoxic lesions of the primate subthalamic nucleus result in transient dyskinesias of the contralateral limbs. J. Ncurophniol. 68, J 850-11158.

146. Hammond C, Rouzaire-Dubois B., Feger J., Jackson A. and Crossman A. R. (1983) Anatomical and e1ectrophysio­logical studies on the reciprocal proje<:1ions between the subthalamic nucleus and nucleus tegmenti pcdunculopon­tinus in the rat. Neurosciena 9, 41 52.

147. Hammond C and Yelnik J. (19831 Intracellular labelling of rat subthalamic neurons with horseradish peroxidase: computer analysis of dendrites and characterization of axon arborization. Ncul"Oscience 8, 781·- 790.

148. Hancock M. B. (1986) Two-color immunoperoxidase staining: visualization of anatomical relationships between immunoreactive neural elements. Am. J. Anat. 175, 343352.

149. Hartmann-von Monakow K., Akert K. and Klinzlc H. (19/R) Projections of the precentral motor cortex and other cortical areas of the frontal lobe to the subthalamic nucleus in the monkey. Expl Brain RcI'. 33, .'95-403.

ISO. Hassani O. K., Fran90is C. Y dnik J. and Fcger .J. (J 997) Evidence for a dopaminergic innervation of the subthalamic nucleus in the rat. Bruin Res. 749, SR 94.

151. Hattori T., Fibiger H. C and McGeer P. L. (197S) Demonstration of a pallido-l1Igral projection innervating dopaminergic neurons. 1. comp. /I/curol. 162, 487 504.

152. Hazrati L.-N. and Parent A. (19911 PmjectioJl from the external pa1lidum to the reticular thalamic nucleus in the squirrel monkey. Brain Res. 550, 142 146.

153. Hazrati L.-N. and Parent A. (1992) Convergence of subthalamic and striatal efferents at pallidal level in primates: an anterograde double-Iabeling study with biocytin and PHA-L. Brain Res. 569,336-340.

154. Hazrati L.-N., Parent A .. Mitchell S. and Haber S. N. (1990) Evidence for interconnections between the two segments of the globus pallidus in primates: a PHA-L anterograde tracing study. Brain Res. 533, 171-175

15S. Hazrati L. N. and Parent A. (19921 The striatopallidal projection displays a high degree of anatomical specificity in the primate. Brain Res. 592,213--227.

156. Heimer L., Harlan R. E .. Alheid Ci. F .. Garcia M. M. and De Olmos J. (1997) Substantia innominata: a notion which impedes clinical-anatomical correlations in neuropsychiatric disorders. Neuroscience 76. 957 -1006.

157. Hersch S. M., Ciliax B. J., Gutekunst C. A._ Rees H. D., Heilman C. J., Yung K. K. L.. Bolam l P., Inee E" Yi H. and Levey A. l. (1995) Electron microscopic analysis of D I and D2 dopamine receptor proteins in the dorsal striatum and their synaptic relationships with motor corticostriatal afferents. 1. Neurosci. 15, 5222 SD7.

157a. Heimer L., Zahm D. S. and Alheid G F. (1995) Basal ganglia. In The Rat Nervous System, 2nd edn (cd. Paxinos G.), pp. 579·-628. Academic, San Diego, CA.

158. Hoover J. E. and Strick P. L. (1993) Multiple output channels in the basal ganglia. Scie111c 259, RI9 821. IS9. lmai H., Steindler D. A. and Kitai S. T. (1986) The organization of divergent axonal projections from the midbrain

raphe nuclei in the rat. J. comp. Nfur,,/. 243, 163 380. 160. Izzo P. N. (1991) A note on the use of biocytin in anterograde tracing studies in the central nervous system:

application at both light and electron microscopic level. 1. Neurosd. Meth. 36, 155 166. 161. Izzo P. N. and Bolam J. P. (1988) Clwlinergic synaptic input tll different parts of spiny striatonigral neurons in the

rat. J. camp. Neural. 269,219--234. 162. Jaeger D., Kita H. and Wi1son C J. (] 994) Surround inhibition among projection neurons is weak or nonexistent in

the rat neostriatum. 1. Neurophvsiol. 72, 2555 -255H. 163. Jayaraman A. (1983) Topographic organization and morphology of peripallidal and pallidal cells projecting to the

striatum in cats. Brain Res. 275, 279 286. 164. Jiang X., Johnson R. R. and Burkhalter A. (1993) Visualization of dendritic morphology of cortical projection

neurons by retrograde axonal tracmg . .I. Neurosci. Melh. 50, 45~60. 16.'. Jimenez-Castellanos J. and Graybiel A. M. (19P) Subdivisions of the dopamine-containing A8 A9 AIO complex

identified by their differential mes()striatal innervation of striosomes and extrastriosomal matrix. Neuroscience 23, 223-242.

166. Joel D. and Weiner I. (1994) The organization of the basal ganglia· thalamocortical circuits: open interconnected rather than closed segregated. Neuro.lciem c 63, 3(,3 379.

167. Joel D. and Weiner I. (1997) The connections "f the primate subthalamic nucleus: indirect pathways and the open-interconnected scheme of basal t(anglia-thalamocortical circuitry. Brain Res. Rev. 23, 62-n.

167a. Johnson L., Koos T., Zaborszky L., Moore K. and Tepper J. M. (1997) GABAA receptor-mediated inhibition of medium spiny neurons by fast spiking interneurons in rat neostriatum. Soc. Neurosci. Abstr. 23. 1279.

382 Y Smith t'I al.

168. Kawaguchi Y., Wilson C. J., Augood S. J. and Emson P. C (1995) Striatal interneurones: chemical, physiological and morphological characterization. Trends Neurosci. 18, S27 535.

169. Kawaguchi Y., Wilson C. J. and Emson P. C (1990) Projection sUbtypes of rat neostriatal matrix cells revealed by intracellular injection of biocytin. J. Neurosci. 10,34213438.

170. Kemp J. M. (1970) The termination of strio-pallidal and strio-nigral fibres. Braill Rcs. 17. 125 128. 171. Kemp J. M. and Powell T P. S. (1971) The site of termination of afTerent t1bres in the caudate nucleus. Phi/. Tram

R. Soc. Lond. 8262,413--427. 172. Kemp J. M. and Powell T P. S. ( 1971) The structure of the caudate nucleus of the cat: light and electron microscopy.

Phil. n·ans. R. Soc. Lond. 8262, 383·-401. 171 Kemp J. M. and Powell T P. S. (1971) The termination of fibres from the cerebral cortex and thalamw, upon

dendritic spines in the caudate nucleus: a study with thc Golgi method. Phil. T/'(l/ls. R. S(I<. LUIld. 8262, 429-439. 174. Kincaid A. E., Penney J. B., Young A. B. and Ncwman S. W. (1991) Evidence for a projection from the globus

pallidus to the entopeduncular nucleus in the rat. Neurosci. Let/. 128, 121 125. 175. Kincaid A. E. and Wilson C. J. (1996) Conicostriatal innervation of the patch and matrix in the rat neostriatum.

J. comp. NeUl·ol. 374, 578-59~. 176. King M. A., Louis P. M., Hunter B. E. and Walker D. W. (19~9) Biocytin: a vers,ltile anterograde ncuroanatomical

tract-tracing alternative. Brain Re.l. 497,361 367. 177. Kisvarday Z. F. and Eysel U. T. (1992) Cellular organisation nf reciprocal patchy networks in layer III of cat viswil

cortex (area 17). Neuroscience 46, 275·2xo. 178. Kita H. (1993) GABAergic circuits of the striatum. In Chemical Signalling in the Bma/ (iallgtia (eds Arbuthnott

G. W. and Emson P. C), pp. 51 1'2. Progress in Brain Research, Vol. 99. Elsevier Science, Amsterdam. 179. Kita H. (\ 992) Responses of globus pallidwi neurons to cortical stimulation: intracellular study in the rat. Brall1 RI'S.

589,84-90. 180. Kita H. (1994) Physiology of two dbynaptic pathways from the sensorimotor cortex to the basal ganglia output

nuclei. In The Basal Ganglia I V- NcH' Ideas and Dala 0/1 Srrw lure and fimCfion (eds Pcrcheron G., McKcnzie J. S. and Feger J.), pp. 263-276. Plenum. New York.

181. Kita H., Chang H. T and Kitai S. T (1983) The morphology of intracellularly labcled UIt subthalamic neurons: a light microscopic analysis . .1. ({)mp. Neuro/. 215, ~45 257.

182. Kita H. and Kitai S. T (19X7) Efferent projections of the subthalamic nucleus in the rat: light and electron microscopic analysis with the PHA-L method . .I. CI!I111' lVclIroi. 260,435-452.

183. Kita H. and Kitai S. T (1990) Amygdaloid projections to the frontal cortex and the striatum in the rat. .1. cnll1J1. N<!urol. 298,4049.

184. Kita H. and Kitai S. T (1991) Intracellular study or rat globus pallidus neurons-- membrane pmperties and respOIN" to neostriatal subthalamic and nigral stimulation. Brain Res. 564, 296--305.

185. Kita H. and Kitai S. T. (1994) The morphology of gk,bus pallidus projection neurons in the rat: an intracellular staining study. Brain Res. 636, 308 ~19.

186. Kita H., Kosaka T and Heizmann C. W. (1990) Parvalbumin-immunoreactive neurons in the rat ncostriatum: a light and electron microscopic study. Bmin Rei. 536, I 15.

187. Kitai S. T. and DeniaLl J. M. (llJxl) Cortical inpuh to the subthalamus: intracellular analysis. Brain RI'S. 214, 411415.

188. Kitai S. T, Kocsis 1. D., Preston R. J. and Sugimori '\1. (1970) Monosynaptic inputs to caudate neurons identilicd by intracellular injection or horseradish peroxidase. Brain RI'S. 109, 601-606.

189. Klockgether T and Turski T. (1993) Toward an understanding of the role or glutamate in experimental Parkinsonism: agonist-sensitive sites in the basal ganglia. Ann. Neurol. 34, 585 593.

189a. Kreiss D. S., Anderson I.. A. and Waiters 1. R. (1996) Apomorphine and dopamine D, receptor agonists increase the firing rates of subthalamic nucleus neurons. Nellroscience 72, X63-876.

190. Kubota Y. and Kawaguchi Y (1993) Spatial distribution of chemically identified intrinsic neurons in relation tll patch and matrix compartments of' rat ne()slriatu!l1. 1. mmp .. Vel/roi. 332,499-513

190a. Kung 1.., Force M .. Chute D . .I. and Robcrts R. C. (19<)1\) Immunocytochemical localization or tyrosine hydroxylase in the human striatum: a postmortem ult rastructural study. 1. (omp. Ncurol. 390, 52 (i~.

191. Kunishio K. and Haber S. "l. (1994) Primate cingulostriatal projection: limbic striatal ""n,us sensorimotor striatal input. 1. comp. Neurol. 350, 337 356.

191a. Kiinzle H. (1975) Bilateral projections from precentral motor cortex to the putamen and other parts of the basal ganglia. An autoradiographic ,tudy in Macaca .I;,scicuiaris. Brain Res. 88, 195- 209.

192. Kiinzle H. (1977) Projections from the primary somatosen,ory cortex to basal ganglia and thalamus in the Illonkey. Brain Res. 30, 481-492.

193. Kiinzle H. (1978) An autLlnldiographic analysis of the ctTcrcnt connections from premntll1' and adjacent prefrontal regions (areas 6 and 9) in Macacajosciculoris. Brain Behal' E)'()!. 15, 185 234.

194. Kuo H. and Chang H. T. (199:n Ventral pallido-stnat,il path'" ay in the rat brain a light and electron microscopic study. 1. comp. Neurol. 321. 6:'9 63(,.

195. Laitinen L. V., Bergenheim .. \. T ,111d Hariz M. I. (1992) Ventroposterolatcral pallidotolllY can abolish all parkinsonian symptoms. S'lcreo{a1'l. FII/7ct. Nl'urosflrg. 58, 14~-21.

195a. Laitinen I.. V., Bergenheilll A T. and Hariz M. I. (1992) Leksell's posteroventral pallidotomy in the treatment or Parkinson's disease. J. Ncurosllrg. 76, 53 61.

195b. Lang A. E., Lozano A. :V1.. Montgomcry E .. Dull1.. fasker R. and Hutchinson W. 11997) Posteroventral medial pallidotomy in advanced Parkinson's disease. :VClt' Engi. 1. Med 337, 1036 1042.

196. Lapper S. R. and Bolam 1. P. (1992) Input from the frontal cortex and the parafascicular nucleus to cholinergic interneufones in the dorsal striatum or the rat. .Veuroscience 51, 533-545.

197. Lapper S. R., Smith Y .. Sadikot A. F .. Parent A. and Bolam J. P. (1992) Cortical input to parvalbumin­immunoreactive neurones in the putamen of the squirrel monkey. Brain Res. 580.215224.

198. Lavoie B. and Parent A. (1990) Immunohistochemical study of the serotoninergic innervatiolJ of the basal ganglia in the squirrel monkey. 1. COJll/,. 'Yeuro!' 299, I 16.

M lcrocircuitry of the basal ganglia 383

199. Lavoie B. and Parent A. (1994) Pedunculopontine nucleus in the squirrel monkey: projections to the basal ganglia as revealed by anterograde tract-tracing methods. 1. comp. Neuro/. 344, 210-231.

200. Le Moine C, Normand E. and Bloch B. (1991) Phenotypical characterization of the rat striatal neurons expressing the DI dopamine receptor gene. Proc. Ililln. Acad. Sei. USA. 88,42054209.

201. Le Moine C, Norrnand E., Guitteny A. F., Fouque B .. Tenule R. and Bloch B. (1990) Dopamllle receptor gene expression by en kephalin neurons in rat forebrain. Proc. naln. Acad. Sei. USA. 87,230- 134.

202. Levesque M .. Charara A., Gagnon S., Parent A. and Deschenes M. (1996) Corticostriatal projections from layer V cells in rat are collaterals of long-range corticofugal axons. Brain Res. 709, 311 .> 15.

203. Levey A. I., Bolam J. P., Rye D. B .. Hallanger A .. Demuth R. M., Mesulam M.-M. and Wainer B. If_ (19~6) A light and electron microscopic procedure for sequential double antigen localization using diaminobenzidine and benzidine dihydrochloride.1. Histochem. Cylochcm. 34, 1449--1457.

204. Levy R., Hazrati L. K, Herrero M. T .. Vila M .. Hassani O. K .. Mouroux M .. Ruberg M .. Asensi H., Agid Y .. Fcger L Obeso J. A., Parent A. and Hirsch E. C /1997) Re-evaluation of the functional anatomy of the ha,al ganglia in normal and parkinsonian states. Neuroscience 76, 335· 343.

205. Liles S. L. and Updyke B. V. (1985) Projection of the digit and wrist area of precentral gyrus to the putamen: relation between topography and physiological properties of neurons in the putamen. Brain RI'S. 339, 24~ 255.

205a. Limousin P., Greene J., Pollak P., Tothwell J., Benabib A.-L and Frackowiak R. (1997) Changes in cerebral activity pattern due to subthalamic nucleus or internal pallidum stimulation in Parkinson's disease. Ann. Ncurol. 42,283-291.

206. Limousin P., Pollak P., Benazzouz A., Hoflinann D., Broussolle E .. Perret J. E. and Benabid A.-L. (1'195) Bilateral subthalamic nucleus stimulation for severe Parkinson's disease. MOI'C/1Ient Disord. 10, 67~ 674.

207. Llewellyn-Smith I. J., Pilowsky P. and Minson J. B. (1993) The tungstate-stabilized tetramelhylbenzidine reaction for light and elcctron microscopic immunocytochemistry and for revealing biocytin-filled neurons. J. >Vel/rosei Meth. 46, 2740.

208. Lozano A. M., Lang A. E., Galvez-Jimenez N., Miyasaki J., Dufl' L Hutchinson W. D. and Dostl'llVsky J. O. (19'15) Effect of GPi pallidotomy on motor function in Parkinson" disease. Lancet 346, 1383 1387.

209. Mahalik T. J. (1988) Direct demonstration of interactions between substance P immunoreactive terminals and tyrosine hydroxylase immunoreactive llL'urons in the substantia nigra of the rat: an ultrastructural stltdy. S.I'napsc 2, 508-515.

210. Martone M. E., Armstrong D. M .. Young S. J. and Groves P. M. (1992) Ultrastructural examination of en kephalin and substance P input to cholinergic neurons within the rat striatum. Brain Res. 594, 253 262.

211. Matsumura M., Kojima J., Gardiner T. W_ and Hikosaka O. (1991) Visual and oculomotor functiolls of the monkey subthalamic nucleus. 1. Neul'Opil,rsiui. 67, 1615 -1632.

212. McDonald A. J. (1991) Organizatilln ot'alllygdaloid projections to the prefrontal cortex and associated striatum in the rat. Neuroscience 44, I 14

213. McDonald A. 1. (1991) Topographical organization or amygdaloid projections to the caudatoputamen lluclcus accumbens and related striatal-like areas of the rat brain. Nl'lIrosciencl' 44, 15-,33.

214. McGeorge A. ]. and Faull R. L 11989) The organization of the projection from the cerebral eortex III the striatum in the rat. Neuroscil!llCl! 29, 503 5.>7.

215. Mesulam M.-M., Mufson E. 1.. \Vainl'f B. H. and Levcy .A. L (In3) Central cholinergic pathways in the rat: an overview based on an alternative nomenclature (Ch I Chb). Neuroscience to, 1185 ,120 I.

216. Mesulam M. M., Mash D., Hersh L .. Rothwcll M. and Cieula C 11992) Cholinergic innervation of the human striatum, globus pallidus. subthalamic nucleus. substantia nigra and red nucleus. 1. comp. Neuroi. 323,252-268.

217. Miller W. C. and Dc Long M. R. 119R7) Allered tonic activity of neurons in the globus pallidus and subthalamic nucleus in the primate MPTP model of Parkinsonism. In 7/1<' Basal Ganglia II (eds Carpenter M. H. and Jayaraman A.), pp. 415-427. Plenum. New York.

217a. Mink J. W. 11996) The basal ganglia: focused selection and inhihition of competing motor programs. Prog Neurohiol 50, 381 -425

218. Mink J. W. and Thach W. T. (1991) Basal ganglia motor control. I. Nonexclusive relation <)f pallidal discharge to five movement modes. J Neurophysiol. 65, 273 300.

219. Mink J. W. and Thach W. T. (1991) Basal ganglia motor mntrol. 11. Late pallidal timing relative to movement onset and inconsistent pallidal coding of movement parameters. I JVeurophysioi. 65, 301 329.

220. Mink J. W. and Thach W. T. (199<) Basal ganglia intrinsic circuits and their role in behaviof. Curl' Opil1. Neurohiol 3, 950-957,

221. Mintz t, Hammond C, Guibert B. and Levicl V. 11986) Stimulation of the subthalamic nucleus enhances the release of dopamine in the rat substantia nigLI. Braill Res 376,40" 408.

222. Mitchell S. 1.. Richardson R. T., Baker F H. and De Long M. R. (1987) The primaw globus pallidu,: neuronal activity related to direction of l1l0wmcnl. E\p/ Brain Res. 68,491 505

223. Moon Edley S. and Graybiel A. M. (19R3) The alfercnt and effcrent connections of the feline nuclew, tegmenti pedunculopontinus pars compacta. J. Wlllp. Ncw'ot 217, IR7-~15.

224. Moriizumi T. and Hattori T. 11l)9~) Separate neuronal pllpulations of the rat globus pallidu, projecting to the subthalamic nucleus. auditory eortn and pedullcultlpontine tegmental area. NeurOlciencc 46, 70 I 710.

225. Moriizumi T.. Nakamura Y., Kitao 1. and Kudo \1. (I'1H7) Ultrastructural analyses of afferent terminals in the subthalamic nucleus of the cat with a combined degeneratil'n and hor:.eradish peroxidase tracing method. J. comp. Neurol. 265. 159174.

226. Moriizumi T., Nakamura Y., Okoyallla S. and Kitao Y. (1987) Synaptic organization of the cat entopeduncular nucleus with special reference to the relationship between the affcrcl1ls to entopeduneulothalamic projection neurom-: an electron microscope study by a combined degeneration and horseradish peroxidase tracing technique. Neuro­science 20,797--816.

227 Mouroux M. and Feger J. (1993) I'vidence that the parafilscicular projection to the subthalamic nucleus is glutamatergic. NeuroReport 4, 6]:<- 61 ~

228. Mouroux M., Hassani O.-K. and Fcger J. (1995) Electrophysiological study of the excitatory parafascicular projection to the subthalamic nuclew, .md evidence for ipsi- and contralateral controb. NcuTOS!iclIU' 67,399-407.

384 Y. Smith er (11.

229. Nakanishi H., Kita H. and Kitai S. T. (1991) Intracellular study of rat entopeduncular nucleus neurons in an ill vitro slice preparation: response to subthalamic stimulation. Brain Res. 549. 285-291.

230. Nambu A. and Llinas R. (1997) Morphology of globus pallidus neurons: its correlation with electrophysiology in guinea pig brain slices. J COlllp. Neuro!' 377.85-94.

231. Nambu A., Takada M .. lnase M. and Tokuno H. (1996) Dual somatotopical representations in the primate subthalamic nucleus: evidence for ordered but reversed body-map transformations from the primary motor cortex and the supplementary motor area. J. Neurosci. 16, 26712683.

232. Nauta H. 1. W. (1979) Projections of the pallidal complex: an autoradiographic study in the cat. Neuroscience 4, 1853-1873.

233. Nauta W. J. H. and Domesick V. B. (1984) Afferent and efferent relationships of the basal ganglia. In FUl1ctiollS oj"the Basal Ganglia (eds Evered D. and O'Connor M.). C[BA Foundation Symposium 107, pp. 3-23. Pitman, London.

234. Nieoullon A. and Kerkerian-Le Golf L. (1992) Cellular interactions in the striatum involving neuronal systems using "classical" neurotransmitters possible functional implication,. MOl'ement Disord 7, 31 I 325.

235. Obeso 1. A., Guridi J. and DcLong M. R. (1997) Surgery for Parkinson's disease. J .'Ycuro! Ncurosurg. Psych ill I. 62. 2-8.

236. Oorschot D. E. (1996) Total 11 umber of neurons in the neostriatal, pallidal. subthalamic. and substantia nigral nuclei of the rat basal ganglia: a stereological study using the Cavalieri and optical disector methods . .I comp. Neu!"o/. 366, 580-599.

237. Pare D. and Smith Y. (1996) Thalamic collaterals of corticostriatal axons: their termination field and synaptic targets in cats. 1. comp. NeU/"o/. 372, 55 I 567

238. Parent A. (1990) Extrinsic connections of the basal ganglia. Trends NeuI"IJsci. 13, 254 2~~ 239. Parent A., Charara A. and Pinault D. (1'195) Single striatotilgal axons arborizing in both pallidal segments and in the

substantia nigra in primates. Brain Res. 698, 280 284. 240. Parent A. and De Bellefeuille L. (1983) The pallidointralaminar and pallidonigral projections in primate as studied

with retrograde double-Iabeling method. Brain Rc.,. 278, 11 -27. 241. Parent A. and Hazrati L.. N. 11993) Anatomical aspects of inl-ormation processing in primate basal ganglia. TrCllds

N eurosci. 16, 111-116. 242. Parent A. and Hazrati L. N. 119(5) Functional anatomy of the basal ganglia. 1. The cortico-basal ganglia -thalamo­

cortical loop. Brain RI'S. Rei" 20, 9 [ 127. 243. Parent A. and Hazrati L. N. (1995) Functional anatomy orthe basal ganglia. 2. 'r he place of subthalamic nucleus and

external pallidum in basal ganglia circuitry. Brain RI'S. Rn. 20, 128 154. 244. Parent A. and Smith Y. 119871 OrganiLation or efferent projections of the subthalamic nuclcus in the squirrel monkey

as revealed by retrograde labding methods. Brain Res. 436, 296 310. 245. Parent A., Smith Y .. Filion 1\1. and Dumas 1. (I9~91 Distincl atlcrcnts to internal and c'temal pallidal segments in

the squirrel monkey. NCllrn.I',' Lel/. 96, 140 144. 246. Park M. R .. Falls W. 1\.1. and Kitai S. T. (1982) An intracellular HRP study of the rat globus pallidus. I. Responses

and light minoscopic analysi,. 1. COli 11' :Vt'lIrol. 211, 2X4 294. 246a. Parthasarathy H. B. and Ciral'biel A. M. (1997) Cortically driven immediate-early gene expression reflects modular

influence of sensorimotor cortcx 011 identilicd striatal neurons in the squirrel monkey . .I. N('/Irosci. 17,2477 24'.11. 247. Pasik P., Pasik T. and DiFigli'l M. (1')79) The internal organization of the neostriatum in mammals. [n iVeo.'lriallllll

(eds Divac I. and Oberg R. U. E.), pp. 5 ~6. Pergamon. Oxford. 248. Pasik P., Pasik T., Holstein C,. R. and Hamori J. (1988) GABAergic elements in the ncur<ll1al circuits of the monkey

neostriatum: a light and electron micrnscoplc immunocytochemical study . .I. COII/p. NCllrol. 270, 157 170. 249. Percheron G. and Filion M. (1991) Parallel proce>'ing in the basal ganglia: up to a point [letter, Cl)mment). Trellds

Neurosci. 14, 55 59. 250. Percheron G .. Fran.;ois C. anJ Yclnik J. (1987) Spatial organisation and information processing in the core of the

basal ganglia. In Thc Basal (j(/nglia If (cds Carpenter M. B. and Jayaraman A.), pp. 205 225. Plenum. New York. 251. Phelps P. E .. Houser C. R. and Vaughn J. E. (I9XS) Iml11uIl()cytochemica1localizatinn Ill' choline acetyltransfcrase

within the rat neostriatum: a correhncd li).':ht and electron microsCl1pic study of cholinergic neurons and synap,es . .I. comp. /I/eurol. 238. 286 307.

252. Pickel V. M. and Chan 1. (1990) Spiny neurtlns lacking choline acetyltransferase immul1llreactivity are major targets of cholinergic and catecholaminergic terminals in rat striatum. 1. Nel/rosci. Res. 25, 26.< 2XO

253. Pickel V. M .. Chan 1. and Sesack S. R. (1992) Cellular basis for interactions between catccholaminergic atferents and neurons containing ku-cnkephalin-Iike immunoreactivity in rat caudate pulamen nuc·lci . .I. Neurosci. Res. 3[, 212230.

254. Pickel V. M., Chan J. and Sesack S. R. 11(93) Cellular substrates for interactions between dynorphin terminals and dopamine dendrites in rat ventral tegmental area and substantia-nigra. Braill Res. 602,275 ·289.

255. Pickel V. M., Sumal K. K .. Heckle)" S. C, Miller R. J. and Reis D. J. (1980) [mmunocytochemicallocalization of enkephalin in the neostriatum of rat hrain: ,t light and electron microscopic study. J ("(ill/I'. ,vcl/m/. 189, 721 -740.

256. Rafols J. A. and Fox C. A. (1,)761 The neurones in the primate ,ubthalamil' nucleus: a Golgi and electron microscopic study. 1. ("(Ill/I'. Neuro/. 1611, I:') I J.:'

257. Rajakumar N., Elisevich K. and Flumerfelt H. A. (1993) Biotmylated dexlran a versatile anterograde and retrograde neuronal tracer. Brain Re.l. 607. 47 53.

258. Rajakumar N .. Elisevich K. and Flumerfelt B. i\. (1994) The pallidostriat<tl projecti()n in the rat: a recurrent inhibitory loop". Braill Rc.,. 6:;1, 332 336.

259. Reiner A .. Veenman C. l.. and HOl1ig M. G. (1993) Anterograde tracing using biotinylated dextran amine. Nell}"o." i. Protocols 93-050-14.

260. Ribak C. E., Vaughn J. E and Roberts F. (1979) The GABA neurons and their axon termmals in rat corpu, striatum as demonstrated by GAD immunocytochemistry. J cumI'. Neurol. 187,261 284.

26 t. Rinvik E., Grofova I., /-Iamm,md c., Feger J. and Deniau .J.- M. (1979) A studv of the afferent connections to the subthalamic nucleus in the monkey and cat using HRP technique. In .4."1'(11/("1:.; in NClIrologr. Vol. 24. The Extra­pyramidal 8.1'.111'11/ (lnd its Disordel"l (eds Poirier L. 1., Sonrkes 1'. L. and Bedard P . .I.), pp. "3 71. Plenum. New Yor~.

IVI icrocircuitry of the basal ganglia 385

262. Rinvik E. and Ottersen O. P. (1993) Terminals of subthalamonigral fibres arc enriched with glutamate-like immunoreactivity: an electron microscopic immunogold analysis in the cat. 1. chem. Neuroanat. 6, 19-30.

263. Romansky K. V., Usunoff K. G., Ivanov D. P. and Galabov G. P. (1979) Corticosubthalamic projection in the cat: an electron microscopic study. Brain Res. 163, 319- 322.

264. Rosales M. G., Flores G., Hernill1dez S., Martincz-Fong D. and Aceves J. (1994) Activation of subthalamic neurons produces NMDA receptor-mediated dendritic dopamine release in substantia nigra pars reticulata: a microdialysis study in the rat. Brain Res. 645, .135~37.

265. Russchen F. T., Bakst I., Amarel D. Cr. and Price J. L. (19X5) 'fhe amygdalostriatal projections in the monkey. An anterograde tracing study. Brain Res. ]29,241-257

266. Ryan L. 1. and Clark K. B. (1991) The role of the subthalamic nucleus in the response of globus pallidus neurons to stimulation of the prelimbic and agranular frontal cortices in rats. Ex/,/ Brain Res. 86,641 651.

267. Ryan L. 1. and Sanders D. 1. (1994) Subthalamic nucleus and globus pallidus lesions alter activity in nigrothalamic neurons in rats. Brain Res. Bull. 34. 19 26.

268. Ryan L. L Sanders D. J. and Clarke K. H. (1992) Auto- and cross-correlation analysis of subthalamic nucleus neuronal activity in the neostriatal-lesioned and globus pallidal-Iesioned rab. Bmin Res. 583, 253 261.

269. Sadikot A. F., Parent A. and Francois C (\ 992) Efferent connections of the centromedian and parafascicular thalamic nuclei in the squirrel monkey: a PHA-L study of subcortical projections. 1. comp. Neuro/. 315, 137-159.

270. Sadikot A. F., Parent A., Smith Y. and Bolam J. P. (1992) Efferent connections of the centromedian and parafascicular nuclei in the squirrel monkey. A light and electron microscopic study of the thalamostriatal projection in relation to striatal heterogeneity. 1. <"fillip Neur,,/. 320, 22R 242.

271. Scarnati E., Florio T.. Cerrito F. and Di Loreto S. (1994) Regulatory action of the dopamincrgic nigrostriatal pathway on the corticostriatal transmission. In The Basal Ganglia n': Nell' Ideas and Dala (In Slru<"lllre and rZlflclioll (eds Percheron G., McKenzie 1. S. and Fegcr J.), pp. 277 2Rl Plenum. New York.

272. Schmued L, Phermsangngam P., Lee H, Thio S .. Chcn E., Truong P., Colt on E. and Fallon 1. (19R9) Collateralization and GAD immunoreactivity of descending pallidal efferent,. Brain Res. 487, U 1 142.

273. Schultz W., Apicella P. and Ljungberg T. (\'193) Responses of monkey dopamine neurons to reward and conditioned stimuli during successive steps of learning a delayed response task. 1. Vellrosci. 13, 894--X99.

274. Schultz W., Dayan P. and Montague P. R. (] 997) A neural substrate of prediction and rc\\ard. Science 275, 1593-1599.

275. Se lemon L. D. and Goldman-Rakic 1'. S. (1985) Longitudinal topography and interdigitation of corticostriatal projections in the rhesus monkey. J lveurosci. 5,776-794.

276. Shammah-Lagnado S. 1., Alhcid G. F. and Heimer L. (1996) Efferent connections of the caudal part of the globus pallidus in the rat. 1. comp. Nel/ro/. 376, 489 507.

277 Shink E., Bevan M. D., Bolam 1. P. and Smith Y. (1996) The subthalamic nucleus and the external pallidum: two tightly interconnected structures that control the putput of the basal ganglia in the monkey. Neuroscience 73, 335·-357.

278. Shink E., Sidibe M., Bouffard 1.-F. and Smith Y. ( 19961 Efferent connections of different functional territories of the internal pallidum in monkeys. SO!". ,veurosei. Ahsl/". 22, 411.

279 Shink E., Sidibe M. and Smith Y. (\ 997) Efferent connections of the internal globus pallidus in the squirrel monkey. 2. Topography and synaptic organization of pallidal effcrenh to the pedunculopontine nucleus. J (fl/I//,. Neurol. 382, 348-363.

280. Shink E. and Smith Y. (1995) Differential synaptic innervation of neurons in the internal and external segments of the globus pallidus by the GABA- and glutamate-containing terminals in the squirrel monkey. J ('(Imp. Neurol. 358, 119-141.

281. Shink E. and Smith Y. (1995) Synaptic organization ofGABAergic terminals in the subthalamic nucleus (STN) of the squirrel monkey. Soc. Nellrosci. Ahsl/". 21,676.

282. Shu S. Y. and Peterson G. M. (1988) Anterograde and retrograde axonal transport of 1'1/£1.1'1:0111.1' vu/gun's leucoagglutinin IPHA-L) from the globus pallidus to the striatum of the rat. 1. Neurosci. !'v[elh. 25, 175 -180.

283. Sidib6 M., Bevan M. D .. Bolam 1. p, alld Smith Y. (1997) Efferent connections of the internal globus pallidus in the squirrel monkey. I. Topography and svnaptic organization of the pallidothalamic projection. J comp. Neurol. 382, .123-347.

284. Sidibe M. and Smith Y. (1996) Differential synaptic innervation of striatofugal neurones projecting to the internal or external segments of the globus p,1l1idus by thalamic atlercnts in the squirrel monkey. J comp. Ncurol. 365, 445-465.

285. Smith A. D. and Bolam J. P. (1990) 1 he neural network of the basal ganglia as revealed by the study of synaptic connections of identified neurones. Tn-nds /I;curosci. 13, 259 -265.

286. Smith 1. D. and Grace A. A. (1992) Role of the subthalamic nucleus in the regulation of nigra I dopamine neuron activity. Synap.w: 12, 287 -303,

287. Smith Y. (1993) A double anterograde tracing method at the electron microscopic level. -Ycurosci. Protocols 93-050-04.

288. Smith Y., Bennett B. D., Bolam 1. P .. Parent A. and Sadikot A. F. (1994) Synaptic relationships between dopaminergic atferents and cortical or thalamic input in the sensorimotor territory of the striatum in monkey. 1. comf'. NeuroJ. 344, 1-19.

289. Smith Y. and Bolam 1. P. (1989) Neurons of the substantia nigra reticulata receive a dense GABA-containing input from the globus pallidus in the rat. Brain Res. 493, 160 167.

290. Smith Y. and Bolam J. P. (1990) Convergence of pallidal and striatal inputs to neurones in the entopeduncular nucleus and substantia nigra of the ral: application of a new double anterograde labeling method at the electron microscopic level. Soc. Neurosci. Ah.llr. 16, 236.

291. Smith y, and Bolam 1. P. (1990) The output neurons and the dopaminergic neurones of the substantia nigra receive a GABA-containing input from the globus pallidus in the rat. J ("omp. Nemo/. 296,47--64.

292. Smith Y. and Bolam J. P. (1991) Convergence ()f synaptic inputs from the striatum and the globus pallidus onto identified nigrocollicular cells in the rat a duuble anterograde labelling study. Neuroscience 44, 45 7~

386 Y Smith d a/.

293. Smith Y. and Bolam J. P. (1992) Combined tracing and immunohistochemical techniques for studying neuronal microcircuits. In Expaimcntai Neuroanatomy: A Praniwi Approach (eds Rickwood D. and Hames B. D.), pp. 239 266. Oxford Unversity Press (IRL), Oxford.

294. Smith Y .. Bolam J. P. and von Krosigk M. (1990) Topographical and synaptic organization of the GABA-containing pallidosubthalamic projection in the rat. Eur. J. Neuro.lci. 2, 500--511.

295. Smith Y., Hazrati L.-N. and Parent A. (l990) Efferent projections of the subthalamic nucleus in the squirrel monkey as studied by the PHA-L anterograde tracing method. J. COlllp. Neuro/. 294,306- 323.

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

297. Smith Y. and Parent A. (1988) Neurons of the subthalamic nucleus in primates display glutamate but not GABA immunoreactivity. Brain Res. 453, 353 -356.

298. Smith Y., Wichmann T. and De Long M. R. (1993) The external pallidum and the subthalamic nucleus send convergent synaptic inputs onto single neurones in the internal pallidal segment in monkey: anatomical organization and functional significance. In The Basal Ganglia IV: /Veil· Ideas and Data on Structure and FflllCrion (cds Percheron G., McKcnzie J. S. and Feger J.), pp. 51-62_ Plenum. New York.

299. Smith Y., Wichmann T. and DeLong M. R. (1994) Synaptic innervation of neurones in the internal pallidal segment by the subthalamic nucleus and the external pallidum in monkeys. J. ClllIlp. N('um/ 343,297 318.

300. Soghomonian J.-J., De;.carries L. and Watkin, K. C. (19k9) Serotonin innervation in adult rat neostriatulll. 11. C1trastruetural features: a radioautographic and immunocytochemical study. Brain Rn. 41H. 67 86.

30 I. Somogyi P., Bolam J. P. and Smith A. D. (19X 1) Monosynaptic cortical input and local axon collaterals of identified striatonigral neurons. A light and electron microscopic ,tudy using the Golgi peroxidase transport degeneration procedure. 1. comp. Neuro!' 195,567-584.

302. Somogyi P., Bolam J. P., Totterdell S. and Smith A. D. (llJ81) Monosynaptic input from the nucleus accumbcns­ventral striatum region to retrogradely labelkd nigrostriatal neurone:,. Brain Rcs. 217. 245 263.

303. Somogyi P. and Frcund T. F. (1989) Immunocytochemistry and synaptic relationships of physiologically character­ized HRP-filled neurons. In Ncuroanatomic,i/ Tract- Tracing AI<'filods 11 (eds Heimer I.. and Zaborszky L.), pp. 239-264. Plenum, New York.

304. Somogyi P. and Hodgsoll A. J. (1985) Antisera to ;-alllinobutyric acid. Ill. fkmonstration of GABA in Golgi-impregnated neurons and 111 conventional electron microscopic sections of cat striate cortex. J. His/(lci1cl17 C\tochem. 33,249-257.

30S. S;Jmogyi P., Hodgson A. J. and Smith A. D. (1979) An approach to tracing neuron networks in the cerebral cortex and basal ganglia. Combination of Golgi staining retrograde transport of horseradish peroxidase and antcr,)grade degeneration of synaptil· boutons in the same m,jterial. Neuroscience 4, 1805 1852.

306. Somogyi P., Priestley J. V., Cucllo A. C. Smith A. D. and Bolam J. P. (1982) Synaptic connections of ,;ubst,1nce P-immunoreactive nerve terminals in the substantia nigra of the rat: a correlated light- and electron-rTIlcr(lscopic study. Cell Tiss. Res. 223, 469486.

307. Somogyi P., Priestley J. v .. Cuello A. C .. Smith A. D. and Takagi H. (1982) Synaptic connections of cnkephalin­immunoreactive nerve terminals in the ncostriatum: a correlated light and electron microscopic study. 1. Nellf"llcrloi. 11, 779- S07.

308. Spooren W. P. J. M .. Lynd-Balta E., Mitchcll S. and Haber S. N. (1996) Ventral pallidostriatal pathway in the monkey: evidence for modulation of ha sal ganglia circuits . .!. comp. Ncurol. 370, 295 -'I~.

309. Spooren W. P. J. M., Veenillg J. (j. and Cools A. R. (1993) Descending efferent connections of the sub-pallidal areas in the cat: projections ll' the subthalamic nucleus, the hypo thalamus and the midbrain. Synapse 15. 104 123.

310 Staines W. A., Atmadja S. and Fibiger H. C. tl9X I) Demonstration of a pallidostnatal pathway by retmgrade transport of HRP-Iabclcd lectin. Brain Res. 206,446 450.

311. Staines W. A. and Fibigcr 11. C. (1984) Collateral projections of neurons of the rat globus pallidus to t be striatum and substantia nigra. Lxpi Brain Res. 56,217 221).

312. Staines W. A. and Hincke M. T. C. (1991) Subslantial alterations in neurochemical and metabolic indices in select basal ganglia neurons folio\> lesions of globus pallidus. Soc Ncurosci. Ahsrr. 17, 456.

313. Starr M. S. (1995) Antiparkinsonian actions of glutamate antagonists alone and with I -DOPA: a review of evidence and suggestions for possible mechanisms. J I1(,UI""/ Tmnsll1. 10, 141 185

3l3a. Starr M. S. (1995) Glutamale/dopamine ])11])2 balance m the basal ganglia and its relevance to Parkinson's disease. S1'Ilapse 19, 264 293.

314. Sugimoto T. and Hattori T. ( 1984) Organizaticlll and efferent projections of nucleus tegmenti pedunculopontinus pars compacta with special reference to its cholinergic aspects. IVeuro.lcicl1(i! 11. 931 946

315. Sugimoto T., Hattori T., Mizuno N., (toh K. and SaW '\11. (1983) Direct projectinns from the centromedian­parafascicular complex tll the subthalamic nucleus in the cat and rat. .I. cO/np. Nel/ro!. 214.209-216.

315a. Surmeier D . .T. and Kitai S. T. (1994) ])opaminergic regulation of striatal efferent pathways. Curr. Opin Ncurohio/. 4.915··919.

315b. Surmeier D. J., Song W.-.l. ,lI1d Van Z. (19961 Coordinated expression of dopamine reeeptors in neostriatal medium spiny neurons. J. Ncurosci. 16, 657<) 65lJ I.

316. Takada M., Li Z. K. and Hattori T. (19871 Long descending direct projection from the ba,;al ganglia to the spinal cord: a revival of the extrapyramidal concept. Brain Rcs. 436. 129-135.

317. Takagi H., Somogyi P .. Somogyi .T. and Smith A. D. (ln3) Fine structural studic, on a type of somatostalin­immunoreactive neuron and its synaptic wnnections in the rat neostriatum: ,j correlated light and electron microscopic study. J. COlii!' :Vel/m!. 214, I 1(,.

318. Tokuno H., Moriizumi r. Kudo IV1., Kit"" Y. and Nakamura Y. (19X9) Monosynaptic striatal inputs to the nigrotegment81 neurons· an electron microsc()pic study in the cat. Brain Re.l. 485, I X9 192.

319. Totterdell S., Bolam J. P. and Smith A. D. (1984) Characterization of pallidonigral neurons in the rat by a combination of Golgi-impregnation and retrogf<fdc transport of horseradish peroxidase: their monosynaptic input from the neostriatum . .1. NC/lrocviO!. 13. 593 61 f,

320. Tremblay L. and Filioll M. (19R9) Responses of pallidal nellfons to striatal stimu];jtion in intact waking monkeys. Bra in Rn. 498, 1- I 6.

Microcircuitry of the basal ganglia 3R7

321. Turner R. S. and Anderson M. E. (I <)971 Pallidal discharge related to the kinematics of reaching movements in two dimensions. 1. Neurophysia/. 77, 10511074.

322. Van der Kooy D. and Hattori T (19kO) Single subthalamic nucleus neurons project to both the globus pallidus and substantia nigra in rat. 1. comp. :'Veurol. 192, 751 768.

323. Veenman C. L., Reiner A. and Honig M. G. (1992) Biolinylaled dextmn amine as an anterograde tracer for single-labcling and double-Iabcling studies . .f. Neul"Osci. M£'Ih. 41, 239-254.

324. von Krosigk M., Smith Y., Bolam J. P. and Smith A. D. (1992) Synaptic organization ofGABAergic inputs from the striatum and the globus pallidus onto neurones in the substantia nigra and retrorubral field which project to the medullary reticular formation. NCllrll.lciel1tc 50, 531 549.

325. Vuillet .1., Kerkerian L.. Kachidian P .. Bosler O. and Nieoullon A. (1989) Ultrastructural correlates of functional relationships between nigral dopaminergic (lr cortical alferent fibres and neuropeptide Y -containing neurons in the rat striatum. Neurosci. Le!l. 100,99-104.

326. Walker R. H .. Arbuthnott G. W. i1nd Wright A. K. (1989) Electrophysiological and anatomical observations concerning the pallidostriatal pathway in the rat. Exp/ Bwin Re.l. 74,303 310.

327. Wassef M .. Berod A. and Sotelo C (1981) Dopaminergic dendrite, in the pars reticulata of the rat substantia nigra and their striatal input. Combined ,mmunocytochemical localization of tyrosine hydroxylase and anterograde degeneration. Neurosciel1ce 6, 21~5 2139.

32R. Wichmann T .. Bergman H. and DeLong VI. R. (1994) The primate subthalamic nuc1ew,. I. Functional rropertics in intact animals. 1. Neuropliysio/. 72, 494 506.

32'.1. Wichmann T. Bergman H. and Delong '1'1. R. (1994) The primate subthalamic nucleus. III Changes in motor hehavior and neuronal activity in the internal rallidum induced by subthalamic inactivation in the V1PTP model of Parkinsonism. 1. Neurophvsiol. 72. 5: I -530.

329a. Wichmann T and DeLong M. R. (1996) hll1ctional and pathophysiological models of the basal ganglia. ClIrr. Opill. Nellrohio/. 6,751 758.

3311. Wichmann T, Vitek 1. L. and De Long :\1. R. {1995) Parkinson's disease and the basal ganglia: lessons from the laboratory and from neurosurgery. The l,'ellroscien!isl 1,236--244.

331. Williams M. N. and Faull R. L. M. (19X5) The striatonigral projection and nigrotectal neurons in the rat. A correlated light and electron microscopic study demonstrating a monosynaptic striatal input to identified nigrotectal neurons using a combined degeneratilln and horseradish peroxidase procedure. Neur<J.IciclJcc 14,991 IOto.

33~. Wilson C. .I. (1990) Basal ganglia. In The Sl'llul'lic OrgulJi:ali(!n of'the Brain (ed. Shcrherd G M.). pp. 279 316. Oxford University Press. New Yprk.

332a. Wilson C. .I. (1995) The contribution nf cortical neurons to the firing pattern of striatal ,piny nCllrom. In Mode/s of Jl1jimnalioll Pro('fs.I'illg ill lile Ba.\(J/ (iang/iu (cds Houk J. C. Davis J. 1.. and Beiser D. G.). pp. 22 50. MIT. Cambridge. MA.

333. Wilson C. 1.. Chang H. T and Kitai S. T (1990) Firing p<ltlerns <1nL! synaptic potentials of idcntified giant aspiny lI1terneurons in the rat neostriatum. J Neu/'Osci. 10, 50R 519.

334. Wilson C. .I. and Groves P. M. (191\0) Fine structure and synaptic connections of the common spiny neuron of the rat neostriatum: a study employing intracellular injection of horseradish peroxidase. J (omp Neural. 194, 599-615.

335. Wilson C. J. and Phclan K. D. (llJX2) DualtopographiL' reprc,cntation of neostriatum in the ghlhlls pallidus of rats. Brain Rcs. 243, 354--359.

336. Woolf N. 1. and Butcher L. L. (19R61 Cholinergic systems in the rat brain: Ill. Projections from the pontomesen­cephalic tegmentum to the thalamus. lectum. basal ganglia and basal forebrain. Brain Res. Bull. \6, 603-637.

337. Wouterlood F. G. and lorritsma-Byham B. (1993) The anterograde neuroanatomical tracer biotinylated dextran­amine: comparison with the tracer Phaseolll.l' l'ul!{aris-Ieucoagglutinin in preparations for electron microscopy. J. Neurosci. Meth. 48, 75 87.

33R. Wouterlood F. G .. Bol J. G. J. M. and Steinbusch W. M. f19R7) Double-label immunocytochemistry: combination of anterograde neuroanatomical tracing with Pl1a.l'COIIl.1 \'ldgaris Icucoagglutinin and enzyme immunocytochemistry of target neurons. J. flislociJem. Crlo( hem. 35, R 17 R23.

339. Wurtz R. H. and Hikosaka O. (19X61 Role of the ba,," ganglia in the initiation of saccadic eye movements. Prog. Braill Rcs. 64, 175 190.

340. Xu Z. C, Wilson C. J. and Emson P. C (1991) Restoration of thalamostriatal projections in rat neostriata I grafts: an electron microscopic analysis. J. ('"mp. Scum/. 303, 22 34.

341. Yeterian E. H. and Pandya D. N. (1991) Prefrontostriatal connections in relation to cortical arehitectonic organization in rhesus monkeys . .l ('(llIlp . . ',"mml. 312, .'13 -67.

342. Yeterian E. H. and Van Hoesen C. W (197X) Cortico-striate projcctions in the rhesus monkey: the organization of certain cortico-caudate connectioll'. Hraill Res. 139, 4.1 63

343. Yung K. K. L., Smith A. D., Levc; A l. and Bolam .I. P. (1996) Synaptic connections hetween spiny neurons of the direct and indirect pathways in the ncostriatum (lf the rat: evidence from dopamine receptor and neuropeptidc immunostaining. EIII'. J Neum.lci H, X61 xm.

344. Zahm D. S. and Brog J. S. (199~) On the ,ignificance of subterritories in the "accumbcns" part <If the rat ventral striatum . . Veuro.lcicl1(,c 50.751 7il7

(A(cepted 6 jOllual'l' 199R)