Basal Ganglia: Internal Organization - mrcbndu.ox.ac.uk · basal ganglia, that is, the GPi (or EP) and the SNr, by two routes, the so-called direct and indirect pathways. In the direct

Basal Ganglia: Internal OrganizationJ P Bolam, M T C Brown, J Moss, and P J Magill,MRC Anatomical Neuropharmacology Unit, Oxford, UK

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Introduction

The basal ganglia are a group of subcortical nucleiinvolved in a variety of processes, including motor,associative, cognitive, and mnemonic functions. Thedorsal division of the basal ganglia consists of thestriatum (divided into the caudate nucleus and puta-men by the internal capsule in primates and otherspecies), the external segment of the globus pallidus(GPe; simply globus pallidus in rodents), the internalsegment of the globus pallidus (GPi; entopeduncularnucleus (EP) in several species, including rodents andcats), the subthalamic nucleus (STN), and the sub-stantia nigra (SN). The latter structure is divided intotwo main parts, the dorsal pars compacta (SNc), inwhich the dopaminergic nigrostriatal neurons arelocated, and the more ventral pars reticulata (SNr).In addition to these structures that are associated withmotor and associative functions of the basal ganglia,there is a ventral division of the basal ganglia (ventralstriatum or nucleus accumbens; ventral pallidum,which is equivalent to GPe and GPi; and the ventraltegmental area, which is a medial continuation of theSNc). The ventral division of the basal ganglia isprimarily associated with limbic functions. Thenomenclature of divisions of the basal ganglia canbe particularly confusing to a reader new to thefield. For this reason a table (Table 1) of commonlyused terms and their synonyms or homologous struc-tures is included.The main transmitter used by neurons of the basal

ganglia is g-aminobutyric acid (GABA); as many as99% of all basal ganglia neurons are GABAergic. Theonly exceptions are glutamatergic neurons of theSTN, dopamine neurons of the SNc, and one popula-tion of interneurons in the striatum that utilizes ace-tylcholine. The major inputs to the basal ganglia areglutamatergic and are derived from the cerebral cor-tex and the thalamus. The main point of entry of thecortical and thalamic information to the basal gangliais the striatum, although there are also significantprojections to the STN (Figure 1). Virtually the entirecortical mantle projects onto the striatum. The corti-costriatal projection is derived from several classesof cortical pyramidal neurons that predominantly

innervate the ipsilateral striatum but also the contra-lateral striatum. The corticosubthalamic projectionis derived from more restricted regions of the cortex(see below). The corticostriatal and thalamostriatalprojections are highly topographically organized andimpart functionality onto the striatum and, conse-quently, other divisions of the basal ganglia. Themain synaptic targets of the cortical and thalamicinputs to the basal ganglia are the medium-sizeddensely spiny projection neurons of the striatum(�Figures� 2� and� 3�).

In what is now considered the classical view of basalganglia circuitry, the functional organization is suchthat cortical and thalamic information is processedwithin the striatum and integrated with the manyother inputs that reach the basal ganglia (e.g., fromamygdala, hippocampus, and dorsal raphe), which pri-marily innervate the striatum, and then the ‘processedinformation’ is transmitted to the output nuclei of thebasal ganglia, that is, the GPi (or EP) and the SNr, bytwo routes, the so-called direct and indirect pathways.In the direct pathway, cortical and thalamic informa-tion is transmitted directly from the striatum to theoutput nuclei. In the indirect pathway, cortical andthalamic information is transmitted indirectly to theoutput nuclei via the complex network interconnectingthe GPe and STN. The basal ganglia then influencebehavior by projecting, via the output nuclei, to thethalamus (mainly the ventral anterior and ventral lat-eral nuclear complex, mediodorsal nucleus and theintralaminar nuclei) that in turn projects back tothe cortex or by projecting to subcortical regions thatare involved in movement, including the superior col-liculus, the pedunculopontine nucleus (PPN), lateralhabenula, and reticular formation (Figure 1).

Overlying this feed-forward organization of thebasal ganglia are many feedback pathways. Themajor one of these is the dopaminergic projectionfrom the SNc that predominantly innervates thestriatum but also innervates the STN and GPe.This projection modulates the flow of cortical andthalamic information through the basal ganglia.Loss of these dopamine neurons in Parkinson’s dis-ease leads to an imbalance of the flow of corticalinformation through the basal ganglia in favor ofthe indirect pathway and the motor symptomsassociated with this disorder. Other feedback sys-tems include the serotonergic projection from thedorsal raphe and the projection from the GPe tostriatum (see later).

Basal Ganglia: Internal Organization 97

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Striatum

The principal neurons of the striatum, the medium-sizedensely spiny neurons (MSN; Figure 3), give rise tothe direct and indirect pathways. The MSNs have aperikaryon about 15mm in diameter and give rise toseveral dendrites that are initially spine free but thenbecome densely laden with spines after the first bifur-cation. They account for up to 97% of striatal neuronsin rodents but a smaller proportion in primates. Theyutilize GABA as their major neurotransmitter andare subdivided into two major subpopulations on thebasis of their projection region, pattern of axonal col-lateralization, and neurochemical content. One sub-population gives rise to the direct pathway, theypreferentially project to the output nuclei of the basalganglia (but also send a collateral to the GPe), andselectively express the neuropeptides, substance P anddynorphin, and D1 dopamine receptors. The othersubpopulation gives rise to the indirect pathway, theyexclusively project to the GPe and express enkephalinand D2 dopamine receptors. Both populations alsogive rise to local axon collaterals, the principal targetofwhich are otherMSNs.Axon terminals derived fromMSNs form symmetric synapses (Gray’s type 2) andtheir morphological features are similar in all theirtarget regions (Figure 4(a)). Their spines are the maintarget of corticostriatal afferents and at least part ofthe thalamostriatal projection; both projectionsform asymmetric synapses (Gray’s type 1; Figure 2).An individual cortical axon gives rise to only very fewsynapses with an individual MSN; since MSNs possessin the region of 10000–15000 spines, the implicationis that there is a massive convergence of corticalaxons (and possibly thalamic axons) on an individualMSN. The MSNs are also the principal target of thedopaminergic feedback from the SNc (spine necks,dendrites, and perikarya; Figure 2).

Table 1 Nomenclature

Commonly used name for aparticular structure

Homologous structure and/orsynonyms

Striatum Neostriatum, caudate-putamenGlobus pallidus (rat) External segment of globus

pallidus (GPe; primate)Lateral globus pallidus (GPl;

primate)Entopeduncular nucleus (rat) Internal segment of globus

pallidus (GPi; primate)Medial globus pallidus (GPm;

primate)Ventral striatum Nucleus accumbens

Cortex

StriatumSTN

Thalamus

GPe

SNc SNr/GPi

Brain stemspinal cord

SC RF PPN

Output or feedback

HBN

Figure 1 Simplified block diagram of the basal ganglia andtheir principal connections. The nuclei of the basal ganglia areincluded in the light blue box and consist of the striatum,the external segment of the globus pallidus (GPe), the subtha-lamic nucleus (STN), the substantia nigra pars reticulata andthe internal segment of the globus pallidus (SNr/GPi), and thesubstantia nigra pars compacta (SNc). The two major inputsto the basal ganglia are from the cortex and the thalamus(mainly the intralaminar nuclei). The SNr and GPi constitutethe output nuclei of the basal ganglia. The basal ganglia influ-ence behavior by the output nuclei (SNr/GPi) projecting to thethalamus and thence back to the cortex, and projections to thesuperior colliculus (SC), the reticular formation (RF), the ped-unculopontine nucleus (PPN), and the lateral habenula (HBN).Dopamine neurons of the SNc provide a massive feedbackprojection to the striatum and to the GPe and STN, whichmodulates the flow of cortical and thalamic information throughthe basal ganglia. In the now classical description of the orga-nization of the basal ganglia, the output from the striatum to theoutput nuclei is referred to as the ‘direct pathway’ of informationflow through the basal ganglia. This pathway leads to a disinhi-bition of basal ganglia targets and is considered to be asso-ciated with basal ganglia behavior. The ‘indirect pathway’consists of the projection from the striatum to the GPe andthe projection of the GPe to the STN and thence to the outputnuclei. However, recent evidence suggests that the indirectpathway is much more complicated, involving a complex net-work interconnecting the GPe and the STN and the outputnuclei. Furthermore, the STN receives input from both thethalamus and cortex. Activity in the indirect pathway is believedto underlie, at least in part, the resting inhibitory output from theGPi/SNr, and activation of the indirect pathway leads to agreater inhibition of basal ganglia targets and is considered tobe associated with the attenuation of basal ganglia behavior.Dark blue indicates structures that are principally GABAergic,red indicates structures that are principally glutamatergic, yel-low indicates structures that are dopaminergic, and greenindicates structures with variable neurochemistry.

98 Basal Ganglia: Internal Organization


The striatum also contains at least three populationsof GABA interneurons: (1) fast-spiking, parvalbumin(PV)-positive interneurons; (2) those that express nitricoxide synthase (NOS); and (3) those that expresscalretinin. The PV-positive neurons receive majorinputs from the cortex, thalamus, and neurons of theGPe (see the next section) and provide an inhibitoryinput to theMSNs. The striatum also contains a popu-lation of large cholinergic interneurons that receiveinput from the cortex, thalamus and MSNs, and inturn innervateMSNs. The interneurons are also targetsof the dopaminergic input from the SNc.The interneur-ons account for only a small proportion of striatalneurons (!3–10%, depending on species). In additionto its functional division into the direct and indirectpathways, the striatum possesses subcompartments,the striosomes (or patches), matrix, and matrisomes,which possess different neurochemical markers andhave different input/output characteristics.

GPe

The main extrinsic synaptic target of MSNs that giverise to the indirect pathway are the neurons of theGPe. All GPe neurons are GABAergic and differen-tially express the calcium-binding proteins PV or cal-bindin. They are arranged in such a way as to expose

Figure 2 Synaptic connections of cortical, thalamic, and dopa-mine terminals in the striatum. (a) Electron micrograph of a sec-tion immunolabeled to reveal the vesicular glutamate transporter 1(VGLUT1) as a marker of glutamatergic corticostriatal terminalsand tyrosine hydroxylase (the rate-limiting enzyme in the synthe-sis of catecholamines; TH) as a marker of dopaminergic nigros-triatal axons and terminals. The VGLUT1 immunoreactivity wasrevealed by means of an immunogold method (electron-denseparticles, which appear as dense black blobs), and the TH wasrevealed by an immunoperoxidase method (amorphous, electron-dense reaction product giving the labeled structure an overalldark appearance). The majority of cortical terminals typicallyform asymmetric synapses (Gray’s type 1; arrowheads) with

dendritic spines (sp) of the principal neuron of the striatum, themedium-size densely spiny neuron (MSN; see Figure 3). Notethat cortical terminals make synaptic contact with the dendriticshafts of MSNs to a much lesser extent and also make synapticcontact with the dendritic shafts of interneurons. The TH-immuno-reactive axon makes symmetric synaptic contact (Gray’s type 2;small arrows) with the neck of the spine that receives the inputfrom the cortical terminal. This spatial relationship between corti-cal terminals and nigrostriatal terminals has been considered theprincipal site of interaction between dopamine and glutamate inthe striatum and, indeed, the basal ganglia as a whole. Note thatdopaminergic terminals also contact the dendritic shafts and peri-karya of MSNs and of interneurons. (b) Electron micrograph of asection of striatum immunolabeled in a manner similar to (a)except that the vesicular glutamate transporter 2 (VGLUT2) wasused as a marker of thalamostriatal terminals. Axon terminalsderived from the thalamus make synaptic contact with a higherproportion of dendritic shafts than do corticostriatal terminals,although the relative proportions of spines and shafts varies withthe thalamic nucleus of origin. In this micrograph, one VGLUT2-positive terminal forms an asymmetric synapse (arrowheads) witha spine (sp; top left). A second VGLUT2-positive terminal formsasymmetric synaptic contact (arrowheads) with a dendritic shaft(den; lower right). Both the postsynaptic spine and the postsynap-tic dendritic shaft receive synaptic input (small arrows) from TH-positive terminals, indicating that, at least in qualitative terms, thespatial relationship between glutamatergic thalamostriatal term-inals and dopaminergic terminals is similar to the relationshipbetween corticostriatal and dopaminergic terminals. Scale bar"200nm (a, b). From Moss J and Bolam JP (unpublished).



the� maximum� extent� of� their� dendri�tic� arbor� to� theincom�ing� striat�al� afferent�s.� Thus� their� principal� inputis� from� the� striat�um;� pallidal� neu�rons� are� ensheat�hedby� striat�al� terminals� in� a� manner� similar� to� neurons� ofthe� GPi� (�Figure� 4(a)� and� see� below�).� However,� GPeneuron�s� also� receive� pro�minent� inputs� from� the� STN(�Figures� 4(e)� and� 4(f)�)� and� from� the� local� axon� col-lateral�s� of� other� pallidal� neu�rons.� Indiv�idual� GPeneuron�s� in� turn� give� ris�e� to� pr�ojection�s� to� funct�ionallyrelated� territo�ries� of� the� STN,� the� outp�ut� nuc�lei� of� thebasal� ganglia,� a�nd� the� SNc� (Figure� 5),� wher�e� theyform� symmet�ric� synapse�s� predom�inant�ly� with� the

cell� bodies� an�d� proximal� dendri�tes� of� their� targetneuron�s� (Figure�s� 4(b),� 4(c)�,� and� 6).� In� addition,� allGPe� neurons� give� rise� to� local� axon� colla�terals� thatunderl�ie� a� complex� and� structure�d� microci�rcuitrywithin� the� GPe� (�Figure� 5).� About� a� quarte�r� of� GPeneuron�s� give� rise� to� collateral�s� that� inner�vate� thestriat�um� in� addition� to� the� proje�ctions� de�scribedabove� (Figure� 5)�.� Their� principal� sy�na�ptic� targ�etswithin� the� stria�tum� are� the� p�roxima�l� reg�ions� of� the� PV-positiv�e� a�nd� NOS�-positive� G�ABAer�gic� interneurons.Because� the� ma�in� synaptic� ta�rge�ts� o�f� the� PV-positiveGABA�ergic� interneur�ons� are� the� M�SNs,� and� an� indi-vidual� interneur�on� can� innerv�ate� several� hundr�edMSNs�,� GPe� neurons� can� theoretical�ly� control� theactivi�ty� of� every� neuron� in� the� striat�um.� Thus�,� byvirtue� of� their� extensive� ax�on� co�llaterals,� GPe� neuronsare� in� a� pos�ition� to� influ�ence� the� activi�ty� of� neuron�s� atevery� level� of� the� ba�sal� gan�glia.� The� stra�tegicallyimpo�rtant� placeme�nt� of� their� synapse�s� on� the� pro�xi-mal� regions� of� their� target� neu�rons� (�Figure� 6�),� theirGABA�ergic� nature,� and� their� high� resting� dischargeimply� a� cri�tical� role� in� the� modul�ation� of� the� flow� ofinformat�ion� throu�gh� the� basal� ganglia.

STN

The� S�TN� is� a� small� nucleus� located� below� the� thala-mus;� it� con�sists� of� a� relatively� homogene�ous� popula-tion� of� neurons� that� extend� thei�r� dendri�tes� in� theprinc�ipal� plane� of� the� nucleu�s.� The� most� dist�inguish-ing� charac�teristic� of� this� nucleus� is� that,� unlike� themajori�ty� of� neuron�s� in� the� basal� ganglia� (99%�),� neu-rons� of� the� STN� use� glut�amate� as� a� neurotr�ansmitterand� thu�s� ex�ert� excitat�ory� influenc�es� on� thei�r� targe�ts.Tradit�ionally,� the� princ�ipal� inputs� of� STN� ne�uronshave� been� con�sidered� to� be� derived� from� the� GPe,and� indee�d� these� ne�urons� pr�ovide� the� majo�r� inhi�bi-tory� input� to� the� STN� (�Figure� 4(c)�).� In� fact�,� the� STNis� reciproca�lly� conn�ected� to� funct�ional�ly� relatedregion�s� of� the� GPe.� Two� other� major� inputs� to� theSTN� are� derived� from� the� cortex� and� intralaminarthalamic� nuclei.� The� glutamatergic� corticosubthalamicinput� is� mainly� derived� from� the� motor,� premotor,� andprefrontal� cortices� and� is� exclusively� ipsilateral� and,� atleast� in� part,� is� derived� from� collaterals� of� corticalneurons� innervating� the� striatum.� The� corticosubthala-mic� axon� terminals� form� asymmetric� synapses� princi-pally� with� small-diameter� dendrites,� and� this� pathwayis� the� fastest� route� by� which� the� cortex� can� influence� theSTN� and,� through� the� projections� of� STN� neurons,� theoutput� neurons� of� the� basal� ganglia.� The� thalamic� inputto� the� STN� is� also� glutamatergic,� gives� rise� to� asymmet-ric� synapses� with� small-diameter� dendrites,� and� isderived� from� those� thalamic� nuclei� that� also� innervatethe� striatum.� The� STN� also� receives� input� from

Figure� 3� Golgi-impregnated� medium-size� densely� spiny� neuron(MSN)� in� the� rat� striatum.� This� is� the� principal� neuron� of� thestriatum, accounting for up to 97% of all striatal neurons. Theyare GABAergic, give rise to the output from the striatum, and giverise to local axon collaterals. The cell body is approximately 15mmand in this focal plane gives rise to four primary dendrites. Thedendrites are initially spine free and then become densely ladenwith spines, usually after the first bifurcation. An individual MSNpossesses 10000–15000 spines, each of which receives a gluta-matergic input at its head (see Figure 2). The axon is not visible inthis micrograph, but segments of Golgi-impregnated axons (muchfiner structures), presumably derived from other neurons, arepresent in the field. At this anatomical level, the MSNs givingrise to the direct and indirect pathways are indistinguishable, asare MSNs from different species.



dopamine� neurons� of� the� SNc,� serotonergic� neuronsfrom� the� dorsal� raphe� ,� and� cholinergic� inputs� ofthe� PPN.

The� main� outputs� of� the� STN� are� to� functionallyrelated� regions� of� the� output� nuclei� of� the� basalganglia,� that� is,� the� SNr� (Figure� 4(d)) and GPi (or EP).Individual� STN� neurons� also� innervate� the� GPe(Figures� 4(e)� and� 4(f)),� the� PPN,� and� the� dopamineneurons of the SNc. In each target, the terminals ofSTN neurons form asymmetric synapses, and at leastsome have been shown to be enriched in glutamate(Figure 4(e)). The placement of STN terminals ismainly on the proximal regions of their targets. Theglutamatergic nature of STN neurons, their relativelyhigh resting discharge rate, and their responsiveness toexcitatory inputs from the cortex and thalamus under-lie a critical role in setting the level of activity in basalganglia output neurons.

SNr and GPi

The SNr and the GPi (or EP in rodents) represent themajor output nuclei of the basal ganglia, sending theiraxons to the thalamus and thence back to the cortexor to subcortical structures involved in the control ofbehavior, including the superior colliculus, parvi-cellular reticular formation, lateral habenula, and thePPN (Figure 1). The relative importance of the twooutput nuclei in the control of behavior varies amongspecies of different orders. Thus, output to thalamusfrom the GPi in primates is probably more importantthan the output from the SNr whereas in rodents, theoutput from the SNr is probably more importantthan that from the EP.

Basal ganglia output neurons are large GABAergicneurons with long, infrequently branching, aspiny

Figure 4 Characteristic features of synaptic terminals of neu-rons of the basal ganglia. A series of electron micrographs illus-trating typical ultrastructural features, synaptic specializations,and neurochemistry of synaptic terminals derived from the striatum(a), the external segment of the globus pallidus (GPe) (b,c), andthe subthalamic nucleus (STN; (d–f)). The sections illustrated in(a), (c), and (f) were labeled by the postembedding immunogoldmethod to reveal g-aminobutyric acid (GABA) immunoreactivity,and the section illustrated in (e) was processed to reveal glutamate(GLU) immunoreactivity. (a) A striatal terminal (farthest to the left)in the internal segment of the globus pallidus (GPi) labeled follow-ing an injection of the anterograde tracer biotinylated dextranamine (BDA) in the putamen of a squirrel monkey. The terminal isidentified by the electron-dense reaction product formed by thehistochemical reaction to reveal the BDA. It is in symmetric synap-tic contact (arrow) with a dendrite (den) and is immunoreactive forGABA (as indicated by the high density of immunogold particlesoverlying it). Two neighboring boutons (b1 and b2), which alsopossess the morphological features of striatal terminals, are alsoimmunoreactive for GABA. These terminals are derived from thestriatal medium-size densely spiny neurons. Contrast these withbouton b3, which forms an asymmetric synapse (arrowhead) anddoes not display GABA immunoreactivity. This bouton possessesmorphological features of a terminal derived from the STN. (b, c)Terminals derived from the GPe forming symmetric synaptic con-tacts (arrows) with a dendritic shaft (den) in (b) and a perikaryon(peri) in (c). The terminal in (b) is in the rat entopeduncular nucleus(equivalent to GPi) and was labeled after an injection of the ant-erograde tracer Phaseolus vulgaris leucoagglutinin in the GP ofthe rat. The bouton in (c) is in the STN and was labeledafter an injection of BDA in the GPe of the squirrel monkey. Thissection was incubated to reveal GABA immunoreactivity, and thelabeled bouton displays a high concentration of immunogold par-ticles overlying it, indicating that it is enriched in GABA. Note the

similarity in the morphological characteristics of the pallidal bou-tons despite the fact that they are from different species and indifferent nuclei. (d) A terminal derived from the STN. This terminalis in the rat substantia nigra pars reticulata and was anterogradelylabeled following the injection of the anterograde tracer biocytin inthe STN. It forms an asymmetric synapse (arrowhead) with adendrite (den) that contains retrogradely transported horseradishperoxidase (HRP) from the ventromedial thalamic nucleus, thusidentifying it as a dendrite of a basal ganglia output neuron. (e,f)Adjacent sections of the same anterogradely labeled STN boutonin the GPe of squirrel monkey that forms an asymmetric synapse(arrowheads). The bouton is enriched in glutamate immunoreac-tivity (in (e)) but is not immunoreactive for GABA (in (f)). Notethe similarity in the morphological features of the subthalamicterminals in different species and in different nuclei. Scale bar "0.5 mm (a–f). From Smith Y, Bevan MD, Shink E, and Bolam JP(1998) Commentary: Microcircuitry of the direct and indirect path-ways of the basal ganglia. Neuroscience 86: 353–387.



dendrites. In the GPi at least, they are similar to GPeneurons in that their dendrites are arranged in such away as to expose their maximum surface to theincoming striatal afferents. Their major input isfrom the MSNs of the striatum that give rise to the

direct pathway; thus dendrites and perikarya areensheathed in afferent terminals, most of which arederived from the striatum (Figure 4(a)). They alsoreceive a prominent afferent input on their perikaryaand proximal dendrites from the GABAergic neurons

GP

EP

STN

a SNc

SNr

GP

STR

b

STN

ab

SNc

SNr

Figure 5 Individual neurons of the rat globus pallidus (GP) innervate multiple regions of the basal ganglia. Partial reconstructions ofindividual neurons from the rat GP that were labeled with neurobiotin in vivo by the juxtacellular method following electrophysiologicalcharacterization. These neurons were reconstructed from serial sections using a camera lucida drawing tube. The cell bodies and dendritesare shown in red, and the axon in black. In both cases the drawing of the axon has been cut in two; the ends of the axons marked ‘a’ connectwith the endsmarked ‘b’. The upper neuron gave rise to local axon collaterals within the GP, and the main axon traveled through the internalcapsule to the entopeduncular nucleus (EP), subthalamic nucleus (STN), and substantia nigra pars compacta (SNc) and pars reticulata(SNr). In addition to local axon collaterals and clear projections to the STN, SNc, and SNr, the lower neuron gives rise to two collaterals thatinnervate the striatum (STR). About a quarter of labeled GP neurons gave rise to collaterals that innervated the STR. Observations similarto these have been made in the external segment of the primate GP. The neuron of origin of those structures shown in gray could not bedistinguished beween the two neurons. Scale bar"300mm. From Bevan M, Booth P, and Bolam JP (unpublished neurons).



of the GPe (Figure 4(b)) and glutamatergic neurons ofthe STN (b3 in Figures 4(a) and the labeled boutons inFigures 4(d)–(4f)). Individual basal ganglia outputneurons thus receive synaptic input from both thedirect pathway and the indirect pathway. The highresting discharge rate of neurons in the GPi and SNrunderlies a tonic inhibition of neurons in the targetregions of the basal ganglia under resting conditions.Increased activity of striatal afferents to these neuronsleads to a reduction in their firing rate and hence

reduced inhibition (i.e., disinhibition) of the targetsof the basal ganglia. This disinhibition is consideredto be a key factor in the way the basal ganglia influ-ence behavior.

SNc

The SNc consists principally of dopamine neuronsalthough some evidence suggests it also has a popula-tion, albeit small, of GABAegic neurons. The dopa-mine neurons lie in a densely packed band with themajority of dendrites following the plane of the com-pacta (Figure 7). Some dendrites, particularly of thoseneurons located in the ventral part of the compacta,also descend into the SNr (Figure 7). Dopamine neu-rons receive a dense innervation from GABAergicterminals derived from the striatum and the GPeand also receive glutamatergic input from the STN,cholinergic terminals from the PPN, and serotonergicterminals from the dorsal raphe. The axon emergesfrom the cell body or primary dendrite (and, rarely, asecondary dendrite). Dopamine neurons do not giverise to local axon collaterals within the SN, althoughit is evident that the dendrites can release dopamineand thus influence neighboring neurons. The maintarget of the axon is the striatum, but the GPe andthe STN also receive a significant dopaminergic inputvia collaterals of the main axon. Individual dopamineneurons give rise to a remarkable number of synapses.Estimates vary between about 250 000 and 330 000synapses at the level of the striatum, plus any addi-tional synapses arising from collaterals in the GP andSTN. The axon terminals of dopamine neurons giverise to symmetric synapses. The major targets in thestriatum are the spines, dendritic shafts, and peri-karya of MSNs (Figure 2). Synaptic contact on spinesgenerally occurs at the neck, and the spine invariablyreceives a glutamatergic terminal derived from thecortex or thalamus, forming an asymmetric synapse(Figure 2). This spatial relationship underlies themodulatory role of dopamine on the excitatory influ-ence from cortex and thalamus.

Concluding Remarks

For the sake of clarity, this description of the inter-nal organization of the basal ganglia has been sim-plified, omitting many of the less well understood(but probably still important) synaptic connections.Furthermore, the description relies heavily on dataderived from the dorsal division of the basal ganglia.Nevertheless, the basic principles of the connections

Figure 6 Globus pallidus (GP) neurons form multiple contactswith the proximal regions of their target neurons. Light micrographof the substantia nigra pars reticulata (SNr) of a rat, in whichanterograde tracer was deposited in the GP and revealed by aperoxidasemethod. The perikarya of two SNr neurons are presentin the center of the field (peri) and are apposed by many antero-gradely labeled large axonal boutons (some indicated by smallarrows) derived from the GP. This ‘basket-like’ innervation is typi-cal of the manner in which GP neurons innervate their targetneurons. Note that this section was taken from an animal thatalso received an injection of anterograde tracer in the striatum;the brown-labeled structures are thus of striatal origin. Scale bar"!20mm. From Smith Y and Bolam JP (unpublished).



described here also apply to the ventral division ofthe basal ganglia. One can thus conclude from thestudy of the functional organization of the basalganglia that the complex functions of the basal gang-lia are underpinned by an equally complex cellularand synaptic architecture.

See also: Basal Ganglia: Functional Models of Normal andDisease States; Basal Ganglia: Motor Functions; BasalGanglia: Acetylcholine Interactions and Behavior; BasalGanglia: Physiological Circuits; MPTP ParkinsonismModel; Procedural Learning: Striatum; Striatum: InternalPhysiology.

Further Reading

Alexander GE and Crutcher ME (1990) Functional architecture ofbasal ganglia circuits: Neural substrates of parallel processing.Trends in Neurosciences 13: 266–271.

Bevan MD, Booth PAC, Eaton SA, and Bolam JP (1998) Selectiveinnervation of neostriatal interneurons by a sub-class of neuronin the globus pallidus of the rat. Journal of Neuroscience 18:9438–9452.

Bolam JP, Bergman H, Graybiel A, et al. (2006) Molecules, micro-circuits and motivated behaviour: Microcircuits in the striatum.In: Grillner S and Graybiel A (eds.)Microcircuits: The Interface

between Neurons and Global Brain Function, pp. 165–190.Cambridge, MA: MIT Press.

Bolam JP, Booth PAC, Hanley JJ, and Bevan MD (2000) Synapticorganisation of the basal ganglia. Journal of Anatomy 196:527–542.

DeLong MR (1990) Primate models of movement disorders ofbasal ganglia origin. Trends in Neurosciences 13: 281–285.

Gerfen CR and Wilson CJ (1996) The basal ganglia. In: BjorklundA, Hokfelt T, and Swanson L (eds.) Handbook of ChemicalNeuroanatomy, vol. 12, Part III, pp. 369–466. Amsterdam:Elsevier.

Graybiel AM (2005) The basal ganglia: Learning new tricks andloving it. Current Opinion in Neurobiology 15: 638–644.

Lacey CJ, Bolam JP, and Magill PJ (2007) Novel and distinctoperational principles of intralaminar thalamic neurons andtheir striatal projections. Journal of Neuroscience 27:4374–4384.

Sadek AR, Magill PJ, and Bolam JP (2007) A single-cell analysis ofintrinsic connectivity in the rat globus pallidus. Journal ofNeuroscience 27: 6352–6362.

Smith Y, Bevan MD, Shink E, and Bolam JP (1998) Commentary:Microcircuitry of the direct and indirect pathways of the basalganglia. Neuroscience 86: 353–387.

Tepper JM, Abercrombie ED, and Bolam JP (eds.) (2007) SpecialIssue: GABA and the Basal Ganglia: From Molecules to Sys-tems. Progress in Brain Research 160.

Tepper JM and Bolam JP (2004) Functional diversity and specificityof neostriatal interneurons. Current Opinion in Neurobiology14: 685–692.

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Figure 7 Micrographs and a digital reconstruction of an individual dopamine neuron in the rat substantia nigra pars compacta (SNc),recorded in vivo and then labeled with neurobiotin by the juxtacellular method. The neurobiotin, together with immunoreactivity for tyrosinehydroxylase (TH), were revealed by fluorescencemethods ((a), inset). In this section the TH immunoreactive elements were revealed by agreen fluorescent marker and the double labeling for TH and the neurobiotin by the yellow fluorescence. The labeled neuron was thusconfirmed to be dopaminergic by the presence of immunoreactivity for TH. After neurochemical characterization, the neurobiotin andimmunoreactivity for TH were localized by peroxidase reaction products, and the main panel in (a) shows the labeled neuron in the denselayer of TH-positive neurons in the SNc. The digital reconstruction in (b) shows the typical arrangement of the majority of dendrites ofdopamine neurons that follow the plane of the SNc, with some dendrites descending into the SN pars reticulata (SNr). The axon of thisneuron was followed to the globus pallidus, where is gave rise to a cluster of boutons, and then to the striatum. Scale bar " 25 mm;(a, inset) 500mm (b). From Brown MTC, Bolam JP, and Magill PJ (unpublished).



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Basal Ganglia: Internal Organization - mrcbndu.ox.ac.uk · basal ganglia, that is, the GPi (or EP) and the SNr, by two routes, the so-called direct and indirect pathways. In the direct