3 Kunzle, H. (1977) Exp. Brain Res. 30, 481-492 4 Goldman, P. S. and Nauta, W. J. H, (1977) J. Comp. NeuroL 171,369-386 5 Selemon, L. D. and Goldman-Rakic, P. S. (1985) J. Neurosci. 5, 776-794 6 Fotuhi, M., Koliatsos, V. E., Alexander, G. E. and DeLong, M. R. (1989) 5oc. Neurosci. Abstr. 15, 285 7 Flaherty, A. W., Graybiel, A. M., Sur, M. and Gerraghty, P. (1989) Soc. Neurosci. Abstr. 15, 659 8 Selemon, L. D. and Goldman-Rakic, P. S. J. Comp. NeuroL (in press) 9 Carpenter, M. B., Carleton, S. C., Keller, J. T. and Conte, P. (1981) Brain Res. 224, 1-29 10 Kuo, J-S. and Carpenter, M. B. (1973) J. Comp. Neurol. 151, 201-236 11 DeVito, J. L. and Anderson, M. E. (1982) Exp. Brain Res. 46, 107-117 12 Ilinsky, I. A., Jouandet, M. and Goldman-Rakic, P. S. (1985) J. Comp. Neurol. 236, 315-330 13 Kievit, J. and Kuypers, H. G. J. M. (1977) Exp. Brain Res. 29, 299-322 14 Goldman-Rakic, P. S. and Porrino, L. (1985) J. Comp. Neurol. 242, 535-560 15 Ilinsky, I. A. and Kultas-Ilinsky, K. (1987) J. Comp. Neurol. 262,331-364 16 Haber, S. (1985) J. Comp. Neurol. 235, 322-335 17 Asanuma, C., Thach, W. T. and Jones, E. G. (1983) Brain Res. Rev. 5, 237-265 18 Alexander, G. E., DeLong, M. R. and Strick, P. L. (1986) Annu. Rev. Neurosci. 9, 357-381 19 Hikosaka, O. and Wurtz, R. H. (1983) J. Neurophysiol. 49, 1268-1284 20 Hikosaka, O. and Wurtz, R. H. (1983) J. Neurophysiol. 49, 1285-1301 21 Hikosaka, O. and Wurtz, R. H. (1985) J. Neurophysiol. 53, 292-308 22 Goldman-Rakic, P. S. (1987) in MotorAreas of the Cerebral Cortex (Ciba Foundation Symposium 132) (Porter, R., ed.), pp. 187-200, Wiley

23 Selemon, L. D. and Goldman-Rakic, P. S. (1988) J. Neurosci. 8, 4049-4068 24 Groves, P. M. (1983) Brain Res. Rev, 5, 109--132 25 Goldman-Rakic, P. S. (1982)J. Comp. NeuroL 205, 398-413 26 Graybiel, A. M. and Ragsdale, C. W. (1978) Proc. NatlAcad. Sci. USA 75, 5723-5726 27 Pert, C. B., Kuhar, M. J. and Snyder, S. H. (1976) Proc. Natl Acad. Sci. USA 73, 3729-3733 28 Donoghue, J. P. and Herkenham, M. (1986) Brain Res. 365, 397-403 29 Gerfen, C. R. (1989) Science 246, 385-388 30 Gerfen, C. R. (1984) Nature 311,461-464 31 Gerfen, C. R. (1985) J. Comp. Neurol. 236, 454-476 32 Gerfen, C. R., Herkenham, M. and Thibault, J. (1987) J. Neurosci. 7, 3915-3934 33 Jimenez-Castellanos, J. and Graybiel, A. M. (1987) Neuroscience 23,223-242 34 Jimenez-Castellanos, J. and Graybiel, A. M. (1989) Exp. Brain Res. 74, 227-238 35 Joyce, J. N., Sapp, D. W. and Marshall, J. F. (1986) Proc. Natl Acad. Sci. USA 83, 8002-8006 36 Loopuijt, L. D., Sebens, J. B. and Korf, J. (1987) Brain Res. 405, 405-408 37 Besson, M-J. Graybiel, A. M. and Nastuk, M. A. (1988) Neuroscience 26, 101-119 38 Freund, T. F., Powell, J. and Smith, A. D. (1984) Neuroscience 13, 1189-1215 39 Bouyer, J. J., Park, D. H., Joh, T. H. and Pickel, V. M. (1984) Brain Res. 302,267-275 40 Pasik, P., Pasik, T. and DiFiglia, M. (1979) in The Neostriatum (Divac, I. and Oberg, R. G. E., eds), pp. 5-36, Pergamon Press 41 Penney, J. B., Jr and Young, A. B. (1983) Annu. Rev. Neurosci. 6, 73-94 42 Albin, R. L., Young, A. B. and Penney, J. B. (1989) Trends Neurosci. 12,366-374 43 Reiner, A. et al, (1988) Proc. Natl Acad. 5ci. USA 64, 5733-5737 44 Barinaga, M. (1990) Science 247, 20-22

reviews

Neurotransmittersand neuromodulatorsin the basal ganglia Ann M. Graybiel AnnM. Graybielis at the Departmentof Brainand Cognitive Sciences, Massachusetts Institute of Technology, Cambridge,MA 02139, USA.

The basal ganglia have become a focus for work on neurotransmitter interactions in the brain. These structures contain a remarkable diversity of neuroactive substances, organized into functional subsystems that have unique developmental histories and vulnerabilities in neurodegenerative diseases. A new view of the basal ganglia is emerging on the basis of this neurochemical heterogeneity, suggesting that dynamic regulation of transmitter expression may be a key to extrapyramidal function. Kinnier Wilson's famous quip about the basal ganglia, that these deep-lying structures of the forebrain have the 'characteristics of basements, viz. darkness '1, still partly rings true today, but there has been much recent progress in work on the basal ganglia at both behavioral and cellular levels*. First, there is growing evidence that the functions of the basal ganglia involve not only strictly sensorimotor aspects of movement *The basal ganglia, as the name implies, include deep-lying structures of the cerebral hemisphere (the striatum, the pallidum and also the amygdala). Functionally, the striatopallidal complex acts in conjunction with its allied nuclei- the subthalamic nucleus (reciprocally connected with the pallidum), and the substantia nigra, with its dopamine-containing pars compacta and its pars reticulata (interconnected with the striatum).

244

© 1990, E!sevierSciencePublishersLtd,(UK)

programming, but also conditional aspects of planning movements, program selection, and motor memory and retrieval. In fact, in addition to disorders of movement, certain forms of drug addiction, and major mental disorders including schizophrenia-like states and obsessive-compulsive disorder, have been linked to abnormalities in the basal ganglia and their allied nuclei. Second, the basal ganglia have been found to contain remarkably high levels of many of the neurotransmitters and neuromodulators known to exist in the mammalian brain, and there are changes in multiple neurotransmitter systems in basal ganglia disorders. Dysfunction of the dopamine-containing nigrostriatal tract has long been recognized in Parkinson's disease, and dopamine-containing neurons are affected by drugs ranging from cocaine to antipsychotics to the anti-parkinsonian drug L-DOPA. Many psychoactive drugs can also act at nondopaminergic receptors in the basal ganglia, including receptors for opioids (e.g. morphine), cannabinoids (e.g. marijuana), and benzodiazepines (e.g. Valium). Even drugs such as haloperidol, once thought to act solely on dopamine receptors, are now known to act on other receptors as well. Third, there is intense investigation of the molecular biology and developmental biology of the basal ganglia. The gene for

0166- 2236/90/$02.O0

TINS, VoL 13, No. 7, 1990

Huntington's disease has been localized to the short (or into the subthalamic loop, discussed below). This arm of chromosome 4, and hereditary links have been arrangement, considered in conventional terms, found for some other syndromes thought to reflect means that the excitatory drive from the cortex abnormalities in the basal ganglia. The basal ganglia disinhibits the thalamus and brainstem. As thalamoare also becoming model systems for work on neural cortical connections are thought to excite the cortex, development and plasticity, both in the normal brain the end result of the cortex-basal ganglia-thalamusand in brain transplants. This review highlights new cortex circuit would be excitation of the cortex. This doubly inhibitory loop has become central to findings on the transmitter organization of the basal ganglia, and proposes that understanding this organ- many theories about the role of the basal ganglia in ization can be of great help in tying together these movement and thought disorders, in part because it seems to coordinate with Hughlings Jackson's classic three main lines of current research. concept of 'release', whereby damage to higher Neurotransmitters and the basic circuit of the centers takes away control over lower centers that basal ganglia then function to produce the positive signs and The basal ganglia form a forebrain system that symptoms of disease. The rigidity and tremor of collects signals from a large part of the neocortex, Parkinson's disease, the hyperkinetic states of choreoredistributes these cortical inputs both with respect to athetotic disorders, and even the free-wheeling one another and with respect to inputs from the limbic mental states in schizophrenia and drug addiction and system, and then focuses the outputs of these the repetitive actions of obsessive-compulsive disredistributed, integrated signals to particular regions order have been considered as manifestations of a of the frontal lobes and brainstem involved in aspects disinhibition of thalamocortical systems (see Refs 5-8 of motor planning and motor memory. Why does the and references therein). Release from GABA-based brain have this enormous extrapyramidal forebrain inhibition in the brainstem is important in the actiloop? After all, there are massive transcortical (and vation of saccade-related neurons in the superior transthalamic) pathways linking other neocortical colliculus, which fire (are 'released') exactly when areas and the limbic system to the frontal cortex. intervening nigrotectal neurons in the SNr are inhibiWhat is the evolutionary advantage and functional ted (see G. Chevalier and J. M. Deniau, this issue). specialization conferred by having, in addition, sets of But what has brought special fascination to the study pathways running through the basal ganglia? of basal ganglia pathways is that, aside from these One key to this riddle may lie in the neurotransmit- outlets to the brainstem, their main target is the ters and neuromodulators of the basal ganglia. The frontal lobes, including the supplementary motor area, basal ganglia contain neurotransmitter-specific com- the zone of the human neocortex that shows differenpartments that bring different inputs under different tial activity when a person, without executing a motor neurochemical control. Moreover, classic neurotrans- act, imagines or plans it9. mitters (e.g. ~,-aminobutyric acid) co-exist with Interestingly, this basic release circuit is itself neuropeptides in various combinations in the principal controlled by a pallidal side-loop that leads from the circuits and interneurons of the basal ganglia, so that pallidum to the subthalamic nucleus and back to the different combinations of cortical inputs, when pro- pallidum. The subthalamic nucleus is now thought to jected into the basal ganglia, are channeled not only excite the pallidum with a glutamatergic input, and so into different output pathways but also into different to increase the inhibitory effect of the pallidum on the chemical environments. Finally, the neurotransmit- thalamus (Fig. 1A; see Ref. 5). Lesions of the ters in the side-loops of the basal ganglia - notably subthalamic nucleus, by breaking this loop, release dopamine in the nigrostriatal system - can markedly the thalamus from inhibition and result in the hyperalter the pattems of neurotransmitter expression in kinetic syndrome of ballism. Such lesions can also the main through-circuits and interneurons of the release movements in monkeys made parkinsonian by basal ganglia. The great diversity of neurotransmit- treatment with the neurotoxin-precursor MPTP (1ters in the basal ganglia may thus reflect their role in methyl-4-phenyl-l,2,3,6-tetrahydropyridine) (see M. the dynamic modulation of behavior based on sensori- DeLong, this issue). motor, memory-related and conditional cues derived from the neocortex and limbic system. Slow neurotransmitter systems in the basal The distribution of classic neurotransmitters wit]~lin ganglia the basal ganglia is notably straightforward, given the The basic circuit of the basal ganglia seems to work rich variety of neuroactive substances present by 'fast' neurotransmission, that is, at the classic there 2-4 (Fig. 1A). This situation fits the simple synaptic time-scale of about 1 ms. There is also much anatomy of the 'basic circuit' of the basal ganglia (Fig. evidence for slow neurotransmission in the basal 1A). The dominant afferents, which come from the ganglia, both in the basic circuit and its interneuronal cerebral cortex, are thought to be glutamatergic (or modulators, and in its side-loop involving the substanpossibly aspartergic) and uniformly excitatory. Within tia nigra pars compacta (SNc) and related dopaminthe basal ganglia, the predominant neurotransmitter is ergic cell groups in the midbrain (Fig. 1B). Neurothe inhibitory amino acid y-aminobutyric acid (GABA). peptides, dopamine and acetylcholine acting at G Most of the neurons in the striatum and pallidum are protein-coupled receptors, and glutamate acting at GABAergic. So are neurons of the pars reticulata of NMDA receptors, may all participate as slow neurothe substantia nigra (SNr), a nucleus that shares some modulators in these pathways (Fig. 1B). properties with the pallidum. The GABAergic The potential power of such modulatory control neurons of the striatum project to the GABAergic mechanisms was first grasped after the revolutionary neurons of the pallidum and SNr, which in tum project finding that in Parkinson's disease, there is a severe out of the basal ganglia to the thalamus and brainstem deficit in dopamine in the nigrostriatal tract, and that TINS, VoL 13, No. 7, 1990

245

cerebral cortex

neocortex

F¥ +

striatum

thalamus

d. str.

n.v. thalamus pallidum

. •h•(CPH)

d. pall.

SOM,NPY

ACh

ANT-6

s.coll.

STN

groups A8-Ag~,,

cell

/

A

B

Fig. 1. (A) The 'basic circuit' of the basal ganglia and its classic neurotransmitters (GLU, glutamate; GABA, 7-aminobutyric acid). The cerebral cortex projects into a doubly inhibitory striatopallidothalamic path leading back to the frontal lobes (a parallel striato-nigrothalamic path is not shown; see Fig. 1B and Refs 2-5). This basic circuit is modulated by striatal interneurons (e.g. cholinergic neurons; ACh, acetylcholine), and by other inputs including those involving the subthalamic nucleus (STN) and substantia nigra pars compacta (SNc). The SNc is part of the A8-AgA 10 cell complex of Dahlstr6m and Fuxe (A8 is roughly equivalent to the retrorubral nucleus, A9 to the SNc, and AlO to the ventral tegmental area of Tsai). This 'basic circuit' anatomy holds not only for the caudate nucleus and putamen (dorsal striatum) and globus pallidus (dorsal pallidum), but also for the limbic-related ventral striatum (nucleus accumbens-olfactory tubercle region) and its corresponding ventral pallidum, SNr, the substantia nigra pars reticulata. Note that dopamine (DA)-containing dendrites of SNc neurons (thought to release dopamine by dendritic release) extend into the SNr. This means that despite many similarities between the SNr and the globus pallidus, these structures are fundamentally different. Other abbreviation: F, frontal lobe. (For more complete outlines of the anatomical paths see Refs 2--4 and A. Parent, this issue.) (B) Expanded view of basic circuit for the caudate-putamen (dorsal striatum, d.str.) and globus pallidus (dorsal pallidum, d. pall.) emphasizing some of the neuropeptides that distinguish different

striatopallidal and striatonigral paths. Most or all of the neuropeptides in striatal projection neurons are contained in GABAergic neurons (cf. Fig. 1A). These neuropeptides are t~'e only substances so far identified that distinguish the striatopallidal pathways respectively directed toward the subthalamic nucleus (via GPe) and the thalamus (via GPi). Most of the other molecular tags so far identified for striatopallidal (and striatonigral) fibers - including cannabinoid receptors 62, epidermal growth factor-like immunoreactivity 63 and calcineurin immunoreactivity 64 - also are general to all or nearly all striatopallidal output fibers. The peptide LysS-Asng-neurotensin (8-13) (LANT-6) is contained in many GABAergic pallidal neurons 65. The large interneurons of the striatum are cholinergic, and as some large neurons contain the peptide-processing enzyme carboxypeptidase H (CPH) 66 or the peptide LANT-6 65, some cholinergic interneurons are probably also peptidergic. Especially in dopaminergic cell group AIO (ventral tegmental area), but variably in the SNc (cell group Ag), dopamine (DA)-containing neurons also contain cholecystokinin (CCK) or neurotensin (NT) or both (see references in Ref. 2). Other abbreviations: DYN, dynorphin; ENK, enkephalin; F, frontal lobe; NPY, neuropeptide Y; n.v. thalamus, ventral tier nuclei of thalamus; s. coll., superior colliculus; SNc, substantia nigra pars compacta; SNI, substantia nigra pars lateralis; SNr, substantia nigra pars reticulata; SOM, somatostatin; t,p.c., pedunculopontine nucleus.

dopamine replacement therapy could be an effective treatment for this disorder (see M. Carlsson and A. Carlsson, this issue). In the light of earlier treatment of parkinsonian patients with anticholinergics, this finding soon led to the proposal that dopamine (released from nigrostriatal fibers) and acetylcholine (released from cholinergic interneurons in the striatum) were in a 'balance' that could be tipped toward the hyperkinesia of chorea (too little acetylcholine) or to the hypokinesia of parkinsonism (too little dopamine). This theory has been amended by 246

discoveries about multiple transmitters in the basal ganglia, and of multiple receptor subtypes. But the concept that dopamine and acetylcholine are of central functional importance in the striatum and the basal ganglia as a whole is still generally accepted. In fact, it has now been suggested that overactivity of dopamine in the 'limbic' regions of the striatum (predominantly but not exclusively the ventral striatum) could trigger mental illness. Alterations in dopamine receptor functions have been reported in such disease states 1° (see G. Sedvall, this issue). TINS, Vol. 13, No. 7, 1990

Neuropeptides make up the other great class of transmitter repertoires if they happen to lie on either neuroactive substances in the basal ganglia distin- side of a striosomal border. The neurochemical guished by their potential for prolonged actions. differences between striosomes and matrix are not These peptides are now thought to be ubiquitous co- all-or-none (see Table I), but they are large enough to transmitters in the 'fast' GABAergic pathways in the suggest that the same transmitter might have differstriatum and pallidum (see Fig. 1B and Table I). ent effects in these two compartments. In fact, in the Neuropeptides also occur in some neurons of the most direct pharmacological attempt yet made to test dopaminergic cell groups of the midbrain, A8, A9 and transmitter functions in striosomes and matrix, Kernel A10 (see Fig. 1B for definitions). The striatum and et al. 23 have found that dopamine release elicited m related nuclei are particularly attractive systems for vitro by cholinergic stimulation has different propstudying these neuropeptides and other slow trans- erties in the striosome-rich middle of cat caudate mitters, because the distributions of these neuro- nucleus and in the relatively striosome-poor dorsochemicals relate in an ordered fashion to the anatomy, lateral part of the nucleus. pathology and development of the basal ganglia. Striosome-matrix chemoarchitecture and striatal connections Striosomes and heterogeneity of neurotransThe striosome-matrix compartmentalization first mitter s y s t e m s in the striatum Virtually all striatal neurotransmitters, both classi- recognized by transmitter histochemistry turns out to cal and non-classical, are distributed differentially with be an architecture to which virtually all input-output respect to macroscopic, histochemically distinct compartments in the striatum 11-21. We first detected these biochemically specialized compartments in sections stained for acetylcholinesterase (ACHE) activity 15. As shown in Fig. 2, small AChE-poor zones, which have about the same diameters as columns in the cortex, are embedded in the otherwise AChE-rich tissue of the striatum. We called these zones striosomes ('striatal bodies') to set them off from the large extrastriosomal matrix*. They make up 10-20% of the volume of the striatum and form three-dimensional labyrinths (for reviews and references, see, for example, Refs 3,4,16-19). It was soon found that striosomes are also distinguishable on the basis of the enkephalin-like, substance P-like, and somatostatin-like immunoreactivity that they exhibit 2°. Moreover, it was shown that the AChE-poor striosomes (first detected in human, monkey and cat striatum) correspond to the opiate receptor patches described for rat striatum in the first documentation of opiate receptor-site binding in the brain 21, and that they also correspond to the dopamine island system of the developing striatum is. In the years since, work from a number of laboratories has demonstrated striosomal ordering for (1) transmitters, (2) transmitter precursor mRNAs, (3) transmitterrelated enzymes, (4) transmitter binding sites, (5) transmitter uptake sites, and also (6) other substances that may play roles in transmitter metabolism. Similar heterogeneity in neurotransmitter distributions occurs in the ventral striatum2~. Table I summarizes some of these findings for the caudateputamen. There is an interesting complexity to these distributions. For example, for any one transmitter system, different subtypes of receptor-related ligand binding (e.g. pharmacologically defined D1 and D2 dopamine receptors) may have opposite patterns in the two compartments. This organization means that striatal regions less than 1 mm apart can have sharply different neuro* Especially in reports on the rat, the striosomes are also referred to as 'patches' after the opiate receptor patches of the striatum (see below and Ref. 21). For the cat and monkey, there is a strong argument for retaining the designation striosomesfor zones that are histochemically distinct: as discussed below, there are patches of afferent fibers and of projection neurons in the matrix of these species as well as physiologically defined patches.

TINS, VoL 13, No. 7, 1990

Fig. 2. Photograph of a thin coronal section through the striatum of the human brain, stained for the enzyme, acetylcholinesterase (ACHE). The main nuclei of the striatum are shown [caudate nucleus, putamen and ventral striatum (V.STR.)], together with the plate of internal capsule fibers (INT. CAP.) that largely separates the caudate nucleus and putamen. Asterisks mark examples of AChE-poor striosomes, which are surrounded by the AChE-rich extrastriosomal matrix. Scale bar is 2 mm. 247

TABLE I. Compartmental distribution of striatal neurotransmitters and neuromodulators Neurotransmitters/neuromodulators

Striosomes

Matrix

Dopaminergic markers ~-c D1 binding sites D2 binding sites DA uptake sites Synthetic enzyme (TH) Phosphoprotein (DARPP-32)

>

+

> > > +

Cholinergic markers M1 binding sites M 2 binding sites Nicotinic binding sites Choline uptake sites Synthetic enzyme (CHAT) Degradative enzyme (ACHE) ChAT-positive perikarya

> = ?

+

? > > > +

Serotonergic markers d 5-HT-like immunoreactivity

>

GABAergic (+ related) e-g GABA-A binding sites GABA-B binding sites GAD-positive neuropil GABA-positive interneurons, projection neurons Benzodiazepine binding sites

+ + >

+ +

+ > (some annular)

+

Peptide-immunoreactive cell bodies (c) and neuropil (n) ~-m Substance P (SP) (and PPT mRNA) Substance K (SK) (neurokinin A) Neurokinin B (NKB) Dynorphin (DYN) Enkephalin (ENK) Neurotensin (NT) Somatostatin (SOM) Lysa-Asng-neurotensin (8-13) (LANT-6) Galanin

>(c,n)(some annular) ? ? >(c,n)

? ? >(c)

>(n,c?) >(c,n) +(c) ?

+(c) ?

Peptide/peptide mRNA co-existence patterns g'j'n SP-DYN (GABA) SP-DYN-ENK (GABA) NKB mRNA-ENK mRNA NKB mRNA-SP mRNA ENK-NT (GABA) SOM-NPY

+

+

+ ? ? ? +

+ ? ? ? +

References for Table I (See also reviews cited in Refs 2-5.) a Graybiel, A. M. and Moratalla, R. (1989) Proc. Natl Acad. ScL USA 86, 9020-9024 b Halpain, S., Girault, J-A. and Greengard, P. (1990) Nature 343, 369-372 c Marshall, J. F., Navarrete, R. and O'Dell, S. J. (1989) Soc. Neurosci. Abstr. 15, 906 d Lavoie, B., Smith, Y. and Parent, A. (1988) Soc. Neurosci. Abstr. 14, 719 e Faull, R. L. M. and Villiger, J. W. (1988) Neuroscience 24, 433-451 f Chesselet, M-F. and Robbins, E. (1989) Brain Res. 492, 237-244 g Besson, M-J., Graybiel, A. M. and Quinn, B. Neuroscience (in press) h Sugimoto, T. and Mizuno, N. (1987) J. Comp. Neurol. 257, 383-395 i Reiner, A. (1987) Brain Res. 422, 186-191 j Penny, G. R., Afsharpour, S. and Kitai, S. T. (1986) Neuroscience 17, 1011-1045 k Lee, J-M. et al. (1986) Brain Res. 371, 152-154 I Skofitsch, G. and Jacobowitz, D. M. (1985) Peptides 6, 509-546 m Chesselet, M-F. and Robbins, E. (1989) Neurosci. Left. 96, 47-53 n Burgunder, J. M. and Young, W. S., III (1989) Neuroscience 32, 323-335 o Chesselet, M-F. and Hook, V. Y. H. (1988) Regulatory Peptides 20, 151-159 p Barnes, K., Matsas, R., Hooper, N. M., Turner, A. J. and Kenny, A. J. (1988) Neuroscience 27, 799-817 q Chesselet, M-F., Gonzales, C. and Levitt, P. (1989) 5oc. Neurosci. Abstr. 15,909 r Goto, S., Hirano, A. and Rojas-Corona, R. R. (1989)Acta NeuropathoL 78, 65-71 s Cowan, R. L., Wilson, C. W. and Emson, P. C. (1987) Soc. Neurosci. Abstr. 13, 1573 t DiFiglia, M., Gravetand, G. A. and Schiff, L. (1987) J. Comp. NeuroL 255, 137-145 u Augood, S. J., Lawson, D. E. and Emson, P. C. (1989) 5oc. Neurosci. Abstr. 15, 909 v Besson, M-J., Graybiel, A. M. and Nastuk, M. A. (1988) Neuroscience 26, 101-119 w Sugimoto, T., Itoh, K., Yasui, Y., Kaneko, T. and Mizuno, N. (1985) Brain Res. 347, 381-384

Peptide processing/degrading enzymes °,p Carboxypeptidase H Endopeptidase 24.11 Other q-u Calcium-binding proteins Calbindin 28K Parvalbumin Calcineurin Cytochrome oxidase NADPH diaphorase (NADPHd) Butyrylcholinesterase Limbic-associated membrane protein (LAMP)

> >

+ +

(>)

> + + > > (>)

>(dorsally)

Symbols: >, more are detectable in compartment indicated; +, present in compartment indicated; =, about equal compartmental representations; (>), variable compartmental distribution from animal to animal of a given species; ?, uncertain compartmentalization. Abbreviations: ACHE, acetylcholinesterase; CHAT, choline acetyltransferase; DARPP-32, dopamine and cAMP-regulated phosphoprotein; GASA, ~-amino butyric acid; 5-HT, 5-hydroxytryptamine; NPY, neuropeptide Y; PPT, preprotachykinin; TH, tyrosine hydroxylase. The neurochemical distributions noted are graded, not all-or-none. For example, in cat caudate nucleus, dopamine uptake-site binding is about 50% lower, and D1 doparnine and M1 muscarinic cholinergic receptor binding about 15-30% higher, in striosomes than in the matrix a,v. There are marked species differences in the clarity of compartmental distributions, and, within species, regional differences and gradients in expression of most of these compounds. Pharmacologically defined subtypes are shown, not subtypes defined by cloning. Many peptides are carried to the striatum in fibersw. This table includes peptides known to occur in striatal neurons. (For receptors, see Refs 2,4.) 248

connections of the striatum, and also many of its interneuronal connections, conform (see reviews in Refs 2-5 and Fig. 3). The differences in the connections of striosomes and matrix make functional differences between these stfiatal compartments likely. The matrix compartment receives the stfiatal inputs most directly related to sensorimotor processing. By contrast, stfiosomes (as well as the ventral striatum) tend to receive inputs from neural structures affiliated with the limbic system 2a. In the rat, different cortical layers have also been reported to observe stfiosomal architecture in their corticostfiatal projection patterns 25. There is provocative new eviTINS, VoL 13, No. 7, 1990

dence that the limbic system partly Sensory and Suppl. Motor, Premotor, splits its projections to the stria- I Prefrontal, Motor Ctx. Insular Ctx. Premotor Prefrontal tum into a hippocampus-centered Cingulate G. Cortex Cortex Amygdala system that focuses on the matrix, and an amygdala-centered system that favors striosomes26. This would mean that the striosome/ matrix division is not simply limbic/ non-limbic, but is a more differentiated subdivision sensitive to differences in information processing within these forebrain networks. Interestingly, a similar division has been found for the nucleus accumbThalamus VL VA,MD ens 27. The hippocampus has been implicated in spatial (place) and factual memory, whereas the amygdala has been linked to crossGPi [ modal and affect-related learning and memory. Thus, cortical input systems to the striosomes and GPe ,'~N matrix may be subject to conditioning by different memory mechanisms of the forebrain. In fact, an increasing number of studies suggests a special role for the stfiatum in motor-system plasticity I ~1 Sup.Coll. (procedural memory, habit forma[ tion, conditioned behaviors; see, Fig. 3. Schematic summary of some of the basal ganglia pathways discussed in the text. The for example, Refs 28-30). Such a striatum is shown as the stippled rectangle. Note differences in the input-output connections of the role could be reflected in the very striosome (S) and matrix (M) compartments (modular organization of matrix is not indicated). No high levels of NMDA receptor direct connection from striosomes to the pallidum has been indicated, but evidence does not binding sites in the stfiatum31, conclusively argue against a weak pathway. The input of the striosomes to the substantia nigra is sites that have been implicated in shown as reaching the region in or around the striosome-projecting part of the pars compacta; Hebbian learning in hippocampal again, definitive evidence on the exact site is lacking. Other abbreviations: GPe, external segment of the globus pallidus; GPi, internal segment of the globus pallidus; MD, mediodorsal thalamic long-term potentiation. One of the most interesting nuclei; SNc, substantia nigra pars compacta; SNr, substantia nigra pars reticulata; STN, subthalamic extensions of the striosome- nucleus; VA, ventral anterior thalamic nuclei; VL, ventral lateral thalamic nuclei. matrix dichotomy is to the dopamine-containing neurons of the midbrain, which are whether there is any stfiosomal projection to the divided into different sets projecting predominantly to pallidum; if so, it is thought to be small4°). This striosomes (part of the SNc) or to the matrix (much of arrangement suggests that the stfiosomes, with their cell group A8). This division (see Fig. 3 and Refs special neurochemistry and special linkages to some 19,32-34 and references therein) points to another branches of the limbic system, modulate part of the means for differential regulation of the striosome- dopaminergic input to the striatum, possibly in rebased and matrix-based circuits of the basal ganglia. It lation to motivational information from the limbic further suggests that dopaminergic drug therapies and system, whereas the matrix might be more tightly cell-replacement grafting treatments could have dif- linked to specific sensory and motor parameters. ferent functional effects depending on whether they These compartmental distinctions may be related to are targeted predominantly toward striosomes or the physiologically defined units in the stfiatum, matrix. The distinctive neurochemical properties of including conditionally active, memory-related, the striosome-projecting part of the SNc (see Refs anticipation-related, and sensorimotor types (see, e.g., 3,32,35) could be important clinically if there is, as Refs 30,42). There are considerable, but selective, suggested by some reports, differential vulnerability cross-compartment connections between striosomes of the different dopaminergic groups in parkinsonian and matrix involving several of the biochemically disorders (see Refs 36,37 and references therein). distinct classes of striatal interneurons (those containDifferential vulnerability of striatal neurons in strio- ing acetylcholine, somatostatin and GABA) and probsomes and matrix has also been reported in cases of ably some projection neurons as well (see Refs 43,44 and A. D. Smith and J. P. Bolam, this issue). Thus, Huntington's disease (see M. DiFiglia, this issue). The outputs of the striosome and matrix compart- information projected to the two compartments can be ments are as distinct as their inputs T M . The integrated in a transmitter-specific fashion. matrix projects mainly to the pallidum and the SNr, which together form the main GABAergic broadcast Neuropeptides mark functionally distinct systems of the basal ganglia leading toward the cortex output systems of the basal ganglia and brainstem4°,41. By contrast, the outputs of There are dramatic differences in the neuropepstriosomes reach mainly the dopamine-containing SNc tides that are expressed in the pathways leading to and/or its immediate surrounds 19,41 (it is unclear each of the two main segments of the globus paUidus

¢__1

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J

249

A

I' B

C

Fig. 4. Comparison of compartmental organizations of cerebral cortex (above) and striatum (below). Like layers and columns in the cortex (see hatching), the neurochemically specialized striosomes (darkly shaded forms) and probably comparable modules in the matrix (fine outlines) are specialized by virtue of having particular sets of (A) input and (B) output connections. There are also neurochemical gradients and regional differences in connections (see light shading in striatum and Ref. 2). (C) Cortical columns and layers are also known to be functional compartments. There is not yet comparable evidence for functional individuality of striosomes or the modules in the matrix. The striatum does not contain pyramidal cells but, as in the cortex, some neurons in the striatum have dendrites that cross compartments, whereas others do not.

(external, GPe and internal, GPi) and to the nigral complex, the main output centers of the basal ganglia (Fig. 1B, Table I, and see Refs 2-5 and references therein). What makes these neuropeptide distributions particularly interesting is that they differentiate functionally distinct striatal output pathways that seem neurochemically uniform when only their classic neurotransmitter (GABA) is considered. For example, the GPe (which projects to the subthalamic nucleus) is rich in enkephalin and neurotensin, the GPi (which projects to the motor thalamus) is rich in substance P and dynorphin, and the ventral pallidum (which projects into prefrontal thalamocortical pathways) contains mixed distributions of these peptidergic fibers (Fig. 1B). This arrangement could have major functional consequences if co-existing neuropeptides impose distinct response properties on the striato-pallidothalamic 'release circuit' and on its subthalamic gain-control loop. Such a proposal is consistent with the fact that neurons in GPe and GPi have different firing characteristics (see G. E. Alexander and M. D. Crutcher, this issue). These peptide-specific fiber pathways not only conform to known subdivisions of basal ganglia circuitry, but are also associated with distinct extrapyramidal disease states. For example, Reiner and colleagues have shown that enkephalin-like immunoreactivity is lost in the external pallidum in early-stage Huntington's disease, but that substance P-like immunoreactivity is preserved in the internal pallidum 250

in the same brains (see Ref. 5 and M. DiFiglia, this issue, for more extended reviews). 'Matrisomes' and modular organization of the striatal matrix One of the major puzzles that has emerged is how to relate the striking differences in neuropeptides in different striatal output pathways to the functional organization of striatal neurons. It is thought that most projections to the pallidum originate in the matrix. With few exceptions, modules have not yet been neurochemically identified in the matrix. There is growing evidence, however, that the matrix nonetheless has a modular design. First, striatal inputs from sensorimotor cortex and other striatal inputs have patchy distributions in the matrix (see, for example, Ref. 45). Second, the output cells of the matrix have also been shown to cluster, possibly in relation to the different projection systems leading from the striatum to the GPe, GPi and SNr (Refs 16, 40,41 and references therein). These newly detected modules in the matrix (provisionally designated 'matrisomes'), are probably related to physiologically defined modules such as the microexcitable zones described by Alexander and DeLong46. This kind of modularity seems well-suited to bring about new associations among different functional representations of the body, and it may permit these representations to interact selectively with other sensorimotor input modules and even with ~N5, VoL 13, No. Z 1990

information in nearby limbic-afferented striosomes. Why are these modules in the matrix not obviously marked neurochemically, as striosomes are? It is as though the entire striatum is modular in design, much as the cortex is known to be, but that the striosomes are special among all modules in being neurochemically distinct (see Fig. 4). On the other hand, though it is not yet possible to link this modular organization of the matrix to the distributions of neuropeptides in striatal output pathways from the matrix, this will perhaps be feasible when more is known about the regulation of neuropeptides in striatal neurons (see below). The apparent near-uniformity of the neuropeptide distributions in the matrix may be misleading, hiding quantitative cell-by-cell differences among peptides in different matrix-neuron assemblies.

Regulation of neuropeptide gene expression in the basal ganglia A fascinating new line of evidence suggests that the expression of some neuropeptides in striatal neurons

is regulated by the inputs to the striatum. The experiments of Hong, Costa and collaborators on the effects of modifying the dopaminergic inputs of the striatum were early models for this growing field47. Levels of peptide mRNA transcripts and neuropeptides in the striatum can be markedly altered by dopamine agonist and antagonist treatments, and by electrical stimulation of the medial forebrain bundle, which contains nigrostriatal fibers (see Table II and references therein). Treatments affecting other striatal inputs and neurotransmitters alter neuropeptide expression as well48,49. Much of this altered expression reflects a response at the level of gene transcription. But not all of it does. For example, exposure to reserpine increases striatal neurotensin levels even in the presence of protein synthesis blockade~°. These changes are not confined to neuropeptides. For example, levels of glutamic acid decarboxylase (GAD) mRNA change in parallel with changes in levels of enkephalin mRNA transcripts following 6-hydroxydopamine lesions 51. Thus, pre- and post-translational

TABLE II. Dopaminergic regulation of striatal peptide and peptide mRNA levels ENK (ENKmRNA)

DYN SP (DYN mRNA) (PPTmRNA)

SK (PPTmRNA)

D1 and D2 antagonist (e.g. haloperidol; blocks dopamine receptors) a-g

Increase

Increase Decrease or no change

Decrease

6-Hydroxydopamine (6-OHDA) lesion h-m

Increase

Decrease Decrease or no change or no change

D1 antagonist (e.g. SCH23390)c,g.j,n-q

Increase

No change

D 2 antagonist (e.g. sulpiride)d,e,j,n-q

Decrease No change or no change

NKB (PPTmRNA)

NT

SOM (PPS mRNA)

Manipulation Increase

Increase (decrease)

Increase

No change

Decrease

Decrease or no change Decrease

Increase

Indirect agonist (e.g. reserpine; releases catecholamines) q

Increase

(patches)

Indirect agonist (e.g. amphetamine; releases catecholamines, blocks uptake) p-s Direct agonist (e.g. apomorphine) r's

Increase

-

Increase

Increase

Increase

Increase

Increase

Increase

(patches)

D1 agonist (e.g. SKF38393)J,J,q,t

No change

Increase

D2 agonist (e.g. LY17155) I'q't

Increase

No change

Electrical stimulation of medial forebrain bundle t

Increase

-

-

No change

-

-

Increase

-

-

Decrease

(patches)

-

Increase

No change

Referencesfor Table II a Tang, F., Costa, E. and Schwartz, J. P. (1983) Proc. NatlAcad. Sci. USA 80, 3841-3844; b Quirion, R., Gaudreau, P., Martet, J-C., St-Pierre, S. and Zamir, N. (1985) Brain Res. 3310, 358-362; c Morris, B. J., H611t,V. and Herz, A. (1988) Neuroscience 25, 525-532; d Bannon, M. J., Elliott, P. J. and Bunney, E. B. (1987) ~Viol. Brain Res. 3, 31-37; e Frey, P., Fuxe, K., Eneroth, P. and Agnati, L. F. (1986) Neurochem. Int. 8, 429-434; f Goedert, M., Iversen, S. D. and Emson, P. C. (1985) Brain Res. 335, 334-336; g Cruz, C. J. and Beckstead, R. M. (1988) Brain Res. 457, 29-43; h Walaas, S. I., Sedvall, G. and Greengard, P. (1989) Neuroscience 29, 9-19; i Burgunder, J. M. and Young, W. S., III (1989) Neuroscience 32,323-335; j Jiang, H-K., McGinty, J. F. and Hong, J. S. (1990) Brain Res. 507, 57-64; k Normand, E. etal. (1989) Brain Res. 439, 39-46; I Merchant, K. M., Bush, L., Gibb, J. W. and Hanson, G. R. (1988) 5oc. Neurosci. Abstr. 14, 114; m Weiss, L. T. and Chesselet, M-F. (1989)/Viol. Brain Res. 5, 121-130; n Mocchetti, I., Naranjo, J. R. and Costa, E. (1987)J. PharmacoL Exp. Ther. 241, 1120-1124; o Oblin, A., Zivkovic, B. and Bartholini, G. (1987) Brain Res. 421,387-390; p Letter, A. A., Matsuda, L. A., Merchant, K. M., Gibb, J. W. and Hanson, G. R. (1987) Brain Res. 422,200-203; q Bannon, M. J., Rubenstein, A. and Haverstick, D. M. (1988) Soc. Neurosci. Abstr. 14, 875; r Li, S. J., Sivam, S. P., McGinty, J. F., Huang, Y. S. and Hong, J. S. (1987) J. Pharmacol. Exp. Ther. 243,792-798; s Li, S. J. etal. (1988) J. PharmacoL Exp. Ther. 246, 403-408; t Bannon, M. J., Kelland, M. and Chiodo, L. A. (1989) J. Neurochem. 52,859-862 TINS, VoL 13, No. 7, 1990

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regulation of neurotransmitter expression now join the receptor regulation and autoreceptor effects of classical pharmacology (see M. J. Zigmond et al., this issue) as mechanisms for modulation of transmitter efficacy in the striatum. The shifts in striatal neuropepfide expression that are induced by some drug treatments follow stfiosome-matrix compartmentalization. Such compartmental changes were first shown for enkephalin, which, in cats and monkeys, is normally preferentially expressed in matrix neurons but after colchicine pretreatment appears in striosomal neurons as well~2. It is now known (see Table II and accompanying references) that dopamine agonist treatments in the rat bring about heightened striosomal expression of at least three other neuropeptides - substance P, dynorphin and neurotensin. Agonlst treatments or o~methylparatyrosine can similarly induce the appearance of dopamine-rich islands in the striatum of adult rats. These findings suggest that the compartmental shifts in pepfide gene expression reflect, at least in part, compartmental shifts in dopamine in striosomes and matrix. Indirect effects - for example, via the influence of dopamine on cortical inputs to striosomes - could also play a role. In either case, the strong implication is that neurotransmitter expression in the striatum - and in its output paths to the pallidum and substantia nlgra - reflects dynamic regulation ultimately dependent on dopaminergic neurons. Thus, changes in activity at dopaminergic terminals may set off a cascade of events that lasts not only for the millisecond or second durations of synaptic transmission, but for the hours and even longer times taken to reflect altered gene expression. Such changes could be related to the long-term drug-induced changes in behavior attributed to the basal ganglia. Development of neurochemical heterogeneity in the basal ganglia This assessment of the potency of compartmentalized dopaminergic systems in the mature striatum finds strong parallels in studies of the striatum's development. Early on, dopamine-containing fibers form 'islands' in the caudoputamen, and only later do they spread through its full expanse 11,12. We now know that the dopamine islands mark the locations of future striosomes, and that the different dopaminecontaining fiber systems innervating striosomes and matrix must be the mature versions of the 'islandic' and 'diffuse' (non-islandic) systems originally observed in the embryo and neonate (see Refs 18,35). Many subsequent studies on the origins and maintenance of modular patterning in the striatum have been keyed by these early findings, and work on the development of this system has become an important branch of mammalian developmental neurobiology (see Refs 18,53-57 and references therein). The proto-stfiosomes lead the matrix developmentally in many characteristics. Most neurons of future striosomes (S cells) undergo final cell division during a restricted early developmental time-window, and most neurons of the matrix (M cells) arise later 18,53. S neurons are the first to express two molecules that function in calcium (Ca2+)-regulated cascades and that are later widely expressed by striatal cells, Ca 2+calmodulin-dependent protein kinase 2 and DARPP32 (Refs 54,57). The earliest evidence for synapto252

genesis in the striatum (as seen with antibodies against synaptic vesicle protein) is also in the island regions s4. Finally, S neurons are the first to send their axons to the substantia nigra ~. The inevitable 'chicken and egg' question is whether the incoming dopamine-containing axons instruct the striatum to form striosomes, or whether these neurochemically distinct modules form as an outcome of schedules intrinsic to the neurons themselves, or both. Current immunohistochemical evidence favors the existence of an intrinsic schedule: clusters of S neurons become distinguishable from matrix before the dopamine islands form. However, this does not rule out the possibility that small numbers of dopamine-contalning pioneer fibers help to trigger the neurochemical heterogeneity. We still need to learn whether the formation of striosomes represents a type of discrete compartmentalization with similarities to the compartment formation in the mammalian hindbrain. The progression of events leading to mature striatal chemoarchitecture is not over by birth. There are remarkable and still unexplained changes in the distributions of many transmitter markers during the early postnatal period. Just at the time these early postnatal changes occur, there is a wave of cell death in the striatum and transient expression of glycoconjugate boundaries around the developing striosomes (see Ref. 56 and references therein). Thus, early postnatal plasticity in the system, in which the neurochemical character of the striosomes and matrix changes, may occur in the context of transient architectural scaffolding and changes in the cell populations present. Functional effects of neurotransmitter diversity in the basal ganglia A fundamental feature of the nervous system is that: it divides up its massively parallel incoming signals in order to combine them in novel ways. In current phraseology, the nervous system is made up of distributed systems. Probably this lies at the heart of the division of the striatum into striosomes and matrix (and matrisomes), and accounts for the remarkable splitting of peptide representations in striatal outputs to the pallidum. By means of these compartmental divisions, and the restricted cross-compartment connections present, the basal ganglia can selectively bring together - or keep separate - their different inputs, and reorganize activity patterns before distributing the information to the rest of the brain. This view suggests that the basal ganglia contain a neural network capable of selectively reconfiguring cortical information in ways designed to influence the frontal cortex and a small set of brainstem motor pathways. But we still must ask: what do the neurotransmitter specializations of these striatal and pallidal compartments do to constrain and condition this re-sorting process? Would the basal ganglia function differently if the only transmitters they contained were the classic transmitters of the 'basic circuit' rather than these transmitters in combination with so many neuropeptides? One intriguing possibility is that the neuropeptides serve as gain-control devices, adjusting activity levels in the basic circuit and its side-loops (see Ref. 58). It is notable that so many of the neuropeptides in the ~NS, Voi 13, No. Z 1990

8 Koob, G. F. and Bloom, F. E. (1988) Science 242,715-723 9 Roland, P. E. (1987) in MotorAreas of the Cerebral Cortex (Ciba Foundation Symposium 132) (Bock, G., O'Connor, M. and Marsh, J., eds), pp. 251-265, Wiley 10 Seeman, P., Niznik, H. B., Guan, H-C., Booth, G. and Ulpian, C. (1989) Proc. Natl Acad. 5ci. USA 86, 10156-10160 11 Olson, L., Seiger, A. and Fuxe, K. (1972) Brain Res. 44, 283-288 12 Tennyson, V. M. etal. (1972) Brain Res. 46, 251-285 13 Butcher, L. L. and Hodge, G. K. (1976) Brain Res. 106, 223-240 14 Pert, C. B., Kuhar, M. J. and Snyder, S. H. (1976) Proc. Natl Acad. 5ci. USA 73, 3729-3733 15 Graybiel, A. M. and Ragsdale, C. W. (1978) Proc. NatlAcad. 5ci. USA 75, 5723-5726 16 Desban, M., Gauchy, C., Kemel, M. L., Besson, M. J. and Glowinski, J. (1989) Neuroscience 29, 551-566 17 Groves, P. M., Martone, M., Young, S. J. and Armstrong, D. M. (1988) J. Neurosci. 8, 892-900 18 Graybiel, A. M. (1984) Neuroscience 13, 1157-1187 19 Gerfen, C. R. (1984) Nature 311,461-464 20 Graybiel, A. M., Ragsdale, C. W., Yoneoka, E. S. and Elde, R. P. (1981) Neuroscience 6, 377-397 21 Herkenham, M. and Pert, C. B. (1981) Nature291,415-418 22 Groenewegen, H. J., Meredith, G. E., Berendse, H. W., Voorn, P. and Wolters, J. G. (1989)in NeuralMechanisms in Disorders of Movement (Crossman, A. and Sambrook, M. A., eds), pp. 45-54, Libbey 23 Kemel, M-L., Desban, M., Glowinski, J. and Gauchy, C. (1989) Proc. Natl Acad. 5ci. USA 86, 9006-9010 24 Donoghue, J. P. and Herkenham, M. (1986) Brain Res. 365, 397-403 25 Gerfen, C. R. (1989) Science 246, 385-388 26 Ragsdale, C. W. and Graybiel, A. M. Proc. Natl Acad. Sci. USA (in press) 27 Kelley, A. E. and Domesick, V. B. (1982) Neuroscience 7, 2321-2335 28 Mishkin, M., Malamut, B. and Bachevalier, J. (1984) in Neurobiology of Learning and Memory (Lynch, G., McGaugh, J. L. and Weinberger, N. M., eds), pp. 65-77, Guilford Press 29 Hikosaka, O., Sakamoto, M. and Usui, S. (1989) ]. NeurophysioL 61,780-798 30 Saint-Cyr, J. A., Taylor, A. E. and Lang, A. E. (1988) Brain 111,941-959 31 Monaghan, D. T. and Cotman, C. W. (1985) ]. Neurosci. 5, 2909-2919 32 Jimenez-Castellanos, J. and Graybiel, A. M. (1987) Neuroscience 23,223-242 33 Gerfen, C. R., Herkenham, M. and Thibault, J. (1987) J. Neurosci. 7, 391 5-3934 34 Langer, L. F. and Graybiel, A. M. (1989) Brain Res. 498, 344-350 35 Gerfen, C. R., Baimbridge, K. G. and Thibault, J. (1987) ]. Neurosci. 7, 3935-3944 36 Turner, B. H., Wilson, J. S., McKenzie, J. C. and Richtand, N. (1988) Brain Res. 473, 60-64 37 Hirsch, E. C., Graybiel, A. M. and Agid, Y. A. (1988) Nature 334, 345-348 38 Graybiel, A. M., Ragsdale, C. W. and Moon Edley, S. (1979) Exp. Brain Res. 34, 189-195 39 Gerfen, C. R. (1985) J. Comp. NeuroL 236, 454 40 Gimenez-Amaya, J-M. and Graybiel, A. M. (1990) Neuroscience 34, 111-126 41 Jimenez-Castellanos, J. and Graybiel, A. M. (1989) Neuroscience 32,297-321 42 Kimura, M., Rajkowski, .1. and Evarts, E. (1984) Proc. Natl Acad. 5ci. USA 81, 4998-5001 Selected references 43 Kawaguchi, Y., Wilson, C. and Emson, P. C. (1989) 1 Wilson, S. A. K. Modern Problems in Neurology p. 142, ). Neurophysiol. 62, 1052-1068 William Woocl 44 Bolam, J. P., Izzo, P. N. and Graybiel, A. M. (1988) 2 Graybiel, A. M. and Ragsdale, C. W. (1983) in Chemical Neuroscience 240, 853-875 Neuroanatomy (Emson, P. C., ed.), pp. 427-504, Raven Press 45 Malach, R. and Graybiel, A. M. (1986) J. Neurosci. 6, 3 Graybiel, A. M. (1989) in Neural Mechanisms in Disorders of 3436-3458 Movement (Crossman, A. and Sambrook, M. A., eds), pp. 46 Alexander, G. E. and DeLong, M. R. (1985)2. NeurophysioL 3-15, Libbey 53, 1417-1430 4 Semba, K., Fibiger, H. C. and Vincent, S. R. (1987) Can. J. 47 Hong, J. S., Yang, H-Y. T., Fratta, W. and Costa, E. (1978) NeuroL Sci. 14, 386-394 J. Pharmacol. Exp. Ther 205, 141-147 5 Albin, R. L., Young, A. B. and Penney, J. B. (1989) Trends 48 Uhl, G. R., Navia, B. and Douglas, J. (1988) J. Neurosci. 8, Neurosci. 12, 366-375 4755-4764 6 Carlsson, A. (1988) Neuropsychopharmacology 1, 179-203 49 Uhl, G. R., Ryan, J. P. and Schwartz, J. P. (1988) Brain Res. 7 Laplane, D. etal. (1989) Brain 112, 699-725 459, 391-397

basal ganglia occur in the medium-sized projection neurons of the striatum, and in their axons. These striatal neurons are noted for their low resting rates of neuronal firing, and they get turned on phasically. If, as in the peripheral nervous system 59, peptide release requires high rates of firing, then under different stimulus conditions the classic transmitter in these neurons (GABA) could act alone or in combination with one or more co-existing neuropeptides. This, in turn, could result in the selection of different striatal input-output linkages under different conditions, and could increase or decrease the gain of each striatal output pathway. As these pathways lead into different functional circuits, such peptidergic modulation could have highly specific functional effects, for example, enhancing or diminishing the efficacy of the subthalamic loop. To the degree to which the basal ganglia collectively serve as a gain-control system (an idea long suggested by clinical observation of the hypokinetic and hyperkinetic symptoms of basal ganglia disease), having a concentration of neuropeptide modulators in the main input side of the basal ganglia (the striatum) could be crucial in providing the fluctuating activity levels necessary to scale movements in time and space. Such modulation could also be part of a program-selection mechanism. It is particularly interesting that the expression of many of the neuropeptides in these striatal neurons is under the control of dopamine. Schultz and his coworkers6° have reported that the dopaminergic neurons of the substantia nigra in the monkey mainly fire in relation to sensory stimuli of interest to the animal rather than firing before self-initiated movements (as many striatal neurons do). Conceivably, then, the dopaminergic inputs to the striatum could tune the striatal neurons, and could do this in part by influencing peptide mobilization and release by these neurons. Some dopamine-containing neurons actually end on the necks of spines on these striatal projection neurons, as though to control the efficacy of the cortical inputs from terminals on the spine heads (see A. D. Smith and J. P. Bolam, this issue). Dopamine acting at D1 receptors may also influence corticostriatal throughput by interacting with NMDA receptormediated regulation of protein phosphorylationOL Each of these possibilities involves modifiability at the time-scales of fast and slow synaptic transmission, but also allows effects of longer duration. Such multiple time-frames seem more appropriate than fast transmission alone to account for the range of functions in which the basal ganglia have now been implicated the control of movement (especially willed movement), aspects of the motivation for action, and motor memory.

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50 Bean, A. J., During, M. J., Deutch, A. and Roth, R. H. (1989) J. Neurosci. 9, 4430-4438 51 Vernier, P. etal. (1988)J. Neurochem. 51, 1375-1380 52 Graybiel, A. M. and Chesselet, M-F. (1984) Proc. NatlAcad. ScL USA 81, 7980-7984 53 van der Kooy, D. and Fishell, G. (1987) Brain Res. 401, 155-161 54 Newman-Gage, H. and Graybiel, A. M. (1988) J. Neurosci. 8, 3360-3375 55 Fishell, G. and van der Kooy, D. (1987) J. Neurosci. 7, 1969-1978 56 Steindler, D. A., O'Brien, T. F. and Cooper, N. G. F. (1988) J. Comp. Neurol. 267, 357-369 57 Foster, S. L. etal. (1987)J. Neurosci. 7, 1994-2018 58 Graybiel, A. M. (1984)in Functions of the Basal Ganglia (Ciba Foundation Symposium 107) (Evered, D. and O'Connor, M.,

eds), pp. 114-143, Pitman Press 59 Lundberg, J. M. et aL (1982)in Systemic Role of Regulatory Peptides (Bloom, S. R. etaL, eds), pp. 145-168, Schattauer 60 Schultz, W. et aL (1989) in Neural Mechanisms in Disorders of Movement (Current Problems in Neurology 9) (Crossman, A. R. and Sambrook, M. A., eds), pp. 145-156, Libbey 61 Halpain, 5., Girault, J-A. and Greengard, P. (1990) Nature 343,369-372 62 Herkenham, M. et al. Proc. Natl Acad. Sci. USA (in press) 63 Fatlon, J. H. etal. (1984)Science 224, 1107-1109 64 Goto, S., Hirano, A. and Rojas-Corona, R. R. (1989) Acta Neuropathol. 78, 65-71 65 Reiner, A. (1987) Brain Res. 422, 186-191 66 Chesselet, M-F. and Hook, V. Y. H, (1988) Regulatory Peptides 20, 151-159

Extrinsic connedions of the basal ganglia Andr6 Parent

Andr~ Parentis at the Departmentof Anatomy, Facultyof Medicine, Laval University, Quebec City, Canada 61K7P4.

Recent neuroanatomical studies undertaken with various powerful neural tracing methods have radically changed our concept of the organization of the basal ganglia. This paper briefly reviews some of the findings that have led to the conclusion that the major components of the basal ganglia can no longer be considered as single undifferentiated entities. Instead, each of these structures is characterized by several distinct afferent and efferent chemospecific subsystems by which they can modulate and convey the multifarious information that flows through the basal ganglia. This paper focuses mainly on data obtained in primates, but also stresses the importance of comparison with non-primate species. The circuitry of the basal ganglia is classically known as being composed of multiple intrinsic loops, through which most of the key structures of the system are reciprocally linked, and of a smaller number of projection pathways, which allow the basal ganglia to exert their influence upon distant target structures. Although this general concept of the basal ganglia circuitry is still valid, the numerous neuroanatomical studies undertaken during the past decade, with ever more powerful and sophisticated methods, have greatly expanded our knowledge of the anatomical and functional organization of the basal ganglia. This paper summarizes some of these findings, particularly those that have challenged and even radically changed our way of ttfinking about the arrangement of this set of structures, which plays a crucial role in the control of psychomotor behavior. The striatum: three levels of organization and heterogeneity The striatum is the largest and major receptive component of the basal ganglia. It receives massive projections from the cerebral cortex, the thalamus and the substantia nigra pars compacta (SNc), and less prominent ones from the pallidum or globus pallidus (GP), the subthalamic nucleus (STN), the dorsal raphe nucleus, and the pedunculopontine tegmental nucleus (PPN). In contrast, the striatum projects massively only to GP and SN. The striatum is composed of a large number of medium spiny

254

projection neurons and a small number of large and medium-sized interneurons 1,2. Among the various striatal afferents, those from the cortex are by far the most prominent. They are of the utmost importance as they impose upon the striatum a pattern of functional regionalization that is maintained throughout the basal ganglia. Most cortical areas project topographically to the striatum. In monkeys the sensorimotor cortex projects mostly to the putamen where a somatotopic representation of the leg, ann and face occurs in the form of obliquely arranged strips 3. In contrast, associative areas of the prefrontal, temporal, parietal and cingulate cortices project mainly to the caudate nucleus4. Finally, afferents from limbic and paralimbic cortical areas as well as from the amygdala and the hippocampus terminate largely in the ventral portion of the striatum, which includes the nucleus accumbens, the deep layers of the olfactory tubercle, and the ventral part of both the caudate nucleus and the putamen5. On the basis of these projections, the striatum can be subdivided into sensorimotor, associative and limbic territories (Fig. 1). However, since overlap exists among the different corticostfiatal projections, these three territories should be viewed more as a continuum rather than stfiatal subdivisions with strict boundaries. Another level of organization is imposed upon the striatum as a result of the fact that cortical areas reciprocally interconnected via corticocortical connections tend to share common zones of termination in Abbreviations Used in the Text CM-PF, centromedian-parafascicular complex GP, globus pallidus or pallidum GPe, external segment of GP GPi, internal segment of GP GPv, ventral palliclum PPN, pedunculopontine nucleus SN, substantia nigra SNc, pars compacta of SN SNr, pars reticulata of SN STN, subthalamic nucleus

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TINS, VOI. 13, NO. 7, 1990