Chapter II The basal ganglia

CHAPTER II

The basal ganglia CHARLES R. G E R F E N AND CHARLES J. WILSON

1. INTRODUCTION The basal ganglia are a major neural system which receives cortical inputs, processes these inputs and feeds them back to the cortex via connections through the midbrain and thalamus. While most cortical areas provide inputs to the basal ganglia, including frontal, parietal, temporal and limbic cortices, the thalamic feedback is directed principally to frontal cortical areas, including prefrontal, premotor and supplementary motor areas (Alexander and Crutcher 1990; Alexander et al. 1986, 1990). This thalamic feedback, which parallels ascending cerebellar connections through the thalamus to primary motor cortex (Schell and Strick 1984), involves the basal ganglia in motor function. Diseases of the basal ganglia result in profound movement disorders. However, the complexity and variety of such disorders makes characterizing a typical function that is affected by basal ganglia disorders elusive. In some diseases hypokinetic disorders predominate, such as in Parkinson's disease, whereas hyperkinetic disorders are typical in Huntington's chorea and Tourette's syndrome. Significant advances have been made in recent years that point to specific neuroanatomical and neurochemical substrates involved in these extremes of movement disorders. However, such theories are recognizably simplified and do not explain the full complexity of movement disorders (Albin et al. 1989; DeLong 1990). For example, slowed reaction time that typifies the hypokinetic dysfunction of Parkinson's disease is dependent in part on the context of cues that trigger movements (Brown et al. 1993; Brown and Robbins 1991; Jahanshahi et al. 1993). Further understanding of basal ganglia function incorporates recent work that points to the essential cognitive, motivational and memory components involved in the generation of normal volitional movements. To understand the role that the basal ganglia perform in the complex integration of information involved in the generation of volitional movements its neuroanatomical and neurochemical organization may be broken down into component parts. First, the organization of cortical inputs to the basal ganglia most likely provide the fundamental functional determinants of this neural system. Second, how such cortical inputs are processed is determined by the organization of the subnuclei of the basal ganglia. Included is the organization of the target neurons of cortical inputs in the striatum, connections of these neurons that progress through the basal ganglia, and a variety of local and multisynaptic feedback circuits amongst subnuclei. Third, the organization of the output of the basal ganglia, and the interface with midbrain and thalamic nuclei, determines the effects that are fed back to the frontal cortex. The basal ganglia provide a singular challenge to elucidating functional organization of a neuronal system. Unlike the cortex in which neurons are distributed in distinct Handbook of Chemical Neuroanatomy, Vo112. Integrated Systems of the CNS, Part III L.W. Swanson, A. Bj6rklund and T. H6kfelt, editors 9 1996 Elsevier Science B.V. All rights reserved.

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layers that aid in the characterization of functionally distinct areas, the principal components of the basal ganglia are, for the most part, characterized by a homogeneity of neuronal distribution. However, what the basal ganglia lack in cytoarchitectural features they make up for in the variety of neurochemical markers that are contained in connectionally defined neuronal populations. Modern neuroanatomical methods, which provide detailed mappings of the axonal connections of neurochemically defined neurons have begun to reveal the functional organization of the basal ganglia. The ability to localize a broad spectrum of neurochemical components within identified neurons, aided in recent years by the work of molecular biology that has provided probes for neuroanatomical localization, has had a dual impact. On the one hand, such probes have aided in the characterization of neurochemically defined pathways. On the other hand, the alteration of many of these markers with pharmacologic treatments has aided in understanding how these pathways are functionally interconnected to carry out the processing of cortical inputs by the basal ganglia. Several principles emerge from analysis of the functional organization of the basal ganglia at the systems level (Gerfen 1992). Fundamental to the function of the basal ganglia is the organization of cortical inputs and how the basal ganglia process these inputs. The outputs of the striatum are organized to convert the excitatory inputs from the cortex so as to have antagonistic effects on the output of the basal ganglia. The balance between these antagonistic effects, which determines the output of the basal ganglia, are regulated by the intrinsic circuitry of the striatum and by various feedback loops between the components of the basal ganglia. Some of these feedback loops are regulated by the patch-matrix organization of the striatum, which is the functional equivalent of the laminar organization of the cortex (Gerfen 1989). Finally, the organization of the output of the striatum in relation to the organization of the output of the basal ganglia, which interfaces with the feedback circuits through the thalamus to the frontal cortex, provides the means of extracting certain types of information from the cerebral cortex. We propose that the cortical inputs to the striatum, the major nucleus of the basal ganglia, are a representation of cortico-cortical connections, and that the organization of the basal ganglia reflect this representation.

2. ORGANIZATIONAL OVERVIEW The basal ganglia are composed of a number of subcortical nuclei, which, for the purposes of this review will be regarded as including the striatum, the globus pallidus, the subthalamic nucleus, the entopeduncular nucleus (in cats and rodents) or the internal segment of the globus pallidus (in primates), the substantia nigra and the pedunculopontine nucleus. The principal components of the basal ganglia, as they appear in coronal sections of the rat brain, are diagrammed in Figure 1 and their major connections, in sagittal section, are diagrammed in Figure 2. The striatum, which is composed of caudate, putamen and nucleus accumbens, is the major nucleus of the basal ganglia, in that it is the target of inputs from most areas of the cortex and provides output to the other components of the basal ganglia. Cortical input to the striatum is excitatory (Kitai et al. 1976) with glutamate being the main neurotransmitter used by corticostriatal neurons (Spencer 1976; McGeer et al. 1977). The output of the striatum is inhibitory (Deniau et al. 1976), with all of the output neurons using GABA as a neurotransmitter (Yoshida and Precht 1971). There are two main output streams from the striatum, which have as their common final target GABA 372

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Fig. 1. Diagrams of coronal (frontal) sections through the rat brain at levels from rostral (A) to caudal (F) in which the major components of the basal ganglia are designated. neurons in the entopeduncular nucleus (internal segment of the globus pallidus in primates) and in the substantia nigra pars reticulata (this organization was early described by Nauta and Mehler 1966). One striatal output stream provides a direct path 373

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Fig. 2. Diagrams of sagittal brain sections depicting the major connections of the basal ganglia. A. Descending pathways from the cerebral cortex to the striatum (CP and Acc) and from the striatum through the 'indirect pathway, including the globus pallidus (GP) and subthalamic nuclei (STN) and 'direct pathway' to the output nuclei of the basal ganglia, the entopeduncular nucleus (EP) and substantia nigra pars reticulata (SNr), which provide inputs to the thalamus, superior colliculus (SC) and pedunculopontine nucleus (PPN). B. Feedback pathways within the basal ganglia include 1) thalamo-cortical projections, from the targets of basal ganglia outputs, including the ventral lateral, ventral medial and mediodorsal thalamic nuclei, back to frontal cortical areas; 2) thalamo-striatal projections, from the intralaminar nuclei to the thalamus; and 3) nigro-striatal dopamine (DA) pathway, from midbrain dopamine neurons to the thalamus and frontal cortex. 374

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Fig. 3. Viewof a single striatal spinyprojection neuron, intracellularlyfilledwith biocytin, in a sagittal section of the striatum (A) and at higher magnification (B). Corticofugal fiber fascicles are clearly evident coursing through the striatum. Spinyprojection neurons are labeled within the striatum with calbindin immunoreactivity.

to the entopeduncular nucleus and substantia nigra. The other striatal output stream provides an indirect input to these nuclei, via projections from the striatum to the globus pallidus (external segment of the globus pallidus in primates), which provides an inhibitory input to the subthalamic nucleus, which provides an excitatory input to the GABA neurons of the entopeduncular nucleus and substantia nigra. It is worth emphasizing at the outset that these two output streams have considerable complexity and are not entirely independent. A prime example is the fact that the neurons providing direct projections to the output nuclei of the basal ganglia, also contribute axon collaterals to the indirect pathway. The output nuclei of the basal ganglia are GABA neurons in the entopeduncular nucleus and substantia nigra. These neurons project to ventral tier thalamic nuclei, which project back upon prefrontal and premotor cortical areas. In addition the GABA output neurons of the entopeduncular nucleus project also to the lateral habenula, and those of the substantia nigra project to the superior colliculus and pedunculopontine nuclei. These latter nuclei provide descending projections to motor nuclei, and ascending projections to the thalamus. The GABA output of the basal ganglia provides a tonic inhibition to their projection targets, which is disinhibited by the direct striatal output pathway (Chevalier et al. 1985; Deniau and Chevalier 1985). Thus the major circuit of the basal ganglia is from the cortex, through its component nuclei to thalamic nuclei which project back upon frontal cortical areas. These projections run parallel to cerebellar projections through the thalamus back to motor cortex with the two systems mostly segregated from each other (Schell and Strick 1984). 375

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In addition to these main basal ganglia circuits there are a number of additional connections amongst the components of the basal ganglia that provide short loop feedback systems. One of the major feedback systems is from dopamine neurons in the substantia nigra back to the striatum, the nigrostriatal dopamine system. Other feedback circuits include projections from the globus pallidus to the striatum, from the subthalamic nucleus to the globus pallidus and striatum and from the thalamus back to the striatum. Such feedback circuits contribute significantly to basal ganglia function and their inclusion as additional rather than primary should not be taken as an indication of their importance. 2.1. COMPARISONS BETWEEN RODENTS AND PRIMATES Much of the neuroanatomical work on the basal ganglia that will be described in this review has been carried out in rodents. A reasonable question is whether there are significant differences between the organization of rodents and other animals, notably primates. The most obvious differences between rats and primates are those involving the gross anatomy of the nuclei of the basal ganglia. There are two major examples. The first is the striatum, which in the primate is subdivided by the internal capsule that provides a structural separation between the caudate and putamen nuclei. This structural separation does provide a gross separation of functional regions in the striatum in that the caudate nuclei is the target of prefrontal cortical inputs, whereas the putamen is the target of motor and somatosensory inputs. As the cortical input to the striatum is in large part responsible for its function, the caudate and putamen in the primate are to some extent functionally distinct. However, the internal capsule does not provide a precise divider of functional zones and there is some overlap of inputs from prefrontal cortex to the putamen. In the rodent, which lacks such a distinct structural separation there are nonetheless regional differences in the striatum which are comparable to those of the caudate and putamen, again determined by the regional distribution of inputs from different cortical areas. The second major gross anatomical difference between rats and primates involves the internal segment of the globus pallidus. In primates, this nucleus is situated immediately adjacent to the external segment of the globus pallidus. In rats, the homologous nucleus is separated from the globus pallidus and is embedded in the fiber tract of the internal capsule. In rats, this nucleus is termed the entopeduncular nucleus, which reflects its location. However, the internal segment of the globus pallidus in primates and the entopeduncular nucleus in rats are comparable structures in terms of their connections. Both nuclei represent, along with the substantia nigra pars reticulata, which is nearly identical in both rats and primates, the output structure of the basal ganglia. Despite the gross anatomical differences noted, the major connectional organization of the basal ganglia in rats and primates is remarkably similar. Two of the major features of basal ganglia organization that will be dealt with in some depth in this review, the patch-matrix compartmental organization of the striatum and the organization of direct and indirect output pathways of the striatum, have been demonstrated in both rodents and primates, and appear in the main, nearly identical in organization. Other aspects of the projections of the striatum appear to be also identical, as best demonstrated by papers in which comparable neuroanatomical tract tracing experiments have been done in rats and primates. For example, individual neurons in the striatum have been shown to provide dual inputs to multiple zones in the globus pallidus (Chang et al. 1981; Gerfen et al. 1985; Wilson and Phelan 1982). This dual projection to the globus pallidus has 376

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also been demonstrated to exist in the striatal projection to the substantia nigra in rats (Gerfen et al. 1985). Later, Parent and his co-workers demonstrated a similar organization in primate projections of the striatum (Parent and Hazrati 1993). A second example involves the general topographic organization of the projections of the striatum to the globus pallidus and substantia nigra. In papers that have examined this aspect of striatal organization in the rat (Gerfen 1985) and primate (Parent and Hazrati 1994) using injections of two anterograde tracers into the striatum to chart the topographic distribution of projections to globus pallidus and substantia nigra a remarkably similar pattern of organization is apparent in both. A comparison of the chartings of striatal projections in these two animals from these papers are nearly identical in pattern (Gerfen 1985; Parent and Hazrati 1994). Thus, for the most part, the major organizational principles of basal ganglia organization appear nearly identical in rats and primates. Differences in the organization of the basal ganglia in rats and primates can for the most part be attributed to the expanded cortex in primates. In primates, cortical fields are considerably elaborated and more precisely defined in terms of functional segregation of different cortical areas. While the organization of cortico-striatal patterns appears to follow the same general principles in rodents and primates, the elaboration of more detailed precise mapping patterns appear to predominate in the primate.

3. CEREBRAL CORTEX INPUT TO STRIATUM

The cerebral cortex provides a major input to the striatum. This input originates from most cortical areas, including primary and higher order sensory areas; motor, premotor and prefrontal regions; as well as from limbic cortical areas. It has been well established that this input is organized in a general topographic manner in that the spatial relationships between cortical areas are maintained in the projections to the striatum (Carman et al. 1965; Kemp and Powell 1970; Webster 1961). For example, projections from prefrontal areas are directed mainly to the rostral caudate nucleus (Goldman and Nauta 1977), while cortical inputs from motor cortex terminate primarily in the rostral putamen (Kunzle 1975). More complex is the issue of overlapping projections from functionally related areas. While it is clear that, in general, cortical areas provide input to a much broader area of the striatum than accounted for on the basis of topography alone, the varied and sometimes intricate pattern of this organization have led to a variety of interpretations as to the functional significance. While, the widespread nature of corticostriatal organization is not in doubt, where some have seen patterns of overlap related to patterns of cortical connectivity (Yeterian and Hoesen 1978), others have seen interdigitation (Selemon and Goldman-Rakic 1985). Detailed mapping of the organization of corticostriatal inputs has begun to resolve these issues, showing, in some cases, overlap of inputs from interconnected cortical areas that are organized fairly precisely by the somatotopic organization within such areas (Flaherty and Graybiel 1991; Flaherty and Graybiel 1993a; Malach and Graybiel 1986; Parthasarathy et al. 1992). These issues will be discussed in more detail in a later section. Neurons in layer 5 in most cortical areas provide input to the striatum. All corticostriatal neurons are pyramidal neurons and utilize glutamate as a neurotransmitter. Corticostriatal neurons may be divided into several types based on their connections within the cortex, their projections to other subcortical areas, and their laminar distribution within the cortex. Three corticostriatal cell subtypes have been definitely identified, using double retrograde tracing or intracellular staining or both. Neurons in the frontal 377

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cortex contributing to the pyramidal tract have been shown to contribute axon collaterals to the neostriatum (Cowan and Wilson 1994; Donoghue and Kitai 1981; Landry et al. 1984). The striatal projection of this cell is formed by a very fine collateral formed from the much larger main axon in the course of its trajectory through the internal capsule. While a relatively small component of the corticostriatal pathway, this projection has attracted some interest because of its potential for providing the neostriatum with a copy of the cortical motor signal. A second cortical cell type contributing to the striatum is a bilaterally-projecting corticocortical corticostriatal neuron (Cowan and Wilson 1994; Wilson 1987). This cell is very numerous in agranular cortical regions giving rise to bilateral corticocortical and corticostriatal projections, for example the premotor cortex. Unlike the pyramidal tract neurons, which are located in the deeper part of layer V, these neurons are located in a band at the superficial half of layer V and in the deep half of layer III. The axons of these cells bifurcate twice or more times in the deep cortical layers to form approximately equal-sized branches. Two of them cross the midline to form contralateral projections. An additional branch follows the subcortical white matter laterally to enter the striatum without passing through the striatal part of the internal capsule, and arborizes in the ipsilateral striatum. Additional collaterals travel horizontally, often crossing cytoarchitectonic boundaries to make synaptic connections in other cortical regions on the ipsilateral side. A third corticostriatal neuron has so far been demonstrated only by retrograde labeling (Royce 1983). This is a corticothalamic neuron with a collateral projection to the striatum. It is almost certain that there are other kinds of corticostriatal neurons that have not yet been identified. For example, in cortical regions with few or no collosal projections, such as the granular regions of the somatosensory cortex in the rat, there is a dense band of corticostriatal neurons located in the superficial half of layer V. This band of cells is continuous with the broader band of bilaterally-projecting corticocortical and corticostriatal neurons seen in the motor cortex, but is narrower, and certainly does not have collossal projections. The connections of these cells have not yet been studied in detail. In agranular cortical regions, there are corticostriatal neurons in more superficial layers still, whose identity is unknown. As indicated above, the composition of the corticostriatal projection is greatly dependent upon cortical area, with corticostriatal cells in primary motor and sensory cortices having a much more restricted laminar distribution, and probably a more simple composition, than that of premotor and prefrontal areas (Arikuni and Kubota 1986; Wilson 1987). The intrastriatal axonal arborizations of two corticostriatal cell types in the rat premotor cortex have been described from intracellular staining studies, and were very different, suggesting that each corticostriatal cell type may have a unique pattern of innervation within the striatum (Cowan and Wilson 1994). The striatal collaterals of pyramidal tract neurons made one or more relatively focal arborizations, with dimensions of 100-500 pm on a side. The focal nature of these arborizations suggested a relatively simple topography of the corticostriatal projection formed by these neurons. The other cell type, the bilaterally-projecting corticocortical/corticostriatal neuron, arborized in a much larger striatal volume, with dimensions of 1 mm or greater. Within that volume the axon occupied space in a very sparse fashion, with individual branches running approximately parallel and separated by large uninnervated areas. This pattern is reminiscent of the heterogeneous and complex pattern of labeling seen following small injections of anterograde tracers in the cortex. This pattern is expected from the arborization seen for individual corticostriatal neurons if nearby corticostriatal cells have fine scale similarities in their axonal arborizations. That is, the pattern of labeling seen after 378

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extracellular injections of anterograde tracers in the cortex implies that much of the complex topology of corticostriatal axonal arborizations will be shared among neighboring cells in the cortex. All afferent inputs to the striatum that have been studied so far have formed axonal fields in which the individual axonal branches cross over the dendrites of individual spiny neurons, making synapses mostly en passant. This is the cruciform axodendritic pattern of innervation (Fox et al. 1971), which places each axon into position to contact the maximum number of neurons but minimizes the number of synapses possible with each postsynaptic cell. This is in contrast to the longitudinal axodendritic synaptic arrangement formed by striatopallidal fibers (Fox and Rafols 1976), in which individual axonal branches form multiple synaptic contacts on the dendrites of postsynaptic neurons.

4. STRIATUM The striatum comprises the caudate, putamen and nucleus accumbens. In mammals in which corticofugal fibers coalesce into the internal capsule within the striatum, the caudate nucleus and putamen nucleus are separated by this partition. In animals in which corticofugal fibers are dispersed there is no clear separation between these nuclei, thus the term caudate-putamen is often used. The caudate and putamen, in most species, generally occupy the dorsal part of the striatum. The nucleus accumbens is the rostroventral extension of the striatum, and occupies the area surrounding the anterior commissure in the rostral part of the striatum. The term ventral striatum is generally used to refer to the nucleus accumbens and more caudally, the ventral most part of the striatum (Heimer and Wilson 1975). The olfactory tubercle is sometimes included as a part of the ventral striatum, but in this review will not be discussed. The striatum is composed of one principal neuron cell type, the spiny projection neuron (Bishop et al. 1982; DiFiglia et al. 1976; Wilson and Groves 1980). This spiny projection cell type makes up as much as 95% of the neuron population (Kemp and Powell 1971). These neurons are rather homogeneously distributed such that the striaturn lacks distinct cytoarchitectural organization when all neurons are stained in histologic sections, as contrasted with the laminar organization of the cortex, for example. Using retrograde axonal transport methods Grofova (Grofova 1975) established that these neurons are the projection neuron of the striatum. Cortical input to the striatum targets spiny projection neurons (Somogyi et al. 1981), although not exclusively. Thus the spiny projection neuron is the major input target and the major projection neuron of the striatum. The connections of these neurons are thus the major determinant of the functional organization of the striatum. The remaining striatal neurons are interneurons (Bishop et al. 1982; DiFiglia et al. 1976), in that they do not provide projection axons, but rather distribute axons within the striatum, most of which make synaptic contact with spiny projection neurons. Despite being relatively infrequent, striatal interneurons constitute a variety of morphologic and neurochemically defined types. Among these are the large aspiny neurons, which utilize acetylcholine as a transmitter (Bolam et al. 1984; Kawaguchi and Kubota 1993), and medium aspiny neurons (Bishop et al. 1982; DiFiglia et al. 1976), which utilize GABA as a transmitter (Kita 1993). The latter class of interneurons may be further subdivided on the basis of different peptides and neurochemicals that they contain (Kita 1993; Kubota and Kawaguchi 1993; Kubota et al. 1993). Striatal interneu379

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rons are also rather uniformly distributed within the striatum, although in some cases their axons may be distributed in a heterogeneous manner. 4.1. SPINY PROJECTION N E U R O N Spiny projection neurons take their name from their morphologic appearance (Bishop et al. 1982; Chang et al. 1982; DiFiglia et al. 1976; Wilson and Groves 1980). This neuron cell type is often referred to as the striatal medium spiny neuron. However, as the size discriminator, medium, implies that there are both larger and smaller class neurons, and in the striatum there are no identified smaller neurons, this term is deleted from the classification used in this review and replaced with a more appropriate characteristic feature of these neurons, namely that they are projection neurons. They have a cell body approximately 20-25 pm in diameter, from which radiate 7-10 moderately branched dendrites that are densely laden with spines. The dendrites of an individual neuron extend over an area of approximately 200 pm in diameter. The distribution of the dendrites is not always uniform and may in fact be limited by compartmental boundaries within the striatum, such as those that form the 'patch-matrix' compartments (Kawaguchi et al. 1989). Spiny projection neurons extend a local axon collateral that remains within the striatum. In most cases such collaterals distribute over an area roughly equal in size, but not necessarily in the same area, as the dendrites of the parent neuron (Bishop et al. 1982; Kawaguchi et al. 1990). In some cases the local axon collateral may have an extensive distribution over a very large area within the striatum, extending over 1 mm from the parent neuron (Kawaguchi et al. 1990). Spiny projection neurons also provide an axon collateral which projects out of the striatum to the globus pallidus and/or entopeduncular nucleus/substantia nigra (Kawaguchi et al. 1990). Two major subpopulations of medium spiny neurons, of approximately equal numbers, may be defined on the basis of their projection targets (Beckstead and Cruz 1986; Gerfen and Young 1988; Kawaguchi et al. 1990; Loopuijt and Kooy 1985). One subset, provides an axon projection to the globus pallidus. The other subset provides an axon collateral to the globus pallidus, and additional collaterals to the entopeduncular nucleus and/or the substantia nigra. These projections will be discussed in detail later. Spiny projection neurons all contain glutamic acid decarboxylase (GAD) the synthetic enzyme for the neurotransmitter GABA (Kita and Kitai 1988). In addition, most of those neurons projecting to the globus pallidus alone contain the neuropeptide enkephalin, whereas most of those which project to the substantia nigra contain the neuropeptides substance P and dynorphin (Beckstead and Kersey 1985; Gerfen and Young 1988; Haber and Watson 1983). Spiny projection neurons contain different complements of neurotransmitter receptors, and other proteins that serve to characterize particular subpopulations of striatal output neurons. These will be discussed in further detail below. Spiny projection neurons receive inputs from the cortex, thalamus and amygdala, which make asymmetric synapses on dendritic spines, and to a lesser degree, dendritic shafts. These inputs provide the major excitatory input to these neurons. In addition, a number of inputs from outside the striatum, and from within the striatum provide inputs that function to modify the responsiveness of spiny neurons to the excitatory input. These include inputs from dopamine afferents from the substantia nigra, inhibitory GABA inputs from the axon collaterals of other spiny neurons, inhibitory inputs from GABA (and peptide containing) striatal interneurons, and inputs from cholinergic striatal interneurons. 380

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4.1.1. Cortical input Corticostriatal afferents make synaptic contact primariy with the expanded head of dendritic spines on spiny neurons (Bouyer et al. 1984; Hattori et al. 1978; Kemp and Powell 1970; Somogyi et al. 1981). According to a recent quantitative study in rats (Xu et al. 1989), of all cortical synapses in the striatum, about 90% are formed with dendritic spines, and about 5% with dendritic shafts. The remaining 5% are on somata. While most dendritic spine synapses are certainly formed with spiny projection cells, the smaller number of dendritic and somatic contacts include the combination of all the inputs onto interneurons, as well as contacts made with spiny cell dendritic shafts. The somata receiving cortical inputs generally do not resemble those of spiny neurons. Corticostriatal synapses are almost exclusively asymmetric and contain small rounded vesicles. Although cortical innervation of the striatum is relatively dense, input from any individual corticostriatal axon to an individual striatal spiny neuron is very sparse. Examination of single corticostriatal axonal arborizations suggests that most corticostriatal axons make synapses on a very small proportion of spiny neurons present in the innervated volume, and probably make no more than one synapse on each spiny neuron contacted. This reflects the fact that cortical inputs from individual corticostriatal neurons, is distributed over a relatively large striatal domain and contacts many spiny neurons (Cowan and Wilson 1994). Consistent with the asymmetric character of corticostriatal synapses onto spiny neurons electrophysiologic studies have demonstrated that corticostriatal input evokes a monosynaptic excitatory post-synaptic potential (EPSP) (Kitai et al. 1976; Wilson 1986). At least two types of corticostriatal afferents have been identified, on the basis of the electrophysiologic effects of these inputs (Jinnai and Matsuda 1979; Wilson 1986). One is a fast conducting collateral of neurons projecting to the brainstem and evokes an EPSP with a latency of 3 msec. A second type, which appears to be the major corticostriatal afferent, is a slower conducting afferent that evokes an EPSP with a latency of 10 msec.

4.1.2. Thalamic input Thalamic inputs from from the intralaminar nuclei, including the the parafascicular/ centromedian complex parts, provide inputs to the striatum that are similar to cortical afferents in that they form asymmetric synaptic contacts, and have strong excitatory effects on the spiny cells. Since the pioneering retrograde degeneration studies of (Powell and Cowan 1956) it was believed that the thalamostriatal pathway consisted of a single topographically organized projection tot the neostriatum. More recent studies (Dube et al. 1988; Xu et al. 1991) have shown that this pathway, like the corticostriatal projection, is heterogeneous in nature. There are actually two independent thalamostriatal projections intralaminar nuclear complex, one originating from the parafascicular/ centromedian nuclei and a separate one from rostral parts of the complex including the central lateral and paracentral nuclei. The parafascicular projection, unlike the cortical input, makes its asymmetrical synaptic contacts preferentially with the shafts of dendrites rather than the spines. In one study (Xu et al. 1991), 89% of synapses formed by fibers from the parafascicular nucleus were formed on dendritic shafts in the neostriatum, with only 11% on dendritic spines. This is almost exactly the reverse of the arrangement of cortical axons. The postsynaptic targets of the parafascicular projection have been shown to be spiny neurons, but perhaps neurons of a special class which do 382

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Fig. 6. A-C. Three examples of intracellularly filled striatal spiny projection neurons. Dendrites, shown in black, are densely laden with spines and extend in an area approximately 200-300/lm around the cell body. Local axon collaterals of these neurons, depicted in gray, spread in area approximately 200-400/lm around the cell body, which does not precisely overlap the dendritic spread of these neurons. Adapted from Kawaguchi et al. 1990.

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Fig. 7. The 3 spiny projection neurons from Fig. 6 (A-C) and a fourth spiny projection neuron (D) are drawn to scale in a sagittal section of the striatum showing the denrites (white), local axon collaterals (black) and projection axons of these neurons to the globus pallidus (GP). Spiny projection neurons A and B are of the type that provide a projection axon to the globus pallidus and axon collaterals that extend to the entopeduncular nucleus and/or substantia nigra. Spiny projection neurons C and D provide projection axons that arborize within the globus pallidus but do not extend out of this nucleus. The pallidal axons arborize in two separate zones within the globus pallidus. Spiny projection neuron D is distinguished by the large area over which the axon collateral arborizes within the striatum, extending over 1 cm in areal extent. Also depicted is a large aspiny neuron showing the large area over which its dendrites (white) and axon collaterals (black) extend within the striatum. Adapted from Kawaguchi et al. 1990.

not receive a cortical input or at least do not receive as dense cortical input. In contrast to projections arising from the parafascicular/centromedian nuclei, fibers from the rostral intralaminar nuclei (e.g. central lateral or paracentral nucleus) form synapses similar to those formed by corticostriatal fibers. In the study by Xu et al. (1991), 93% 385

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Fig. 8. A-C) Examples of the axons of type 1 (Kawaguchi et al. 1990) spiny projection neurons in the globus pallidus (GP). Projections of each of these neurons have axons which arborize in the two parts of the globus pallidus, the region immediately adjacent to the striatum and the central region of the globus pallidus. D) The projection axons of examples of type 1 and type 2 spiny projection neurons (Kawaguchi et al., 1990) depicted in a sagittal section. The type 1 neuron is shown to provide a projection axon that terminates within the globus pallidus (GP) and does not extend beyond this nucleus. The type 2 neuron is shown to provide an axon that arborizes within the GP and then extends two collaterals that provide inputs to the entopeduncular nucleus (EP) and substantia nigra, stn: subthalamic nucleus, VTA: ventral tegmental area, SNc: substantia nigra pars

compacta, RR: retrorubral area. Adapted from Kawaguchi et al. 1990.

of these were formed on dendritic spines, and 7% on dendritic shafts. The projections from these two different sets of thalamic nuclei also differ in their innervation of patch and matrix compartments, as described in a subsequent section.

4.1.3. Nigrostriatal dopamine input Inputs from midbrain dopamine neurons that project to the striatum make synaptic contact with spiny neurons. These afferents have been identified at the ultrastructural 386

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level with immunohistochemical localization of either dopamine (Voorn et al. 1986) or the dopamine synethesizing enzyme tyrosine hydroxylase (Arluison et al. 1984; Bouyer et al. 1984; Freund et al. 1984). Most of these afferents make symmetric synapses and contain large round and pleiomorphic vesicles. Of 280 synapses examined by Freund 387

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et al (1984), 59% made synaptic contacts with dendritic spines. Unlike the axospinous synapses formed by cortical or thalamic inputs, these were symmetrical synapses, usually not made on the head of the spine, and these inputs shared the dendritic spine with another bouton forming an asymmetrical synapse (probably from the cerebral cortex or thalamus). Synapses were made onto dendritic shafts in 35% of the cases, and 6% made synapses with somata. It is often suggested that dopaminergic fibers may release dopamine nonsynaptically into the extracellular space, where it could interact with extrasynaptic receptors. Alternatively, dopamine may escape from the synaptic region and diffuse to extrasynaptic receptors on the postsynaptic neuron or other cell processes in the neuropil. With an eye for this possibility, it has been reported that dopaminecontaining synapses are sometimes seen to be in close apposition with the presynaptic part of assymetric forming boutons, presumably of cortical or thalamic origin. However, these close appositions lack synaptic specializations, and they have not been shown to be common than than appositions between any other elements of the neuropil.

4.1.4. Spiny cell local collaterals inputs (GABA and peptide) Spiny projection neurons have axon collaterals within the striatum that make symmetric synaptic contact with other spiny neurons (Wilson and Groves 1980). Axon collaterals of intracellularly labeled spiny neurons were shown to make synaptic contact with the cell soma of spiny neurons (12% of idenified synapses), with the interspine shafts of dendrites (48%) or with the necks of dendritic spines (40%). As with dopamine-containing synapses, collateral axon inputs to the spines contact the spine neck adjacent to asymmetric inputs to the spine heads. Synaptic connections between spiny neurons have also been identified with immunohistochemical markers that are contained in these neurons, including GAD, or either of the peptides substance P or enkephalin. Each of these markers shows a similar synaptic pattern. Each of these markers is contained in different subsets of sources of afferents to spiny neurons, in addition to being contained in the spiny axon collaterals. Thus, in addition to being localized in spiny collaterals GAD is also localized in the axons of some striatal interneurons, and in certain extrinsic afferents such as those from the globus pallidus. Substance P is perhaps a more selective marker for labeling of afferents orgininating from other striatal spiny neurons, although substance P is also localized in some striatal interneurons. Nonetheless, immunohistochemical localization of both GAD (Bolam et al. 1985) and substance P (Bolam and Izzo 1988) in boutons presynaptic to striatal spiny neurons reveal similar distribution patterns. Such inputs are distributed on the cell soma or smooth proximal part of the dendrites, to interspine dendritic shafts or to the dendritic spines. In all cases, the morphological appearance and the distribution of spiny cell collaterals is similar to that of the dopaminergic input. Izzo and Bolam (1986) reported that substance P containing boutons make synaptic contact most often with the more proximal parts of the dendrites, both the soma and smooth parts and the proximal spiny portions. This is somewhat contrasted with the dopamine containing inputs that more frequently target more distal dendritic portions. As will be described in some detail, spiny neurons are subdivided into different subpopulations that are both connectionally and neurochemically distinct, although all share a common morphology and use GABA as a transmitter. Thus, it is of some interest whether the local collaterals of these neurons target neurons of their own subpopulation or those of another subset. Bolam and Izzo (1988) have directly demonstrated that substance P immunoreactive boutons make synaptic contact with striatonigral neurons 388

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(also substance P positive), which establishes that, at least for striatonigral neurons, neurons from the same subpopulations of striatal output neurons make contact with one another. As enkephalin and substance P are contained in different connectionally defined populations of spiny neurons the ultrastuctural localization of synaptic contacts provides some indication of the interactions. In this regard it has been reported that both substance P and enkephalin immunoreactive boutons make synaptic contact with the dendrites of spiny neurons that are immunoreactive negative for the same peptide. This at least raises the possibility that neurons contributing to different output streams are directly contacted by each other, although a more detailed analysis of this question is in order.

4.1.5. Cholinergic input Boutons immunoreactive for choline acetyltransferase (CHAT) make synaptic contacts with striatal spiny neurons as well as other striatal cells (Izzo and Bolam 1988). The cholinergic synapses are symmetric and make contact with the cell somata (20%); dendritic shafts (45%) and with dendritic spines (34%). As with the other symmetrical synapses on dendritic spines, these share the spine with an asymmetrical synapse, usually placed more distally on the spine, similar to afferents from the cerebral cortex and thalamus.

4.1.6. Striatal GABA interneuron inputs In addition to the GABAergic striatal spiny projection neuron, a GABAergic interneuron has been identified within the striatum which comprises approximately 2% of the striatal neuron population. This cell was first positively described using loading with radioactive GABA (Bolam et al. 1983), and was later recognized as a subset of neurons staining more intensely using immunocytochemistry for glutamate decarboxylase (GAD) or GABA (e.g. Bolam et al. 1985). More recently, they have been shown to be positive for the calcium binding protein parvalbumin (Cowan et al. 1990; Gerfen et al. 1985; Kita et al. 1990). These are aspiny interneurons, on average larger than the spiny projection neurons, but smaller than the cholinergic cells. They make numerous symmetrical synapses with the somata and dendrites of spiny neurons, as well as other interneurons. More than any other identified source of input, the synapses from the parvalbumin/GABA interneuron preferentially innervates the somata of spiny neurons (Kita et al. 1990).

4.1.7. Somatostatin interneuron inputs A third type of aspiny striatal interneuron is identified by its immunocytochemical labeling with somatostatin, neuropeptide Y, and NADPH diaphorase. These cells have also been shown to be distinguishable from parvalbumin/GABA interneurons on the basis of morphological and physiological criteria (Kawaguchi 1993). Somatostatin positive synapses are formed mainly on shafts of dendrites and dendritic spines of spiny neurons (Takagi et al. 1983). As before, all the spines involved in this connection receive another asymmetrical synaptic contact. 389

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4.1.8. Other inputs In addition to the dopamine feedback from the substantia nigra, at least two other downstream parts of the basal ganglia provide feedback axons to the striatum. One of these is the globus pallidus, which provides GABAergic input to the striatum (Beckstead 1983; Staines et al. 1981). These have not been studied extensively at the electron microscopic level, however, they may provide a prominent input to the striatum as studies have shown that every pallidal neuron that projects to the substantia nigra provides an axon collateral to the striatum (Staines and Fibiger 1984). In addition, the subthalamic nucleus also provides an input to the striatum. This input is relatively sparse as compared to the density of projections of this nucleus to the substantia nigra and to the globus pallidus (Kita and Kitai 1987). Subthalamic input to the striatum appears to provide asymmetric input to spiny neurons. Although the dopamine input the striatum is the dominant input from the midbrain and brainstem at least two other forebrain projection sytems provide inputs. These include a serotonergic input from the dorsal raphe and a noradrenergic input from the locus coeruleus. Added to the list of sources of afferents to the striatum not covered in depth by this review are those from the amygdala. These inputs will not be dealt with in this review, which does not reflect their probable important contribution to basal ganglia function. 4.2. STRIATAL I N T E R N E U R O N S Striatal interneurons, which extend axons within but not out of the striatum, make up some 5-10% of the striatal neuron population (Bishop et al. 1982; Chang et al. 1982; DiFiglia et al. 1976; Kemp and Powell 1971). This class of neuron presents a variety of morphologically and neurochemically distinct subsets. Two major subtypes are identified on morphologic and neurochemical grounds. One is the neuron type which utilizes acetylcholine as a neurotransmitter, the large aspiny cholinergic striatal neuron (Bolam et al. 1984; Kawaguchi 1992; Kawaguchi 1993; Wilson et al. 1990). The other type, which utilizes GABA as a neurotransmitter, is composed of a number of subtypes, generally termed medium aspiny striatal interneurons (Kita 1993). Striatal neurons, including the interneurons, were once classified according to their somatic diameters. This classification was used primarily because it was compatible with the use of Nissl stains and not because it was sufficient for distinguishing the various cell types. It was successful only insofar as it revealed the presence of a small population of giant cells. Morphological criteria applied to the somatodendritic portion of the cells as they appear after Golgi staining was much more successful, enabling the identification of a number of interneuron types. Again the reason for using somatodendritic morphology in preference to axonal arborizations was based on necessity, rather than choice. The Golgi method did not reliably stain the axon of any of the neurons. However, even using the Golgi method, which was excellent for identification of the spiny cells and the giant aspiny neurons, opinions were divided on the exact number of cell types, suggesting that it was not clearly revealing the identifying characteristics of the interneurons (see, e.g. review in Chang et al. 1982). Nonetheless, several aspiny neuron types could be clearly identified by somatodendritic morphological criteria alone. All authors, beginning with K611iker and his observations on the human striatum (K611iker 1896), have described an aspiny neuron with a large cell body and radiating, sparsely branched dendrites. K611iker reported that this cell had a short axon, but it was 390

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described by Ram6n y Cajal (Ramdn y Cajal 1911) as the principal projection neuron of the striatum, and this view was held by most authors until the late 1970's and 1980's when the spiny neuron was shown to be a projection cell and the role of the large cell came into question (e.g. DiFiglia 1976). Subsequent studies employing staining by intracellular dye injection have shown this cell to have a locally-projecting axon, although its axon may arborize over a large distance in the striatum, and may also be myelinated (Bishop et al. 1982; Kawaguchi 1992; Wilson et al. 1990). Some authors distinguish two cell types in this category, one possessing a low density of dendritic spines and fewer dendritic varicosities, and one with smoother, often varicose dendrites (e.g. Chang et al. 1982). This distinction is subtle, and difficult to make when examining any one Golgi-stained neuron, and is justifiably met with a degree of skepticism, but the axons of these two classes of large ceils are also proposed to have dramatically different axonal arborizations. While one is the giant interneuron of K611iker, the other is proposed to be a rare type of projection neuron. Evidence for a large, relatively rare striatal projection neuron has accumulated from retrograde tracing experiments (Grofovfi 1979). Its existence has been confirmed using combined retrograde tracing and Golgi staining (Bolam et al. 1981). In addition, a large striatal neuron can be distinguished in tissue stained for enkephalin immunoreactivity on the basis of its dense investment of terminals positive for that peptide and for GABA (Bolam et al. 1985; Penney et al. 1988). Most large neurons with radiating dendrites, including those shown to be interneurons, show few synapses on the soma and proximal dendrites (Chang et al. 1982; DiFiglia and Carey 1986). A third morphological cell type often has a large soma, and that is the spidery neuron (DiFiglia et al. 1976; Fox et al. 1971; Yelnik et al. 1991). This cell has a very dense dendritic tree that remains near the cell body, with dendrites and an axon that recurves to form a dense network in the region of the soma. This cell is present in a variety of sizes, including some that are among the largest neurons in the striatum (DiFiglia et al. 1976; Yelnik et al. 1991). A much smaller, but otherwise similar version of the cell is also common among the medium and small aspiny cells. Authors disagree on whether the spidery neuron should be considered one type or should be divided in two based on somatic diameter (DiFiglia et al. 1976; Fox et al. 1971; Yelnik et al. 1991). Most have decided to subdivide the spidery cells on the basis of size, but the wide range of somatic diameters seen for cytochemically defined cell types should probably inspire second thoughts (see below). Among the smaller of the aspiny neurons, authors disagree on the number of categories that should be applied, and the criteria offered for distinguishing them are much less convincing. Many of these cells resemble the larger spidery neurons, but others have straighter, less varicose, and less branched dendrites. A quantitative study of the dendritic trees of striatal neurons in the primate (Yelnik et al. 1991) yielded only one clearly distinguishable group of small neurons, a position also taken by Ram6n y Cajal (1911), but most authors have separated the smaller interneurons cells into two groups on the basis of dendritic branching patterns (Chang et al. 1982; DiFiglia et al. 1976). More recently, striatal interneurons have been identified on the basis of immunocytochemical staining for markers known to be associated with neurons that do not have projecting axons. This method of classifying neurons is somewhat less ambiguous than the morphological criteria that were previously applied and the cell classes generated in this way have replaced the morphological ones for most practical purposes. One cell type is the cholinergic interneuron, which on the basis of cell size alone must correspond to one or more of the morphological classes of large neurons (Bolam et al. 1984; Wilson 391

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et al. 1990). A second clear class of interneuron is the one that stains using antibodies for somatostatin, neuropeptide Y, or nitric oxide synthetase (Dawson et al. 1991), all of which primarily stain a single cell population (Pasik et al. 1988; Smith and Parent 1986; Vincent et al. 1983a; Vincent et al. 1983b). A third class of interneurons is identified by its intense staining with a variety of procedures that reveal GABAergic neurons, including radioactive GABA uptake (Bolam et al. 1983), GABA antibodies (Pasik et al. 1988; Smith et al. 1987), and antibodies against glutamic acid decarboxylase (Oertel and Mugnaini 1984; Ribak et al. 1979). This cell was shown in combined GABA uptake and Golgi studies to be an aspiny interneuron (Bolam et al. 1983), and it is clearly distinct from the GABAergic projection neurons, which show a similar but much less intense pattern of staining, and from the somatostatin-containing neurons (Chesselet and Robbins 1989). More recently, this neuron was shown to be specifically stained with antibodies against parvalbumin, a calcium binding protein (Cowan et al. 1990; Gerfen et al. 1985; Kita et al. 1990). These three classes of interneurons differ in average size, but with overlapping distributions so that no one neuron could be identified as belonging to one of the cytochemical classes solely on the basis of its size. In fact, parvalbuminpositive neurons show a very broad range of somatic diameters, and the largest of these cells are in the somatic diameter range of cholinergic neurons (Cowan et al. 1990; Kita et al. 1990; Kubota and Kawaguchi 1993). A more direct comparison of the morphological and cytochemical cell classes requires labeling techniques that allow both cytochemical identification of the neurons and complete enough staining of the dendritic tree for analysis of its subtle features. The combined Golgi stain and 3[H]-GABA uptake study of (Bolam et al. 1983) has provided a description of the GABAergic interneuron, which showed it to be a medium-sized aspiny interneuron. Because interneurons are relatively few, and we have not learned to bias the Golgi method toward preferring any particular cell type, it is difficult to get adequate samples of identified interneurons using this technique. Immunocytochemical studies of the cell show a portion of the dendritic trees of the neurons, and so tempt investigators to make comparisons With cells from Golgi-stained preparations. In general, these have not been convincing, and claims of 'Golgi-like' staining with cell markers in the striatum have usually been somewhat exaggerated. The best approach would be a method that would give both high resolution of the dendritic tree and allow immunocytochemical demonstration of the same cells, and could do this for a significant sample of neurons of each type. This was achieved by Kawaguchi (Kawaguchi 1993) using intracellular injection of biocytin in slices. The cells were visualized using interference optics so that the largest and the smallest neurons could be preferrentially targeted. Because interneurons are enriched at both extremes of somatic size in the neostriatum, this yields a good proportion of interneurons, but does not necessarily represent the population of somatic diameters accurately. Immunocytochemical identification of cells was combined with biocytin using flourescent double-labelling. Using this approach, Kawaguchi (1993) showed that choline acetyltransferase positive neurons have radiating, often sparsely spiny, dendrites and large somata, matching the description of the giant interneuron of K611iker. This conclusion was reinforced by the finding that cells definitely identified as choline acetyltransferase positive exhibited the characteristic physiological properties of giant striatal neurons with long radiating dendrites (Wilson et al. 1990). Parvalbumin-positive interneurons had smaller, denser dendritic fields and intense axonal arborizations very close to the cell of origin. Thus they matched the qualitative appearance of the spidery neurons seen in Golgi studies. Cells positive for NADPH diaphorase (a marker for the somatostatin/NPY cell type) 392

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differed from the parvalbumin-positive neurons primarily in the density of their dendritic trees and frequency of branching. These cells had more sparse, radiating dendritic trees that branched less frequently. They also had much more sparse and widespread 393

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axonal arborizations. These results suggest that if the Golgi method had revealed their axons more clearly, these two classes of aspiny interneurons would have been more readily distinguishable from the beginning. There are probably more classes of interneurons that will be revealed as new cytochemical markers become available. For these, as for the ones already discovered, some new approaches to revealing their role in striatal function would be welcome. Because of their relatively small density in the striatum, it must be suspected that they do not function in the traditional roles of interneurons, f~vr example, subserving lateral inhibition in the main information-conveying pathway through the striatum or reciprocal inhibition between opposing groups of striatal projection cells. If they do this, it must be done on a very broad scale, as their numbers are always less than 1/10 that of the spiny neurons on whom they must act. The discovery that some of the neurons release neuromodulators such as somatostatin or nitric oxide, or even acetylcholine (which probably acts primarily as a neuromodulator rather than a neurotransmitter in the striatum) suggests the possibility of spatially global modulatory functions for these cells. Even the parvalbumin neuron, which contains the classical transmitter GABA, seems likely to act in a spatially global fashion, as it has been shown that these cells are meshed into a single network by gap junction interconnections between their dendrites (Kita et al. 1990). 4.2.1. Cholinergic neurons

Striatal neurons which utilize acetyl choline as a neurotransmitter, striatal cholinergic neurons, constitute an important type of interneuron population (Bolam et al. 1984; Kawaguchi 1993; Wilson et al. 1990). As discussed above these neurons have been characterized by morphologic studies due to their large size (Chang et al. 1982; DiFiglia et al. 1976; Kawaguchi 1992; Yelnik et al. 1991), with histochemical staining of acetyl cholinesterase (Fibiger 1982), by immunohistochemical studies employing antibodies directed to the synthetic enzyme choline acetyl transferase (Bolam et al. 1984; Kawaguchi 1993; Wilson et al. 1990), and by intracellular filling studies (Kawaguchi 1992; Wilson et al. 1990). Striatal cholinergic neurons have a very large cell body, up to 40 r in diameter from which extend long aspiny dendrites which may split into secondary and tertiary branches. The dendritic fields may cover an area of over l mm with no apparent orientation in any particular axis. Cholinergic neurons extend an axon, which is both extremely fine but extremely extensive in the area which it covers. The fineness of the axon has made it difficult to identify with immunohistochemical techniques. Intracellular labeling of identified cholinergic neurons has shown axons from individual neurons to extend over an area of as much as 2 mm. Input to striatal cholinergic neurons appears to be derived in the form of both excitatory, asymmetric inputs and symmetric, inhibitory input (Bolam et al. 1984; DiFiglia 1987). Both asymmetric and symmetric synapses are distributed over all portions of the neuron, but appear to be densest on the distal dendrites. Asymmetric input to these neurons resembles that from cortex to the medium spiny neuron in ultrastructure, however, identfication of identified cortical inputs to cholinergic neurons has been elusive. There is electrophysiological evidence of direct monosynaptic input from cortex to cholinergic neurons. At least a portion of the symmetric input to cholinergic neurons contain substance P (Bolam et al. 1986). This input is most likely derived from axons collaterals of medium spiny neurons, specifically from the population of substance P-containing striatonigral neurons. 394

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Fig. 11. A) Diagram of a medium aspiny striatal interneuron that had been intracellularly filled with biocytin. B) Distribution of the two major types of non-cholinergic striatal interneurons, parvalbumin-immunoreactive (IR, black dots) and somatostatin-immunoreactive (IR-white dots), in a coronal section of the striatum relative to the patch compartment. Of note is the greater number ofparvalbumin containing neurons in the dorsolateral striatum compared to the ventromedial striatum and the converse pattern of somatostatin containing neurons. Drawing of medium aspiny neuron provided by H. Kita.

Although it is clear that acetylcholine release is important to striatal function the neuroanatomical substrates by which this is regulated have been difficult to clearly identify. One possible mechanism involves the reported increase in acetylcholine medi395

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ated through activation of substance P receptors. Such a mechanism is supported by anatomical evidence, not only with the demonstration of synaptic contact between substance P-containing boutons and cholinergic neurons (Bolam et al. 1986), but also by the localization of substance P (neurokinin-1) receptor mRNA in cholinergic neurons (Elde et al. 1990; Gerfen 1991).

5. GLOBUS PALLIDUS (external segment) The morphology of the globus pallidus has been well studied at both the light and electron microscopic level (DiFiglia et al. 1982), with a variety of labeling techniques, including Golgi impregnation (Francois et al. 1984; Millhouse 1986; Percheron et al. 1984; Yelnik et al. 1984), immunohistochemistry (DiFiglia et al. 1982) and intracellular labeling (Falls et al. 1982; Kita and Kitai 1994). These studies will be only briefly described in the present paper in the context of issues concerning basal ganglia organization. More thorough treatment of the organization of the globus pallidus may be obtained from the original papers cited above or from a review by DiFiglia (DiFiglia and Rafols 1988). There appear to be two major types of neuron cell types within the globus pallidus (Kita and Kitai 1994). One type, has a moderate to large cell soma from which radiate 3-5 dendrites with secondary and tertiary segments, which are aspinous over their entire length and display some varicosities. The dendrites of these neurons are often long, up to 300-400/lm in length, giving a total maximal dendritic coverage of over 1 mm in some cases. Some aspiny neurons display a discoidal dendritic field in that the dendrites spread mainly in a two dimensional field parallel to the border between the globus pallidus and striatum. Other aspiny neurons have dendrites that cover a volume with a more 3 dimensional distribution. While neurons at the border region between the globus pallidus and striatum often display a discoidal pattern, neurons with discoidal dendritic fields are distributed in the central medial regions of the globus pallidus as well. A second type of globus pallidus neuron is distinguished by the spines distributed on its dendrites. The cell bodies of these neurons are generally smaller than those of the aspiny neurons. However, the size and extent of the dendritic fields appear to be similar for the two types, except that spiny neurons did not display a discoid dendrites. Although all pallidal projection neurons appear to utilize GABA as a transmitter, the differences in morphology are matched with some neurochemical differences. For example, the large discoidal type dendrite bearing neurons contain the calcium bind protein parvalbumin, whereas the other pallidal projection neurons do not (Kita and Kitai 1994). Parvalbumin positive neurons are the more abundant of the two types. The projections of pallidal neurons appear to be somewhat different between the two morphologically and neurochemically distinct pallidal neuron populations (Kita and Kitai 1994; Kita and Kitai 1994). Parvalbumin positive/discoidal dendrite-bearing neurons provide axon collateral projections to the subthalamic nucleus, entopeduncular nucleus and substantia nigra, whereas the descending projection of the parvalbuminnegative pallidal neuron is directed primarily to the subthalamic nucleus. Both neuron types appear to project to the striatum, although not all pallidal neurons provide such a projection. Both types of pallidal neuron provide projections to the subthalamic nucleus, entopeduncular nucleus and substantia nigra and to the striatum. In most cases neurons appear to provide collaterals to the subthalamic nucleus and at least one, and usually, all of the other targets. Neurons in the ventral globus pallidus, which are the 396

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target of the projections from the nucleus accumbens (Groenewegen and Russchen 1984; Haber et al. 1985; Hedreen and DeLong 1991; Swanson and Cowan 1975), have a somewhat different projection profile than more dorsal pallidal neurons (Haber et al. 1985; Haber et al. 1993). In the rat it appears that ventral pallidal neurons provide direct inputs to the mediodorsal thalamus and to the reticular thalamic nucleus (Haber et al. 1985; Mogenson et al. 1987). However, in the primate there appears to be a much sparser or non-existent projection from the ventral pallidum to the mediodorsal thalamus (Haber et al. 1993). Most pallidal neurons may be labeled with GAD immunoreactivity and are thus presumed to utilize GABA as a neurotransmitter (Oertel and Mugnaini 1984; Pasik et al. 1988; Smith et al. 1987). This is consistent with the fact that synaptic contacts of pallidal axon terminals with their target neurons are symmetric (Smith and Bolam 1989, 1990, 1991). In addition to GAD immunopositive neurons in the globus pallidus, there are a scattering of cholinergic neurons within the body of the globus pallidus as well as a large number of cholinergic neurons ventral to the globus pallidus (Fibiger 1982; Grove et al. 1986; Ingham et al. 1985). In as much as these neurons appear to be the target of some projections from both the dorsal and ventral striatum, these cholinergic neurons might be considered to be part of the basal ganglia (Grove et al. 1986). These cholinergic neurons have been shown to provide projections to the cerebral cortex (Fibiger 1982; Grove et al. 1986; Ingham et al. 1985, 1988; Saper 1984). 5.1. SYNAPTIC INPUT Neurons in the globus pallidus receive inputs directly from the striatum (Chang et al. 1981; Hedreen and DeLong 1991; Wilson and Phelan 1982), which are inhibitory (Park et al. 1982) and inputs from the subthalamic nucleus, which are excitatory (Kita and Kitai 1987). Inputs from the striatum appear to be the dominant input to pallidal neurons and display a distinct synaptic organization (DiFiglia et al. 1982). Individual fibers from the striatum entwine dendrites of pallidal neurons, making numerous synaptic contacts along an extended region of a dendrite. These synapses are symmetric and on the order of lctm in diameter. These afferents have been demonstrated to contain both GAD and enkephalin-immunoreactivity, consistent with their origin from the striatum. Some estimates place the percentage of such synapses as over 80% of those within the globus pallidus. The manner in which these afferents entwine dendrites forming a mosaic pattern of large synapses gives the globus pallidus appearance of being comprised of radial fibers (DiFiglia et al. 1982). An additional feature of pallidal architecture which enhances this appearance is the bundling of dendrites of separate neurons (Millhouse 1986). The synaptic organization of the globus pallidus, where afferent axons make multiple contacts thus appearing to ensheath pallidal dendrites concerns the possible consequence on convergence of striatal afferents. The radial orientation of pallidal neuron dendrites, orthogonal to the plane of striatal efferent fibers, had suggested a means of convergence in that individual pallidal neurons would spread dendrites across the paths of outputs of many regions of the striatum. However, an alternative organization is suggested by the fact that individual striatal efferents, rather than remaining 'on course' as they traverse the globus pallidus, in fact follow local paths to entwine individual pallidal neuron dendrites. This might suggest that in fact individual striatal efferent neurons make a rather direct transfer to few rather than many pallidal neurons. Such an organ-

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Fig. 12. Diagrams of neurons in the globus pallidus that had been intracellularly filled with biocytin. A and B) Globus pallidus neurons with dendrites distributed in a discoid manner, that is primarily within a single plane. The fiat plane of the discoid distribution is parallel to the border between the striatum and globus pallidus. This type of neuron is distributed throughout the globus pallidus. For the most part dendrites are relatively spine free. These neurons emit an axon collateral that arborizes within the globus pallidus (not shown) and also provides projections out of the nucleus (for neuron A see Fig. 13). C and D) Examples of globus pallidus neurons with dendrites that radiate in all planes around the cell body. These dendrites possess spines. Some of these neurons have axons that arborize extensively within the globus pallidus (shown for neuron D in gray) and axons that project out of the nucleus (not shown). E) An example of a striatal spiny projection neuron drawn to the same scale as the pallidal neurons for comparison. Globus pallidal neurons are redrawn from Kita and Kitai (1994).

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ization would be decidedly different from that of cortical afferents to the striatum, in which individual axons contact the dendrites of many neurons 'en passant'. A second less frequent type of synapse forms asymmetric synapses along all portions of the dendrites of pallidal neurons. These inputs have been demonstrated, using anterograde tracing with PHA-L, to arise from the subthalamic nucleus (Kita and Kitai 1987). 5.2. OUTPUT Descending output of the globus pallidus to other components of the basal ganglia is directed principally to the subthalamic nucleus and to the entopeduncular nucleus (internal segment of the globus pallidus in primates) and the substantia nigra (Haber 399

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et al. 1985, 1993; Kita and Kitai 1994). Ascending outputs of the globus pallidus provide feedback to the striatum (Beckstead 1983; Staines et al. 1981; Staines and Fibiger 1984). In addition, there is a variable projection from the ventral pallidum to the thalamus (Haber et al. 1985, 1993; Mogenson et al. 1987). The source of efferents to the different targets of the pallidal outputs arises from different morphologically and neurochemically defined neuronal types (Kita and Kitai 1994a,b). Of particular note is the synaptic organization of pallidal projection terminals, particularly those that provide input to the internal pallidal and substantia nigra neurons. Pallidal afferents onto these neurons is directed to the cell soma and proximal dendrites, whereas the striatal afferent input is directed to the same neurons' more distal dendrites (Smith and Bolam 1989, 1990, 1991). The organization of these projections will be discussed in more detail below.

6. SUBTHALAMIC NUCLEUS Based on cellular and dendritic morphology neurons in the subthalamic nucleus appear to be of one main type, which nonetheless show a variance in the dimensions of the cell soma and dendritic ramifications (Kita et al. 1983a; Yelnik and Percheron 1979). In rats, the cell somata ovoid or polygonal with a medium size ranging 11-18 r in diameter. Most subthalamic neurons extend 3-4 primary dendrites which taper and branch into secondary and tertiary dendrites. Dendrites show infrequent spines, which, if present, are located on more distal parts of the dendrites. The dendrites spread in varying patterns within the nucleus. In general dendrites appear to distribute in an ovoid area in both the frontal and sagittal planes, thus showing a greater extension in the rostrocaudal dimension than in the dorsal and ventral dimension. In the horizontal plane, dendrites appear to distribute roughly equally in the medial lateral dimension as in the rostro-caudal dimension. Subthalamic neurons across species appear to be similar in morphologic type, although the planar distribution patterns of the dendrites vary from species to species. This presumably reflects different geometries of the afferent inputs in different species. Neurons in the subthalamic nucleus appear to be of one neurochemical type in that most are immunoreactive for glutamate. This is consistent with the fact thta the synapses of subthalamic afferents to neurons in the globus pallidus, entopeduncular nucleus and substantia nigra are asymmetric (Kita and Kitai 1987). Moreover, the electrophysiologic response of neurons postsynaptic to subthalamic afferents following stimulation of the subthalamic nucleus confirms the excitatory nature of these inputs (Nakanishi et al. 1987b; Robeldo and F6ger 1990) 6.1. SYNAPTIC INPUT Neurons in the subthalamic nucleus receive inputs from the globus pallidus, which are inhibitory (Kita et al. 1983b) and inputs from the cortex, which are excitatory (Kita et al. 1983b; Nakanishi et al. 1987a, 1988). Inputs from the cortex are asymmetric and distributed to principally to the dendrites of the neurons. Inputs from the globus pallidus make large symmetric contact which are directed relatively equally to the cell soma (30%), proximal (39%) or distal (31%) dendrites (Smith et al. 1990). This input is distinguished from pallidal inputs to the substantia nigra in which 90% of the synaptic contact is made with the soma or proximal dendrites (Smith and Bolam 1990). 400

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6.2. OUTPUT Neurons in the subthalamic nucleus project axons that target neurons in the globus pallidus and in the entopeduncular nucleus and substantia nigra, as well as a sparse projection to the striatum (Kita and Kitai 1987). These inputs provide an excitatory input to each of the target structures (Kita and Kitai 1991; Nakanishi et al. 1987b; Robeldo and F6ger 1990).

7. SUBSTANTIA NIGRA/ENTOPEDUNCULAR NUCLEUS Together, the substantia nigra and entopeduncular nucleus (internal segment of the globus pallidus in primates) may be considered output nuclei of the basal ganglia in that they provide the interface with brain areas outside the basal ganglia, in particular the thalamus and midbrain structures including the superior colliculus and pedunculopontine nucleus. The neurons that provide these output projections utilize GABA as a transmitter and form a nuclear complex that is continuous from the entopeduncular nucleus (internal segement of the globus pallidus in primates) and substantia nigra pars reticulata. In addition to the GABA neurons in these nuclei, dopamine neurons in the substantia nigra pars compacta provide a feedback pathway to the striatum. The substantia nigra is composed of two main neuron cell types, those that utilize dopamine (Bj6rklund and Lindvall 1984) and those that utilize GABA as a neurotransmitter (Oertel and Mugnaini 1984; Pasik et al. 1988; Ribak et al. 1979). Dopamine neurons are located primarily in the pars compacta, which is a neuron dense zone forming the dorsal part of the substantia nigra (Gerfen et al. 1987). In addition, dopamine neurons are also located in groupings in the ventral neuron sparse zone, the pars reticulata. GABA neurons are localized, for the most part, in the pars reticulata. Dopamine neurons in the substantia nigra, as well as those in the adjacent ventral tegmental area and retrorubral area provide inputs to the striatum (Beckstead 1979; Gerfen et al. 1987; Oertel and Mugnaini 1984; Pasik et al. 1988; Ribak et al. 1979). GABA neurons in the pars reticulata provide inputs to the thalamus, superior colliculus and pedunculopontine nucleus (Beckstead 1979; Gerfen et al. 1982; Oertel and Mugnaini 1984; Pasik et al. 1988; Ribak et al. 1979). Neurons in the substantia nigra have been difficult to classify on the basis of morphologic criteria as classes that may be distinguished clearly by cell body size, dendritic morphology or dendritic spread do not appear (Grofova et al. 1982; Yelnik et al. 1987). The connectional and neurochemical determinants of the two major types of neurons in the substantia nigra do not relate to distinct differences in morphology, although in primates the dimensions of dopamine-containing pars compacta neurons appear to be on average larger than their pars reticulata counterparts. Thus, a generic substantia nigra neuron might be described, with the realization that specific parts of these neurons display a rather wide range of size and shapes. Neurons in the substantia nigra have a medium to large sized irregularly shaped cell soma with axis dimensions ranging from 16-50/~m (long axis) and 8-32/lm (short axis). Several ( 2 4 ) main dendrites radiate from the cell soma and extend over a generally large domain. Dendrites may divide into secondary or tertiary branches of similar size to the main branches, but in general branching is rather restricted. In some cases much smaller, unbranched processes may issue from larger dendrites. The distribution of the dendritic fields is of particular interest due to the organization 402

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of afferent fibers (Francois et al. 1987). In the rat dendritic fields may extend as much as 1-1.5 mm in the rostro-caudal axis, 700 r mediolaterally, and 400 r in the dorso-ventral axis, which covers as much as 70% of the mediolateral dimension and 50-80% of the length of the nucleus (Grofova et al. 1982). However, the orientation of the dendrites of individual neurons varies dependent on the location of the neuron within the pars reticulata. Neurons in the dorsal part of the nucleus have dendrites that spread in all three axis, while neurons in the ventral part of the nucleus have dendrites that remain confined to the ventral plane of the nucleus. Similar organization of neuronal dendritic patterns have been described in the primate as well. As will be discussed in some detail below the organization of the dendritic distributions of pars reticulata neurons is related to the organization of afferent input from the striatum, globus pallidus and subthalamic nucleus (Gerfen 1985; Kita and Kitai 1987). Dopamine-containing neurons in the substantia nigra are similar in many respects to the morphology of pars reticulata neurons (Tepper et al. 1987). The cell somata appear somewhat larger than those of pars reticulata neurons, although, the morphology of the dendrites appear similar. The dendritic distribution of dopamine neurons reveals two distinct populations of neurons. One population is situated in the dorsal part of the pars compacta and possess dendrites which distribute in the plane of the pars compacta. A second population is situated in the ventral part of the pars compacta and in cell groups in the pars reticulata. These neurons posssess dendrites that extend into the pars reticulata. These two populations are also distinct in their efferent projections and neurochemical content, which will be discussed in terms of striatal patch-matrix compartmental organization below. 7.1. SYNAPTIC INPUT TO PARS RETICULATA NEURONS The major sources of input to substantia nigra neurons are GABA inhibitory inputs from the striatum and globus pallidus, and excitatory inputs from the subthalamic nucleus. That the striatum provides an inhibitory, GABAergic input to pars reticulata neurons has been established using electrophysiologic techniques (Chevalier et al. 1985; Deniau and Chevalier 1985; Deniau et al. 1976). The globus pallidus has more recently been established to provide a similar inhibitory input. The synaptic organization of this and the pallidal input to the pars reticulata was described in a comprehensive analysis by Smith and Bolam (Smith and Bolam 1989, 1990; Smith et al. 1990), axonally transported tracer labeling of striatal and pallidal input to identifed pars reticulata neurons projecting to the superior colliculus were examined at the light and electron microscopic level. Striatal input to pars reticulata neurons form symmetric, relatively small, synapses directed principally to distal parts of the dendrites (77% of such input), and only infrequently to the cell soma (3%). In contrast, inputs from the globus pallidus for symmetric, relatively large, synapses directed principally to the perikarya (54% of such input), or to proximal dendrites (32%). The differential distribution of inputs from the striatum and globus pallidus to the distal and more proximal dendrites suggests that, if the inputs are comparable in number, the latter afferent system may exert a dominant control over these pars reticulata neurons. Inputs from the subthalamic nucleus to the pars reticulata provide an excitatory input mediated by the neurotransmitter glutamate (Kita and Kitai 1987; Nakanishi et al. 1987b). At the synaptic level these inputs form asymmetric contacts principally directed to more distal parts of the dendrites of pars reticulata neurons (Kita and Kitai 1987). Thus the distribution pattern of these afferents is similar to that of the striatal inputs. 403

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SNc dopamine neurons

A 1O0 pm

B

Fig. 15. Drawings of two dopamine neurons in the substantia nigra pars compacta that have been intracellularly filled. A) This example is typical of pars compacta neurons that are in the dorsal tier of the nucleus, whose dendrites remain within the pars compacta, for the most part. B) This neuron is an example of pars compacta neurons in the ventral tier of the nucleus which extend dendrites downward into the pars reticulata. Adapted from Tepper et al. 1987.

7.2. SYNAPTIC INPUT TO PARS COMPACTA NEURONS Input to pars compacta dopamine neurons appears for the most part to be similar to that to the pars reticulata for each of the sources of input described above. Input from the striatum, which is identified both directly with anterograde axonal markers, with GABA or with substance P immunoreactivity, appears to provide a major input to pars compacta neurons (Bolam and Smith 1990). However, in the case of input from the globus pallidus the input is somewhat less than that to the pars reticulata neurons (Smith and Bolam 1990). In addition there are other known sources of inputs directed to the pars compacta, that have not been described as being directed to the pars reticulata. One of these is a cholinergic input which provides asymmetric synaptic contacts with pars compacta neurons. Another is from the amygdala, which appears to provide inputs to the major components of the dopamine cell groups, but not to the pars reticulata (Gonzales and Chesselet 1990). In addition, the lateral habenula provides input directed to the pars compacta (Herkenham and Nauta 1979), which has been identified with electrophysiologic techniques as an inhbitory input (Christoph et al. 1986). 404

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Fig. 16. Immunohistochemical labeling of adjacent sections through the rostral part of the substantia nigra showing tyrosine hydroxylase- (A), calbindin- (B) and parvalbumin-(C) immunoreactivity. A) Dopamine containing neurons labeled with tyrosine hydroxylase are distributed in the ventral tegmental area (VTA) and substantia nigra pars compacta (SNc). Of note are the dendrites of SNc neurons that extend downward into the subtantia nigra pars reticulata (SNr). B) Calbindin immunoreactivity labels dorsal tier dopamine neurons in the ventral tegmental area and dorsal tier of the SNc. Ventral tier dopamine neurons in the SNc are not labeled. Calbindin immunoreactive terminals originating from spiny projection neurons in the striatal matrix compartment are distributed in the pars reticulata (SNr) but not in the pars compacta (SNc). This pattern reflects the fact that calbindin-containing matrix spiny projection neurons provide inputs to the SNr, whereas calbindin-negative patch spiny projection neurons provide inputs to the SNc. C) Parvalbumin-immunoreactive neurons are located in the substantia nigra pars reticulata. These neurons are the GABA-containing neurons that provide projections to the thalamus, superior colliculus and pedunculopontine nucleus. From Gerfen et al. 1985.

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Summary of inputs to Substantiia nigra pars retiiculata neurons

sagittal section

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input from subthalamic nucleus input from striatum input from GP

Fig. 18. Summary of inputs to substantia nigra pars reticulata neurons. A) Stylized drawing showing distribution of dendrites of neurons in the two main regions of the substantia nigra pars reticulata (SNr). Two subregions of the SNr are depicted, similar to those of the globus pallidus, in that striatal afferents and the dendrites of the target neurons in demarcate these separate regions. The distribution of striatal afferents to these two subregions are diagrammed in Fig. 23. Dopamine neurons are located in the dorsal subtantia nigra pars compacta (SNc) and in islands of dopamine neurons (SNc)that separate the two parts of the SNr. B) Stylized diagram of the major synaptic inputs to substantia nigra pars reticulata neurons. GABA-containing terminals from the striatal spiny projection neurons make synaptic contact with the distal portions of the dendrites, with individual fibers making multiple contacts with individual dendrites. GABA-containing terminals from the globus pallidus make synaptic contact with the cell body and proximal dendrites of pars reticulata neurons. Glutamate-containing terminals from the subthalamic nucleus make synaptic contact with the distal portions of pars reticulata neuron dendrites, and similar to those from the striatum, individual fibers make multiple contacts with individual dendrites.

7.3. P R O J E C T I O N S

OF PARS RETICULATA

NEURONS

O u t p u t t a r g e t s o f the s u b s t a n t i a n i g r a i n c l u d e the following: the t h a l a m u s , s u p e r i o r colliculus a n d the p e d u n c u l o p o n t i n e n u c l e u s ( B e c k s t e a d 1979; D e n i a u a n d C h e v a l i e r 1992; G e r f e n et al. 1982; K i t a a n d K i t a i 1987; N a k a n i s h i et al. 1987b). N i g r a l i n p u t s to the t h a l a m u s are d i r e c t e d to t w o m a i n p a r t s o f the t h a l a m u s . T h e first are the set o f nuclei, i n c l u d i n g the i n t r a l a m i n a r nuclei, w h i c h p r o j e c t b a c k to the s t r i a t u m . T h e s e c o n d

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major output of GABA neurons of entopeduncular nucleus and substantia n_.ii

A (sagittal)

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B(coronal)

1.0 mm Fig. 19. Diagram of major output of GABA-containing neurons of entopeduncular nucleus (EP) and substantia nigra pars reticulata (SNr). A) Sagittal section showing with white arrows the projections from EP to the thalamus (ventral lateral, vl and lateral habenula, lh) and with black arrows the projections from the SNr to the thalamus (mediodorsal, md; ventral medial, vm and parafascicular-intralaminar complex, pf, il), to the superior colliculus and pedunculopontine nucleus (PPN). B and C) Coronal sections showing thalamic nuclei innervated by the entopeduncular nucleus (with white stippling) and by the substantia nigra pars reticulata (with black stippling).

thalamic target are nuclei which provide projections to frontal cortical areas. The specific nuclei involved, vary from species to species, primarily as a consequence of the organization of cortex. For example, in rodents, the principal target of the substantia nigra is the ventral medial thalamus, which provides a relatively widespread and distributed input to frontal cortical areas, and to the paralaminar medial dorsal thalamus, which projects to the cortical areas thought to be equivalent to the frontal eye fields. Conversely, in primates where frontal cortical areas are subdivided into more discrete cortical areas, thalamic inputs to these areas are correspondingly organized. In primates, the principal thalamic targets of the internal segment of the globus pallidus are the 408

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ventral lateral, pars oralis and ventral anterior, pars parvocellularis nuclei (Schell and Strick 1984), and the target of the substantia nigra is the ventral anterior (VAmc) and paralaminar medial dorsal (MDpc) nuclei (Ilinsky et al. 1985). Many individual pars reticulata neurons have collaterals that target two or more of these targets. The organization of these outputs will be described in more detail.

8. CONNECTIONAL ORGANIZATION OF BASAL GANGLIA The functional organization of the basal ganglia may be considered by breaking down the components of processing that occur as cortical inputs are transformed through the system. First, we will describe the organization of the cortical inputs to the striatum and the continuation of this organization through the circuits of the basal ganglia. There are several determinants of this organization. On the one hand there is a topographic organization that appears to provide for distinct parallel streams from functionally related cortical areas that are processed through the basal ganglia. On the other hand, within each of these zones there is considerable overlap of inputs from widely dispersed cortical areas. We will suggest that the principal organizing scheme in corticostriatal inputs reflects the mapping of the connections of cortico-cortical connections into the striatum. This organization provides the basis of the information that is processed by the basal ganglia. Second, we will describe the organization of projections from the striatum to the globus pallidus and substantia nigra in terms of their organization with the targets of the basal ganglia outputs, principally the thalamus and midbrain structures including the superior colliculus and pedunculopontine nucleus. The organization of these systems reflects in part the organizing principles related to corticostriatal inputs. A second organization emerges in that at each level of projection of one nucleus of the basal ganglia onto another there are dual projection fields. These appear to be related to the organization of the targets of the output structures, and presumably reflect the nature of the information that is provided by the cortex. Third, we will describe the organization of systems that regulate the dopamine feedback system. This organization relates to the 'patch-matrix' compartments in the striatum, which provide for separate pathways from the cortex through the striatum to the dopamine neurons in the midbrain and to the output neurons of the basal ganglia. Finally, a description of the transformation that occurs as a result of the organization of striatal outputs into two main output streams, the so-called direct and indirect striatal output pathways to the output neurons of the basal ganglia in the substantia nigra and entopeduncular nucleus (internal segment of the globus pallidus). The function of this organization appears to transform the excitatory inputs from the cortex to the striatum into antagonistic inputs to the output neurons of the basal ganglia. The relative activity in the two striatal output streams thus determines the activity of the output of the basal ganglia. Among the mechanisms that regulate the relative activity in the two striatal output systems is the nigrostriatal dopamine feedback.

9. RELATIONSHIP BETWEEN CORTEX AND BASAL GANGLIA

The major input to the basal ganglia is that from the cerebral cortex to the striatum. This input is multi-faceted in that there are multiple determinants to its organization. First, there is a topographic organization in corticostriatal inputs that is continued 409

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through the circuits of the basal ganglia. Second, the mapping of cortical inputs through the basal ganglia circuitry does not represent a simple point to point map in that there is overlap, or convergence at each level of the system. The nature of this convergence will be discussed. 9.1. TOPOGRAPHIC ORGANIZATION At each level of the basal ganglia there is an apparent topographic organization in the projections from one level to the next. Thus, the cortical projection to the striatum, the projection of the striatum to the globus pallidus, and the projection of the entopeduncular nucleus (internal segment of the globus pallidus in primates) and substantia nigra to the thalamus, each display a topographic organization in which the spatial organization of the source area is maintained in the projection pattern to the target. However, as will be described further, there are other types of connnections that do not adhere to a strict point-to-point topographic mapping, which are overlain on the general topographic mappings that are seen at each level of the system. A variety of studies of the organization of cortical input to the striatum have described the topographic organization of this system in both the rodent (Beckstead 1979; Berendse et al. 1992a; McGeorge and Faull 1989; Webster 1961) and primate (Goldman and Nauta 1977; Kunzle 1975, 1977, 1978; Kunzle and Akert 1977; Selemon and Goldman-Rakic 1985). In this context topography refers to the maintenance of the relationship between cortical areas in the mapping of their projection fields within the striatum. For example, limbic cortical areas, including the hippocampus, piriform and infralimbic cortices, and amygdala, in as much as it might be considered a cortical area, provide inputs to the ventral striatum, including the nucleus accumbens. The prelimbic cortex, dorsal to the infralimbic cortex, provides input to the medial bank of the striatum. This topographic organization is maintained moving from medial to lateral along the cortex, with projections maintaining their medial to lateral relationships in the projections to the striatum. In general limbic, or allo- and peri-allocortical areas project to the ventral striatum, whereas neocortical areas project to the dorsal striatum. Studies of the projections from the striatum to the globus pallidus and to the substantia nigra have shown a distinct topographic organization, in both the rodent (Gerfen 1985; Groenewegen et al. 1993; Groenewegen and Russchen 1984) and primate (Cavada and Goldman 1989b; Cowan and Powell 1966; DeVito and Anderson 1982; DeVito et al. 1980; Flaherty and Graybiel 1993a; Hedreen and DeLong 1991; Nauta and Mehler 1966). Both the striatopallidal and striatonigral projections innervate dual zones in each target structure (Chang et al. 1981; Gerfen 1985; Wilson and Phelan 1982), both of which are topographically organized. The dual zones of innervation correspond to subregions within each nucleus that are delineated by both the pattern of afferent input, and the organization of the dendrites of the target neurons within the nucleus (for example see Figure 13). The topography of each of these projection zones is apparent in coronal sections, and shows a general maintenance of the medial-lateral and dorsoventral relationship of striatal projections in the termination patterns in the target nuclei. In general this topography is maintained in the projections from the striatum to the globus pallidus. In the projections to the substantia nigra, there is a maintenance of the medial-lateral relationships in the terminal fields and an inversion of the dorso-ventral relationships such that more ventral regions of the striatum project to the dorsal parts of the pars reticulata and dorsal regions of the striatum project to the ventral pars reticulata. Projections from the striatum to the entopeduncular nucleus are also topo410

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graphically organized. The indirect pathway projections, which include the globus pallidus and subthalamic nucleus, also display both dual projection systems and topographic organization. It must be stressed that while topographic relationships are apparent in striatal output organization, there are additional features in the organization of these systems. As in the projections of the cortex to the striatum, the topographic organization is not strictly adhered to and there is some overlap of projection fields (Gerfen 1985). Whereas the topographic organization is readily apparent in the medio-lateral and dorso-ventral axes, in the rostro-caudal axis the projections from any given part of the striatum have an extensive rostro-caudal spread. In addition to the dual projection systems of striatopallidal and striatonigral projections, there is a segregation of projections from the 'patch-matrix' compartments. The dual projection systems and striatal 'patch-matrix' compartments will be discussed in detail below. The output neurons of the basal ganglia, which are the GABA neurons in the entopeduncular nucleus and substantia nigra pars reticulata (Mercugliano et al. 1992; Oertel and Mugnaini 1984; Pasik et al. 1988; Ribak et al. 1979), provide inputs that are topographically organized in their projections to the thalamus and superior colliculus in the primate (Fen61on et al. 1990; Ilinsky et al. 1985). In the rat the details of this topography are difficult to work out due to the small size of the structures involved, nonetheless, several studies employing a variety of methods have described a topographic organization (Deniau and Chevalier 1992; Gerfen et al. 1982). Thalamic nuclei innervated by basal ganglia outputs project back to frontal cortical areas in a topographically organized manner in both the primate (Holsapple et al. 1991; Kievet and Kuypers 1977; Schell and Strick 1984) and rodent (Groenewegen 1988). In the rodent these thalamic nuclei include the ventral lateral (VL), paralaminar mediodorsal (MD) and ventral medial (VM) nuclei. The ventral lateral nulceus, which receives input from the entopeduncular nucleus projects back upon the motor cortex. The paralaminar part of the mediodorsal thalamic nucleus projects back upon medial agranular and 'prefrontal' cortical areas. The ventral medial thalamic nucleus projects in a distributed manner to layer 1 of most of the frontal pole (Herkenham 1979). Other thalamic nuclei innervated by basal ganglia outputs, which include the intralaminar nuclei and lateral habenula, provide feedback projections to the striatum (Beckstead 1984; Berendse et al. 1988; Gerfen et al. 1982; Herkenham and Pert 1981). The continuation of the topographic organization of the corticostriatal system through the circuits of the basal ganglia and eventually onto the thalamus has been described in some detail by Alexander, Strick and DeLong from their work in primates (Alexander and Crutcher 1990; Alexander et al. 1986, 1990). They describe 5 parallel corticostriatal systems related to the major cortical areas of origin which are maintained as semi-segregated parallel pathways through the striatum, both segments of the globus pallidus and substantia nigra. These include circuits originating in motor (premotor and supplementary motor areas), occulomotor (frontal eye field), dorsolateral prefrontal, orbital prefrontal and anterior cingulate cortical areas. Each of these cortical areas provides inputs to corresponding regions of the striatum, which for the most part are segregated from one another. Evidence for the maintenance of the topography of corticostriatal projections through the basal ganglia back through the thalamus to the cortex, comes from studies in the primate by Strick and his colleagues (Holsapple et al. 1991; Hoover and Strick 1993; Schell and Strick 1984; Strick 1985). In one study in which they employed anterogradely transported trans-neuronally transferred viruses as axonal connectional markers which 411

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allow for analysis of the projections of striatal neurons which recieve inputs from defined cortical areas. These studies demonstrated that injections of virus into separate frontal motor cortical areas resulted in labeling of virus in distinct zones of the putamen, and secondarily in distinct zones in both the external and internal segments of the globus pallidus. In another study, Hoover and Strick (1993) injected virus which is retrogradely transported and trans-neuronally transferred into separate frontal motor cortical areas, the primary motor cortex, the premotor area and the supplementary cortical area. The 412

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Fig. 20. Diagram illustrating the concept of the maintenance of a general topographic organization (the maintenance of the spatial organization of the projection of one brain area to another) through the connections of the basal ganglia. Projections from the cerebral cortex to the striatum (cortico-striatal) maintain the spatial relationships within the cortex in the targeted regions in the striatum. Similarly the projections of the striatum to the globus pallidus and substantia nigra/entopeduncular nucleus (EP) maintain the spatial relationships of the striatum in the pattern of inputs to these nuclei. Of note are the dual projection zones of the striatum to both the globus pallidus (GP1 and GP2) and substantia nigra (SNrl and SNr2), such that each of these target nuclei contain two topographically organized maps of striatal inputs. Within the substantia nigra the maintenance of the general topography in basal ganglia connections is evident in the projection of the entopeduncular nucleus (EP) to the ventral lateral thalamus (vl) and of the substantia nigra projection to the ventral medial (vm) and mediodorsal (md) thalamic nuclei. It is important to stress that the topography depicted is only a general organizational feature, the borders in the projections are not precisely delimited, and there are many examples of connections that do not correspond to the topographic organization at all (i.e., the widespread projections in the corticostriatal projections, particularly in the rostral-caudal axis). (

arm representation region of each cortical area was injected. In each case virus was identified in the globus pallidus, having been transported retrogradely to neurons in the thalamic nuclei which project to these cortical areas, the ventrolateral oralis and area X, trans-neuronally transferred and transported in the projection axons of these neurons to the internal segment of the globus pallidus. Trans-neuronally transported virus was localized in spatially separate regions of the internal segment of the globus pallidus. The region in which virus was identified in the globus pallidus from each cortical area was distinct, and topographically related to the cortical area of origin. Together these studies suggest a segregation and rather strict maintenance of the topographic organization of parallel organization of cortical outputs, which is maintained through the basal ganglia circuits to thalamic feedback to the cortex. The topographic organization of the cortical projection to the striatum and the continuation of this organization through each successive level of the basal ganglia circuitry is diagrammed in Figure 20. Although this diagram represents the organization in the rat, a similar organization applies to the primate. It must be emphasized that the regional boundaries indicating target zones of cortical inputs are not absolute and that there is some overlap of projection fields. The organization of the overlap of projection fields will be discussed in some detail below. 9.2. O V E R L A P O F INPUTS: C O R T I C O - C O R T I C A L O R G A N I Z A T I O N The topographic organization of the cortico-striatal system, which is carried through the striato-pallidal, striato-nigral, pallido-thalamic and nigro-thalamic pathways, is fairly well established. This principle of basal ganglia organization is the basis of the concept of parallel pathway loops connecting functional cortical regions through the basal ganglia with thalamic nuclei that project back upon frontal cortical areas (Alexander et al. 1986). However, this organization does not reflect a point to point mapping of cortical areas with the basal ganglia circuit. Another principal organizational feature of the corticostriatal system is the fact that a given cortical area projects to a domain of the striatum that is proportionately larger than the cortical area of origin, and so implies considerable divergence and convergence in the corticostriatal projection. This divergence is particularly extensive in the rostro-caudal dimension (Selemon and G o l d m a n - R a k i c 1985; Yeterian and Hoesen 1978). Yeterian and Van Hoesen (1978) made the observation that the parietal cortex and prefrontal cortex provide inputs that appear to overlap over a fairly extensive rostro-caudal area. As these areas are con413

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C.R. Gerfen and C.J. Wilson

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Fig. 21. Diagram to illustrate a reconciliation of two concepts of basal ganglia organization related to the corticostriatal system, the existence of parallel closed loop circuits from cortical areas through the basal ganglia back to the cortex (Strick et al., 1985) and the widespread and often discontinuous projections of the cortex to the striatum (Kunzle, 1975; Yeterian and van Hoesen, 1978; Flaherty and Graybiel, 1993). Depicted are two cortical areas (area 1 and 2) each which is organized in a somatotopic manner (a,b,c,d and A,B,C,D). The two cortical areas are interconnected with connections between homologous representations in each cortical area. Each cortical area provides an input to a topographically related zone in the putamen, cortical area 1 to a dorsal area and cortical area 2 to a more ventral area. The spatial relationship between the two cortical areas is maintained in the projections to the external (GPe) and internal (GPi) segments of the globus pallidus and in the projections of the GPi to the thalamus and back to the cortex. The maintenance of the spatial projection fields from cortex to striatum to globus pallidus to thalamus and back to cortex forms the basis of the parallel closed loop model. Each cortical area does not provide inputs to the entirety of the recipient area in the putamen, rather it provides input to the subfield of the putamen that corresponds to the topographically related part of the cortical area of origin. In addition, each cortical area provides a secondary input to the homologous region of the topographically related field of the other cortical area. Thus, subarea 'A' of cortical area 1 provides inputs to subarea 'A' of putamen area 1 and subarea 'a' ofputamen area 2. Thus, each cortical area provides a striatal input that has the appearance of being discontinuous as they map onto the appropriate subareas of each target area in the putamen. Such organization is continued through the rest of the basal ganglia circuits. nected by cortico-cortical connections they suggested that cortico-striatal organization is r e l a t e d t o t h e c o r t i c a l c o n n e c t i o n s o f t h e a r e a f r o m w h i c h t h e c o r t i c o - s t r i a t a l i n p u t s arise. T h e y f o r m u l a t e d a r u l e w h i c h s u g g e s t e d t h a t a r e a s o f c o r t e x w h i c h a r e i n t e r c o n n e c t e d b y c o r t i c o - c o r t i c a l c o n n e c t i o n s p r o v i d e o v e r l a p p i n g i n p u t s to t h e s t r i a t u m ,

414

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whereas areas of cortex that are not interconnected do not. Theirs was the first formulation of a concept to explain the widespread nature of cortico-striatal projections from a given region. The rule suggested by Yeterian and van Hoesen (1978) has been examined in subsequent studies with mixed results. Selemon and Goldman-Rakic (1985) confirmed that both parietal and prefrontal cortical areas provide inputs to the striatum that extend over a large expanse in the longitudinal axis, but they focussed on areas of interdigitation and not the areas of overlap in the cortico-striatal projections from these interconnected cortical areas. They concluded that areas of cortico-striatal convergence are not related to patterns of cortical connectivity. However, subsequent, more detailed mapping of the interconnections between parietal and prefrontal cortex (Andersen 1990; Cavada and Goldman 1989a; Cavada and Goldman 1989b) called for a reassessment of this conclusion (Cavada and Goldman 1991). Connections between posterior parietal cortex and prefrontal cortex were shown to have a precise pattern of segregated connectivity, which reflects modality or functionally specific connections. Thus, the posterior parietal area 7a and lateral intraparietal area (LIP), which have visual and visual-motor functions, are interconnected selectively with prefrontal areas 46 and 8a, respectively, whereas, parietal area 7b, which has somatosensory functions, is connected with prefrontal area 45 (Andersen et al. 1990). The specificity of these associational connections was not taken into account in the Selemon and Goldman-Rakic (1985) study. For example, their injection of tracer into the posterior parietal cortex included an extensive area that projected to a larger domain of the prefrontal areas than was injected with the second tracer. Consequently, if the simple concept that cortically connected areas provide overlapping striatal inputs were correct, the result they obtained, with areas of overlap and areas of non-overlap, would be expected. Cavada and Goldman-Rakic (1991) did in fact analyze cortico-striatal inputs in this context and came to the conclusion that the regional distribution of parietal and prefrontal corticostriatal projections did in fact reflect the interconnections between functionally related cortical areas. The concept that functionally interconnected parietal and prefrontal corticostriatal inputs are directed to overlapping regions of the striatum (Yeterian and van Hoesen 1978; Cavada and Goldman-Rakic 1991) suggests that the extensive longitudinal distribution of cortico-striatal inputs is related to cortico-cortical connections. However, in these studies the detailed patterns of overlap and interdigitation that are observed in experiments in which the corticostriatal projections from different cortical areas are examined with separate tracer injections into these areas in the same animal (Selemon and Goldman-Rakic 1985), leaves open the question of the relationship between corticocortical and cortico-striatal organization. The problems of relating the organization of cortico-cortical connections to corticostriatal organization is confounded by the complex connection patterns in each of these systems. Although it is true, as described by Yeterian and Van Hoesen (1978), and later by Selemon and Goldman-Rakic (1985) that cortical areas provide inputs that extend over a considerable rostro-caudal domain, the innervation patterns are by no means uniform. In many instances projections from a given cortical area show distributed but discontinuous patterns of input to the striatum. Examples of such discontinuities have recurred in the literature beginning with studies of Kunzle in the 1970's (Kunzle 1975, 1977). Particularly striking are the multiple representation zones within the striatum from somatosensory and motor cortical areas. Based on functional mapping studies employing 2-deoxyglucose Brown has suggested that multiple innervation patterns in the striatum from somatosensory cortical areas reflect multiple somatotopically organ415

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ized convergence zones in which cortical inputs from different functional modalities, such as motor and somatosensory areas, converge in a combinatorial manner (Brown 1992; Brown and Feldman 1993). The discovery of discontinuous zones of innervation in the projections from somatosensory and motor cortex (Kunzle 1975, 1977) made it possible to exploit the internal organization of these areas to design more detailed studies of the corticostriatal system. These studies have made use of the precise body map contained in motor and somatosensory areas to study the corresponding parts of two different cortical areas, something that could not be accomplished in studies of posterior parietal and prefrontal cortical regions. Graybiel and her colleagues have examined the connectional basis of this organization in a set of careful studies in which they examined the relationship of cortico-striatal inputs from cortical areas that had been mapped in terms of somatosensory and motor function (Flaherty and Graybiel 1991; Flaherty and Graybiel 1993b; Parthasarathy et al. 1992). In one study the projections from different somatosensory areas were examined (Flaherty and Graybiel 1991; Flaherty and Graybiel 1993b). Electrophysiologically mapped regions of areas somatosensory areas 3a, 3b and 1 were injected with anterograde tracers (Flaherty and Graybiel 1991). They found that injections into matched body part represenation sites in different somatosensory areas provided inputs that overlapped in their projections into the striatum, and that these projections displayed multiple innervation zones. Conversely, injections into different body part regions of cortical area S1 provided inputs to multiple non-overlapping striatal regions. In another study Parthasarathy et al (1993) examined the cortico-striatal projections of two frontal cortical areas that are involved in eye movements, the supplementary eye fields and the frontal eye fields. They found that the degree of overlap of corticostriatal inputs from injections of tracer into these cortical areas was directly correlated with the degree of cortical connectivity between the injected areas. Similar to the organization of somatosensory cortical inputs, there were multiple innervation zones within the striatum from these motor cortical areas. When striatal inputs from non-occulomotor supplementary motor cortex were compared with those from frontal eye fields, there was neither an overlap of inputs in the striatum nor was there evidence of interconnections between the cortical areas injected. In a third study the organization of corticostriatal projections of somatosensory (S 1) and primary motor (M 1) projections to the striatum were investigated in the squirrel monkey (Flaherty and Graybiel, 1993). They found, as had been reported before, that injections of tracers into each of these regions provided inputs that are directed to the putamen and distributed in multiple, discontinuous zones. What they also found was that when somatotopically related areas of M1 and S1, such as the hand representation, that the discontinuous zones of each cortical projection zone overlapped in the ipsilateral putamen. This result suggests that each of these cortical areas provide multiple somatotopically organized cortico-striatal projections and that within the striatum, the multiple somatotopically organized regions receive convergent input from each cortical area. However, they also reported that the contralateral projections did not display this same pattern of overlap between homotypic somatotopic zones of the cortex. This led them to suggest that 'neither patterns of cortical connectivity nor homotypical relationships are infallible predictors of corticostriatal overlap'. Graybiel and her colleagues have provided some thoughtful discussion as to the functional implications of their results (Flaherty and Graybiel 1991, 1993b; Parthasarathy et al. 1992). They suggest 'that whether inputs from particular cortical regions converge in the striatum depends on aspects of their functions, which are only sometimes 416

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mirrored by their cortical connectivity.' They suggest further 'that functionally related inputs would converge, with the degree of functional relatedness being determined by the striatal target. This would allow for activity dependent sculpting of the convergence patterns. For example, if the signal sent to the superior colliculus via a striato-nigraltectal connection coded for saccades without respect to body movements, it would be reasonable to have converging inputs from cortical eye field zones to the striatal origin of the pathway, but not ... from ... areas encoding nonoculomotor body movements. By contrast, targeting to output channels consolidating somesthetic signals might call for convergence of cortical inptus, for example deep and cutaneous inputs form areas 3a and 3b, respectively, whether the cortical areas are connected or not.' They suggest that the existence of functionally organized zones within the striatum which, because these zones are discontinuous areas within the striatal matrix, they term 'matrisomes'. According their ideas, the determinant of the overlap of cortical inputs is related to the function of the output of the 'matrisomes'. Thus, they suggest that the functions of 'matrisomes' represent combinations of cortico-striatal inputs that are different from the combinations of cortico-cortical inputs to cortical areas. This latter conclusion has important implications in the context of the functional organization of the striatum, and in particular with the concept of parallel functional cortical-basal ganglia circuits as put forth by Alexander and his colleagues (Alexander and Crutcher 1990; Alexander et al. 1986, 1990). The basis of the 'matrisome' concept is that the mulitple innervation zones provided from a single cortical site, represent functional units in which cortical information is reorganized. Such discontinuous patterns of corticostriatal inputs are clearly established from a number of studies employing a variety of tracers in a number of species over an extended period of time. However, the basis of such patterns is still open to study. The existence of multiple discontinuous zones of corticostriatal innervation, and the combinational convergence of inputs within them, cannot be understood at the tissue level. Some knowledge of the innervation patterns of single corticostriatal cells is required. If every corticostriatal axon arising from a small region of cortex projects to every one of these multiple discontinuous zones, then they represent a single topographic representation that is strangely shaped and nothing more. Each of the zones from one cortical area will have basically the same pattern of convergence as every other. If, on the other hand, individual corticostriatal neurons innervate single matrisomes, then they represent parallel independent output pathways from the cortex. Each set of corticostriatal neurons, specialized for projecting to a single matrisome, could carry slightly different information destined for convergence with information from a different area. The cellular heterogeneity of the corticostriatal projection could find useful work in this scheme, with different corticostriatal cell types from a single cortical region projecting to different matrisomes and converging with a specific cell type from a different cortical region. Even if there were not specific cell types projecting to each of the matrisomes innervated by a cortical region, each matrisome could have a unique functional identity from the point of view of the cortical regions innervating it. Between these extremes are a variety of intermediate schemes. For example, one matrisome (or one set of matrisomes) might be innervated by all corticostriatal neurons in a region. This could be considered the primary striatal recipient zone of that cortical region. Other matrisomes would then be innervated by collaterals from a subset of the axons, forming a secondary set of recipient zones, each with a different subset of corticostriatal innervation. Convergence of inputs from cortical regions could be organized so that each cortical region had a primary recipient zone in the neostriatum, and secondary zones that overlap the 417

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primary zone of a set of other cortical areas. A scheme of this sort could reconcile the data for parallel independent pathways through striatum and that suggesting convergence of cortical inputs. Cellular heterogeneity of the corticostriatal projection could also help to explain the absence of a single simple rule governing the convergence of corticostriatal inputs. Rules based on cortico-cortical connections, like that suggested by Yeterian and van Hoesen (1978) already raise the issue of cellular heterogeneity, because there are a variety of different kinds of cortical neurons that form corticocortical connections. Some of these also make corticostriatal connections. If, for example, only those corticocortical neurons which participate in forward projections (that is, those primarily directed at layers 3 and 4) participate in making overlapping corticostriatal fields, one would expect to see overlapping corticostriatal projections of some interconnected cortical fields but not others. Likewise for the backwards and lateral projections. A variety of combinations are possible given the variety known to exist in corticocortical projections. The history of study of the basal ganglia consists largely of conjecture about different functional modalities combining in a unique manner in the basal ganglia. For example, Nauta suggested that the integration between the limbic and motor systems occured as a consequence of the projections from the ventral 'limbic' striatum, to the dopamine neurons which provide feedback to the dorsal 'non-limbic' striatum (Nauta et al. 1978). One of us suggested that the patch-matrix organization accomplished this integration (Gerfen 1984). However, upon more detailed analysis it now appears that input to the patch compartment is not unique to the limbic cortex, but is a component of non-limbic cortices as well (Gerfen 1989). As will be discussed later, the most recent data suggests that the patches (striosomes) in the striatal regions that receive inputs from non-limbic cortical areas do not receive inputs from limbic cortical areas, but instead are innervated by corticostriatal neuron types that are present in both kinds of cortical areas but are most numerous in the limbic cortex (Gerfen 1989). The emphasis on convergence of information in the striatum has meanwhile shifted to the discontinuous zones of projection in the matrix (matrisomes). The question of organized convergence of information in the matrix continues to be discussed along the same well-established lines. It should be considered that despite the predisposition to explain the basal ganglia as a mixing place for inputs, the unique contribution of the basal ganglia may not arise from the formation of combinations of cortical inputs, but rather from the nature of the computational operation performed on these inputs by striatal neurons. Some of its operations may be performed implicitly by the connectivity of its output system. Later we will describe two features of that connectivity, one related to the separation of the 'direct' and 'indirect' pathways from the striatum to the output nuclei of the basal ganglia, and the other being the 'patch-matrix' compartments. But it should not be overlooked that the intrinsic connections of the striatum, and the electrical properties of the striatum equip it to perform operations on its input that could not be reproduced by the cortical circuitry, even if it were receiving exactly the same afferent information. This is, of course, the essence of the parallel circuit model put forward by Alexander and his collegues (Alexander and Crutcher 1990; Alexander et al. 1986, 1990). 9.3. STRIATAL OUTPUT SYSTEMS: TOPOGRAPHY / CONVERGENCE / DIVERGENCE The topographic organization of cortical inputs to the striatum, of striatal outputs to the globus pallidus (external segment), internal segment of the globus pallidus (en418

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topeduncular nucleus), and substantia nigra, and from these output nuclei of the basal ganglia to the thalamus is the basis of the multiple segregated loop circuit model of cortical-basal ganglia organization (Alexander et al. 1986). On the other hand, as discussed above, there is clear evidence of convergence of cortical inputs to the striatum. Studies of the organization of the outputs of the striatum reveal a similar organization, namely that there is a clear topographic organization plus patterns of convergence (Gerfen 1985). A question that is raised is how these two schemes, topography and convergence, might be reconciled. Hoover and Strick (1993) have shown, using retrogradely trans-neuronally transported virus tracing, that the projections from the output nuclei of the basal ganglia (the internal segment of the globus pallidus) are organized such that the topographic organization within the globus pallidus is maintained through the thalamus back to frontal cortical areas. This suggests that regardless of the organization of the cortical and striatal projection systems that the output organization of the basal ganglia reflects the organization of the frontal cortical areas. Strick and his colleagues argue that the projection from the cortex through the basal ganglia also reflect this organization in that the cortical inputs likewise maintain their topographic organization. Overlain on this topographically organized backbone of cortico-basal ganglia circuitry are convergent (and/or divergent) components. Thus, as demonstrated by Graybiel and her colleagues, somatotopically similar parts of different cortical areas provide inputs to overlapping striatal regions (Flaherty and Graybiel 1993b), which in turn reconverge in the projections of the striatum to the segments of the globus pallidus (Flaherty and Graybiel 1993a). This might be considered to represent a reorganization of cortical information in the patterns of divergence of cortico-striatal inputs and reconvergence in the striato-pallidal projections. However, a more straightforward model would suggest that these patterns represent a topographically organized system which is overlain with secondary connections that represent a mapping in the striatum of cortico-cortical connectivity. This organization is schematically diagrammed in Figure 21. The studies of Strick and Graybiel have focussed on the organization of the connections of cortical areas that provide their major inputs to the putamen. These cortical areas are for the most part those associated with primary motor and somatosensory cortical areas or those cortical areas with inputs to these areas, including premotor and supplementary cortical areas. One of the reasons for studying such areas is that they are organized in a somatotopic manner, which aids in a precise mapping of the projections relative to physiologically defined determinants. Other cortical areas, whose functions are somewhat removed from a direct relationship to defined movement or sensory functions, such as prefrontal or parietal cortical areas, have more widespread patterns of cortico-cortical connectivity. These areas, generally termed associational cortical areas, provide less precisely organized inputs to the striatum, or less precise in patterns that we now recognize. Most likely these inputs might be described as less precise because the functional organization of the cortical areas have not been as well characterized. The corticostriatal inputs from these areas are marked by extensive distribution patterns that display a topographic organization in the medio-lateral axes, but also display extensive distributions in the rostro-caudal axis. Similarly, the projection of the striatal regions that receive these inputs display the same pattern of organization in their projections to the globus pallidus and substantia nigra, a maintenance of the mediolateral topography, with extensive distribution in the rostro-caudal axis. This organization has been observed in both the primate and rodent. Examples of the projections from the striatum to the substantia nigra in the rat are shown in Figure 22 to illustrate the 420

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extent of the rostro-caudal spread of the striatal projection system. Again, this suggests that there is a similar organization in the projections from the cortex to the striatum and in the projections of the striatum. Within these patterns of projection another aspect of the organization of striatal projections is apparent, that is the dual target zones within the substantia nigra. This will be discussed below. The topographic organization of cortical and basal ganglia circuitry has been well documented in both rats and primates. However, as has been discussed for corticostriatal inputs, the organization does not represent a point to point mapping at each stage of the system. The organization of cortico-striatal inputs provides some convergence of inputs from different cortical areas. The possible convergence at other levels of the basal ganglia has been proposed. For example, it has been suggested that the spread of the dendrites of neurons in the globus pallidus and substantia nigra are so extensive that they provide for a convergence of inputs from widespread regions of the striatum. According to this view, the topographic organization of striatal outputs is superseded by the convergence that is a consequence of the dendrites of the target neurons. While we would not argue for a strict topographic organization, there are several reasons to suggest that the extent of convergence of inputs as a consequence of the dendritic spread must be considered with some caution. As has been described the input of individual striatopallidal axons make multiple contacts with individual pallidal neuron dendrites, which appear to ensheath these target dendrites. This feature of synaptic organization is contrasted with that of cortical inputs to the striatum, where individual corticostriatal axons may make only single contacts with many spiny neurons. This organization typifies inputs that might be considered to be transferring input from single cortical neurons to multiple striatal neurons. On the other hand, in the globus pallidus, there appears to be an organization that suggests a rather tighter transferance between striatal neurons and a limited number of pallidal target neurons. There are two other distinctive features of striatal output organization. The first is the segregation of the projections of the 'patch-matrix' compartments of the striatum. This will be discussed in a later section. The second, which has been mentioned, is the dual projection zones of striatal inputs in both the globus pallidus and substantia nigra. As will be described these dual projection systems appear also in the organization of other components of the basal ganglia, including the projection of the subthalamic nucleus. 9.4. STRIATAL OUTPUTS IN RELATION TO NIGRAL OUTPUTS: DUAL OUTPUT SYSTEMS A distinctive feature of striatal output organization is the dual projections from the striatum to subdivisions of the globus pallidus and substantia nigra (Chang et al. 1981; Gerfen 1985; Wilson and Phelan 1982). This organization has also been observed in the primate (Parent and Hazrati 1993). Striatal projections to the globus pallidus have extensive axon arborizations in a region immediately adjacent to the striatum, and a second arborization zone in the central part of the globus pallidus. In the case of the striatopallidal projection, the dual projections have been demonstrated to arise from individual neurons (Chang et al. 1981). The dual striatonigral projection targets a region in the dorsal region of the substantia nigra pars reticulata, and a second zone that lies immediately above the cerebral peduncle. It has not been demonstrated that individual striatal neurons contribute projections to both zones of the pars reticulata, although this is likely. At the least they arise from within the striatal matrix and from very closely 421

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associated neurons. These dual projection systems are not to be confused with the patch-matrix projections. The dual nature of inputs to the globus pallidus and substantia nigra is not only observed in the striatal projections to these nuclei. Kita and Kitai (1987) have also observed a similar organization in the projection of the subthalamic nucleus to these nuclei. The projection patterns charted in their study bear a remarkable resemblance to those from the striatum. This suggests that this aspect of the organization of basal ganglia circuits is maintained not only in the organization of striatal outputs but also in the organization amongst the nuclei that are the targets of this striatal projection. In both the globus pallidus and in the substantia nigra the dendritic morphology of neurons in these nuclei conform to the dual innervation patterns from the striatum 422

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Fig. 23. Illustration of the dual projections from A) the striatum (CP) to the globus pallidus (GP) and substantia nigra pars reticulata (SNr) and from B) the subthalamic nucleus to the globus pallidus (GP) and substantia nigra pars reticulata (SNr). In each system afferents target the same two regions in the GP, an area immediately adjacent to the striatum and second area more medial, and the same two regions in the SNr, an area medial and dorsal adjacent to the substantia nigra pars compacta and a second area situated ventrally against the cerebral peduncle. The dual target zones in both the GP and SNr have neurons whose dendrites appear to conform to the pattern of afferents to these regions (see Fig. 13 and 18). In addition individual striatal neurons and individual subthalamic neurons provide collaterals to both regions in each nucleus. C. Sagittal diagram of projections from substantia nigra to the superior colliculus. Neurons in the two subregions of the substantia nigra pars reticulata (SNr) that are defined by the pattern of striatal and subthalamic afferent inputs project to different parts of the superior colliculus. Dorsal SNr region neurons (white) provide input to the rostral superior colliculus. Ventral-caudal SNr region neurons (black) provide input to the caudal superior colliculus. D. A top view diagram of the superior colliculus on which is depicted the organization of the eye movement saccades that are generated by stimulation of the intermediate layer. Longer saccades are generated in the caudal superior colliculus, shorter saccades are generated in the rostral superior colliculus, and the most lateral rostral zone is involved in fixation. The organization of afferents from the dorsal SNr (white), directed to the rostral, short saccade and fixation region of the superior colliculus, and from the ventral caudal SNr (black), directed to the longer saccade region of the superior colliculus are depicted.

(Gerfen 1985). Thus in the globus pallidus, neurons in the region that is immediately subjacent to the striatum have dendrites that are distributed in a pattern that conforms to a 'shell'-like region of the globus pallidus, whereas neurons in the central region of the globus pallidus are distributed in the central region and do not appear to extend into the pallidal 'shell' region (Kita and Kitai 1994). Similarly, in the substantia nigra there are two zones of neurons in the pars reticulata, ignoring the d o p a m i n e neurons in the pars reticulata. Again, as in the globus pallidus there is one region that forms a 'shell' like structure, in this case forming a region immediately above the cerebral peduncle, and a dorsal zone region that is the region between the ventral 'shell' region and the pars compacta. N e u r o n s in these two regions have dendrites that are distributed so as to conform with the shape of the regions ( G r o f o v a et al. 1982). This organization was first described by G r o f o v a et al. (1982) based on the m o r p h o l o g y of the dendrites of pars reticulata neurons. The organization of the substantia nigra pars reticulata into subregions appears not only to be related to the organization of inputs from the striatum and subthalamic nucleus, but in the organization of its outputs. The organization of the projections of the substantia nigra pars reticulata to the thalamus and to the superior colliculus appear to maintain a rough topography. This topographic organization has been described by Gerfen et al. (1982) and in considerable detail by Deniau and Chevalier (1991). Thus, projections to the ventral medial, mediodorsal, and intralaminar thalamus, as well as those to the projections to the superior colliculus, display a topographic organization. This t o p o g r a p h y involves both the central and peri-peduncular 'shell' region of the pars reticulata neurons. N e u r o n s projecting to a particular topographically related part of any of these structures are organized in one of the two pars reticulata regions. This organization of the nigral o u t p u t neurons was described by Deniau and Chevalier (1991) to have the appearance of distinct lamellae, much like that of an onion. This organization has been remarked upon repeatedly, by Gerfen et al. (1982), Deniau and Chevalier (1991), and Redgrave et al. (1992). The functional signficance of the dual projection systems of striatal outputs may be related to the organization of the target structure of the nigral outputs. In terms of the organization of the substantia nigra projection to the superior colliculus it appears that neurons in the dorsal region project to the rostral superior colliculus, whereas those in 423

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the peripeduncular 'shell' project to more caudal regions. In addition, each of these nigro-tectal projections maintains a medio-lateral topography. Redgrave et al. suggested that the organization of the nigro-tectal organization reflects differences in the of both afferent and efferent organization of the intermediate layer of the superior colliculus that is the target of these inputs (Redgrave et al. 1992). An alternative organization within the superior colliculus that might be the basis for the organization of the nigro-collicular pathway may be related to the map of eye and head movement generation. Neurons in the intermediate layer of the superior colliculus appear to be involved with the generation of eye and head movements. Within this layer, movements generated by stimulation are mapped in an orderly manner such that small saccades are produced by stimulation in the rostral half of the colliculus and larger saccades, accompanied by head movements are mapped in the caudal half. At the rostral-lateral pole of the superior colliculus is a zone which is involved in fixation (Munoz and Wurtz 1992, 1993). This map within the superior colliculus conforms, at least roughly, to the organization of the outputs from the two zones within the substantia nigra pars reticulata. Whether there exists a similar organization of dual outputs from the substantia nigra and from the internal segment of the globus pallidus to the thalamus remains to be determined. In this context the results reported by Hoover and Strick (1993) are compelling. In their study in which virus injected into the cortex was retrogradely and transneuronally transported to the internal segment of the globus pallidus in primates they reported that in addition to the topographic organization of the virus labeling, there were two zones within the nucleus, that correspond to the dual innervation zones from the striatum. This would suggest the existence of dual outputs from the internal segment of the globus pallidus to the thalamus, which in turn converge on particular cortical areas. The organization of the dual pallidal input to the thalamus and the organization of dual thalamic projections back to the cortex remains to be worked out. Several possibilities might be investigated. One is that the dual pallidal outputs to the thalamus might innervate different compartments within the same thalamic target nucleus, in this case VLo and area X. Studies of the projections of the pallidum to this nucleus have revealed a non-homogeneous innervation pattern (Holsapple and Strick, 1991), which is similar in organization to that described by Jones and co-workers for the organization of other ventral thalamic relay nuclei (Rausell et al. 1992; Rausell and Jones 1991a,b). It is possible that one part of the internal segment of the globus pallidus innervates one of the compartments, whereas the other zone innervates the other compartment. If VLo is organized in a similar manner to VPL and VPM, then as described by Jones, these different compartments might project back to different layers of the same cortical areas. Alternatively, the dual pallido-thalamic output might target different thalamic nuclei, VLo and the centro-median thalamic nucleus. In this case these two different thalamic nuclei also provide convergent inputs to the same cortical areas, but again to different laminae. While further work needs to be done to establish the specific functional organizational significance of the dual projection zones in the striatal output systems there are several determinants of this system that are now clear, and distinguish this organization from other aspects of striatal output organization. First, individual striatal neurons innervate both zones of the external segment of the globus pallidus. It is also likely that individual striatal neurons also innervate the two zones of the internal segment of the globus pallidus and the substantia nigra as well. This feature of the dual projection systems is distinct from that of the output organization of the patch-matrix striatal compartments, 424

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which might also be viewed as providing dual projection systems to separate regions of the target nuclei. As will be discussed below, the dual projections from the patch-matrix compartments arise from separate neuron populuations. Second, the separate zones of the substantia nigra provide topographically organized inputs to the superior colliculus, and a similar organization of nigro-thalamic and pallido-thalamic projections seems likely. However, not only do individual neurons provide input to both zones, but each region of the striatum provides inputs to both zones, such that there are dual topographically organized inputs from the striatum to these target nuclei. Redgrave had suggested that different regions of the striatum might innervate the separate output pathways of the nigro-tectal pathway. However, it would appear that each striatal region provides inputs to both. Third, these dual projection systems are a very prominent feature of basal ganglia organization in rats and primates, suggesting that there is a significant functional purpose for this organization. 9.5. SUMMARY OF ORGANIZATION OF CORTICO-BASAL GANGLIA CIRCUITS As discussed above, there appears to be a general topographic organization in the projections of the cereberal cortex to the striatum, and in the organization of the basal ganglia circuits such that a number of functionally defined cortico-basal ganglia 'loops' may be defined. However, the organization of the basal ganglia does not reflect a precise point to point remapping of the cortical inputs. In particular there is substantial evidence that there exists a convergence of inputs from multiple cortical areas in the striatum such that cortical areas that are interconnected provide convergent inputs to the striatum. The patterns of these convergent inputs remains open to study. Several possibilities have been proposed. On the one hand, Graybiel and her colleagues have suggested that the pattern of convergent inputs to the striatum represents a remapping of cortical systems such that functionally related information from different cortical areas converge on 'matrisomes' within the striatum, which determine the output organization of the striatum. On the other hand, Strick, Alexander and DeLong, have proposed that the organization of functional systems within the cortex are carried through topographically segregated parallel loops through the basal ganglia circuits to feedback onto the frontal cortical areas, from which these loops arise. Strick and his colleagues have provided evidence to support the idea that the output structure of the basal ganglia circuits are organized into segregated loops that feed back through the thalamus in a topographically organized manner. Reconciliation of these two models would be provided by the possible convergence of secondary sites of terminations of corticostriatal inputs, related in part to the organization of cortico-cortical connections, onto primary topographically related cortico-striatal projections. In this reconciled model, there would exist both the primary segregated loop model and convergence of functionally related information from different cortical areas onto these cortical-basal ganglia loops. The organization of the output systems of the striatum, and of their targets appear to reflect that of the cortical inputs. There is a general maintenance of a topographic organization, which is overlain with a patterns of convergence. As in the corticostriatal system, the patterns of convergence are most extensive in the rostrocaudal dimension. In addition, there is an additional organization in the basal ganglia loops, that of dual projection systems, which occur at each level of the projections from the striatum to the globus pallidus and substantia nigra as well as in the intermediate system which includes the subthalamic nucleus. This dual projection system arises from individual neurons at 425

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each stage of the basal ganglia circuit. The functional significance of this dual projection system may be related to the organization of the final targets of the basal ganglia output, the superior colliculus and thalamus.

10. STRIATAL PATCH/MATRIX COMPARTMENTS Within the complexity of the striatum it is important to identify those aspects of organization that provide underlying mechanisms which might account for the heterogeneity of functional structure. For example, the underlying organization of striatal output neurons displays considerable homogeneity in that two major subpopulations may be defined connectionally, by their respective projections to the globus pallidus and to the entopeduncular nucleus/substantia nigra, and neurochemically, by their selective expression of dopamine receptor subtypes and certain neuropeptides (Gerfen 1992). The rather uniform distribution of these neurons in all regions of the striatum underscores the homogeneity of this aspect of striatal organization. However, as will be detailed below, although in some respects the regulation of these two subpopulations also reflects a mechanistic uniformity, there are other aspects of regulation that reveal both regional and subregional heterogeneity. Such heterogeneity is related to compartmentally organized systems that are overlain on the organization of striatopallidal and striatonigral output neurons and function to regulate these output neurons. One such system is the so-called 'patch-matrix' striatal compartments which are involved in the way that the dopamine input to the striatum is regulated (Gerfen 1992). Patch-matrix striatal compartments are often described on the basis of neurochemical markers (Gerfen et al. 1985; Graybiel and Ragsdale 1978; Herkenham and Pert 1981). However, as will be described, in some cases such compartmental heterogeneity reflects regulatory processes, particularly in the relative levels of different neuropeptides (Gerfen et al. 1991). Patch-matrix compartments may be defined precisely on the basis of connections of the neurons in these compartments (Gerfen 1984, 1985, 1989; Gerfen et al. 1987). Such a definition is important to understanding the functional organization of the striatum as it is critical to distinguish the underlying mechanisms that give rise to the different regulatory mechanisms that give rise to heterogeneity within the striaturn. Thus, although we will begin with the organization of the nigrostriatal dopamine system to the patch and matrix compartments, it is important to be forewarned that the underlying organization of these compartments are related to the segregation of cortical inputs that target different populations of striatal output neurons that themselves target different neurons in the other components of the basal ganglia. While some neurochemical markers show regulation-dependent distribution patterns relative to the patch-matrix compartments, most notably the neuropeptides in striatal medium spiny neurons (Gerfen et al. 1991), other neurochemical markers show patterns consistent with the connectional determinants of patch-matrix organization. The first of these to be identified as a patch-matrix marker is the binding pattern to mu opiate receptors, which is greatly enriched in the patch compartment (Herkenham and Pert 1981; Pert et al. 1976). Another is the distribution of axon collaterals of striatal somatostatin-containing interneurons (Gerfen 1984; Gerfen et al. 1985). Particularly useful is the localization of the calcium binding protein calbindin in striatal matrix projection neurons (Gerfen et al. 1985). This marker has been particularly useful as displays the same patch-matrix organization in the striatum in rats and primates (Gerfen et al. 1985). These markers, all show consistent patch-matrix distributions relative to one another 426

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in most regions of the striatum and have been useful in establishing the connectional basis of patch-matrix organization. The distribution of these markers is shown in Figure 24. 10.1. NIGROSTRIATAL DOPAMINE SYSTEM Dopamine innervation of the striatum (Bj6rklund and Lindvall 1984) is relatively dense and when considered in total is rather uniform. However, this belies an underlying organization of the nigrostriatal system into patch- and matrix-directed systems (Gerfen et al. 1987; Gerfen et al. 1987; Jimenez and Graybiel 1987; Langer and Graybiel 1989). The first indication of the compartmental organization of the nigrostriatal dopamine system came from developmental studies which revealed that in the early postnatal striatum dopamine input is distributed in patches, and that during subsequent development innervation of the matrix is completed (Olson et al. 1972; Tennyson et al. 1972). Neuroanatomical tracing studies demonstrated that this developmental sequence is a consequence of the dopamine projection to the patch and matrix compartments arise from distinct sets of dopamine neurons in the substantia nigra (Gerfen et al. 1987). The distribution of dopamine neurons in the ventral midbrain, labeled with tyrosine hydroxylase immunoreactivity, and those that project to the striatum are shown in Figure 25. The midbrain areas in which dopamine neurons are distributed include the ventral tegmental area, which is the ventral medial most region of the midbrain, the substantia nigra, which includes the pars compacta, in which dopamine neurons are

r .

i Fig. 24. Patch and matrix striatal compartments are labeled with neurochemical markers. A) The patch compartment is labeled with 3H-naloxone binding to mu opiate receptors (white in the darkfield photomicrograph). B) The matrix compartment is labeled with calbindin-immunoreactivity, which labels spiny projection neurons that provide inputs to the substantia nigra pars reticulata. The correspondence between calbindinpoor zones (black arrows) and mu opiate binding sites (white arrows) is seen to occur in all regions of the striatum. Calbindin-immunoreactivity is relatively weak in the dorso-lateral striatum, which nonetheless contains opiate receptor patches.

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Fig. 25. The organization of the nigrostriatal dopamine (DA) pathway from the midbrain to the striatum (sagittal diagram at upper right) is diagrammed to show the organization of this system to the striatal patch and matrix compartments. Coronal sections at three levels through the striatum (A,B,C) are depicted to show the innervation of the patch and matrix compartments from different subsets of midbrain dopamine neurons from three levels (D,E,F). Neurons providing inputs to the striatal matrix compartment (white in D,E,F) are located in the ventral tegmental area (VTA, A10 DA cell group), in the dorsal tier of the substantia nigra pars compacta (in D: SNc, A9) and in the retrorubral area (in F: RR, A8 DA cell group). Neurons providing input to the striatal patch compartment are located in the ventral tier of the substantia nigra pars compacta (in D,E,F: SNc, A9 DA cell group) and from A9 DA cells located in the substantia nigra pars reticulata (in E and F). There is a general topography in that medially located cells project to the ventral striatum and laterally located cells project to the dorsal striatum. Neurons at each rostral-caudal level in the midbrain project rather extensively to throughout the rostral-caudal extent of the striatum such that neurons at level D project to levels A, B and C in the striatum. d e n s e l y p a c k e d , a n d t h e p a r s r e t i c u l a t a , w h i c h is relatively cell sparse c o m p a r e d to the p a r s c o m p a c t a , a n d the r e t r o r u b r a l area, w h i c h lies c a u d a l a n d d o r s a l to t h e s u b s t a n t i a n i g r a ( G e r f e n et al. 1987). T h e d e s i g n a t i o n o f the s u b g r o u p i n g s o f d o p a m i n e n e u r o n s

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according to regional location, A10 cell group in the ventral tegmental area, A9 cell group in the substantia nigra, and A8 cell group in the retrorubral area, conforms to some extent with their projection targets. The A10 dopamine cell group is generally regarded to project to limbic forebrain areas, such as the septal area, prefrontal cortex, olfactory tubercle and nucleus accumbens. The A9 and A8 cell groups are generally regarded as the origin of the projection to the striatum. As is evident, dopamine containing neurons, which project to the striatum, are distributed in each of these groups, including the A10 cell group, due to the inclusion of the nucleus accumbens within the striatum. As is also seen, these neurons are distributed in a somewhat continuous manner, such that delineation of subgroupings based regional location is somewhat arbitrary. A different parcellation of these neurons is suggested based on the morphology of neuronal dendrites, the expression of the calcium binding protein calbindin, and their projection to either the patch or matrix striatal compartments (Gerfen et al. 1987a,b). Using these determinants the projection of midbrain dopamine neurons to the striatum reveals the following organization. Two sets of striatal projecting dopamine neurons are distinguished, a dorsal and ventral tier. The dorsal tier set provides inputs to the striatal matrix compartment. This set encompasses a continuous group which includes those dopamine neurons projecting to the striatum in the ventral tegmetnal area, the dorsal part of the substantia nigra pars compacta, and the retrorubral area. Several other characteristics apply to this set. First, those neurons in the pars compacta are distinguished by the extension of dendrites within the plane of the pars compacta, distinguished from those of the ventral tier. Second, most of the dorsal tier neurons express, in addition to dopamine, the calcium binding protein, calbindin. Third, there is a rough topography to the organization of the projections to the striatum such that more medially situated neurons project ventrally to the nucleus accumbens and ventral striatum, whereas more lateral and caudal neurons, in the A9 and A8 cell groups, project to the dorsal striatum. The ventral tier set provides inputs to the striatal patch compartment. Neurons in this set are situated in the ventral part of the substantia nigra pars compacta and in groups of cells embedded in the pars reticulata. Ventral tier pars compacata neurons are distinguished by their extension of dendrites ventrally into the pars reticulata. Ventral tier dopamine neurons do not display calbindin immunoreactivity. These neurons display a topographic organization in their projections to the striatum, with dorsally positioned neurons projecting to the patch compartment in the ventral striatum and nucleus accumbens, and ventrally positioned neurons, in the pars reticulta projecting to the dorsal striatal patch compartment. It is worthwhile to note that the numbers of dopamine neurons located in the ventral substantia nigra pars reticulata increases at more caudal levels. Consequently, the common view of the substantia nigra as being composed of two separate zones, a dorsal pars compacta in which dopamine neurons are located, and a ventral pars reticulata in which GABA neurons are located, applies only to the rostral most levels of this nucleus. This organization appears to be common across species from rat to primates. 10.2. STRIATAL OUTPUTS The basis of striatal patch-matrix organization is the segregation of striatal medium spiny neurons that have projections to different components of the substantia nigra and entopeduncular nucleus (Gerfen 1984, 1985; Gerfen et al. 1985). Neurons in the patch compartment project to the location of the ventral tier dopamine neurons, whereas neurons in the matrix compartment project to the location of GABA neurons in the 429

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substantia nigra pars reticulata (Gerfen 1984, 1985; Gerfen et al. 1985). This organization appears common throughout all regions of the striatum, including the ventral striatum and nucleus accumbens. Several lines of experimental evidence have revealed this organization. First, retrograde axonal tracers injected into the dopamine cell rich substantia nigra pars compacta or into the pars reticulata selectively label either patch or matrix neurons (Gerfen 1984; Gerfen et al. 1985). However, these methods are limited by the uncertainty of defining the exact area of uptake of transported tracer. Second, the same result has been obtained in several species, including rats, cats and primates (Gerfen 1984, 1985; Gerfen et al. 1985; Jimenez and Graybiel 1989). Third, the calcium binding protein calbindin selectively labels striatonigral neurons in the matrix compartment and not in the patches (Gerfen et al. 1985). Calbindin immunoreactivity is also contained in the terminals of striatal matrix axon projections to the substantia nigra. The distribution of such terminals is concentrated in the pars reticulata and is absent in both the area in which dopamine neurons are located in both the pars compacta and in those parts of the pars reticulata in which dopamine neurons are located. This distribution pattern confirms axonal tracing studies which suggest that patch compartment neurons projections target dopamine neurons in the substantia nigra and that matrix compartment neurons provide inputs to the GABA neurons in the substantia nigra pars reticulata. A parallel organization appears to also apply to the striatal projection to the entopeduncular nucleus (Rajakumar et al. 1993). The entopeduncular nucleus, the rodent homologue of the internal segment of the internal segment of the globus pallidus in primates, may be considered to be part of a continuous group of GABA neurons that extend into the substantia nigra pars reticulata and provide the major output of the basal ganglia. Similar to the GABA neurons in the pars reticulata, entopeduncular neurons provide a projection to the thalamus (Van der Kooy and Carter 1981).. The thalamic targets of the entopeduncular nucleus, and the internal segment of the globus pallidus in primates, provide projections to frontal cortical areas involved with axial musculature. This is contrasted with thalamic targets of the output of the substantia nigra pars reticulata, which are nuclei that provide inputs to frontal cortical areas involved with eye and head movements. Thus the entopeduncular nucleus and substantia nigra pars reticulata appear to form a continuous somatotopically organized output of the basal ganglia. The entopeduncular nucleus is also distinct from the substantia nigra in lacking an associated dopamine cell group. However, like the substantia nigra the entopeduncular nucleus may be divided into two parts on the basis of output neurons. In addition to those entopeduncular nucleus neurons that project to the ventral lateral thalamus, there is a medially situated part of the nucleus which provides inputs directed to the lateral habenula (Van der Kooy and Carter 1981). The lateral habenula in turn projects to the substantia nigra pars compacta, as well as to brain stem nuclei including the medial and dorsal raphe and to the midbrain tegmentum. Recent studies have shown that the striatal matrix compartment provides inputs directed to the thalamic projecting part of the entopeduncular nucleus, whereas the patch compartment provides inputs to the habenular projecting part of the nucleus (Rajakumar et al. 1993). Given the connections through the lateral habenula to the substantia nigra pars compacta, the organization of the patch-matrix projections to the entopeduncular nucleus suggest that a similar, though different, organization as that seen to the substantia nigra from these striatal compartments. Of note is the fact that whereas the direct striatal patch projection to the substantia nigra pars compacta 430

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appears to target the ventral tier dopamine cell group, the patch projection system through the entopeduncular-habenular connections appears to provide inputs directed to the dorsal dopamine cell group. As discussed above the dorsal dopamine cell group provides input directed to the matrix compartment, whereas the ventral dopamine cell group provides input directed to the patch compartment. One missing piece of connectional data concerning the organization of the patch and matrix compartments is the identification of striatal patch neurons that project to the globus pallidus. Whereas the projection of patch neurons to the substantia nigra and entopeduncular nucleus have been described, these neurons account for only half of the projection neurons in the patch compartment. The other half provide inputs to the globus pallidus (Gerfen and Young 1988). One possibility might have been that patch and matrix neurons provide differential inputs to the striato-pallidal border region versus the central region of the globus pallidus, as these regions are distinguished by the dendritic organization of pallidal neurons and by the existence of dual projections from the striatum. However, it has been clearly demonsrated that individual neurons in the striatum provide axon collaterals to both pallidal regions (Chang et al. 1981; Kawaguchi et al. 1990). Another possibility is that patch neurons might provide a select input to cholinergic neurons in the globus pallidus. These neurons, which are scattered in the dorsal globus pallidus and more numerous in the ventral pallidum, have been shown to receive synaptic input from the striatum (Grove et al. 1986). However, it remains purely speculative whether such inputs originate within the striatal patch compartment. Such a connection makes functional sense in terms of the symmetry of the system, but remains to be examined. The segregation of medium spiny neurons with different projection targets to the patch and matrix compartments provides a morphologic basis for these compartments. Moreover, the dendrites of medium spiny neurons appear to remain confined to the compartment of the parent neuron. This has been established with retrograde axonal tracing studies (Gerfen et al. 1985), with Golgi impregnation studies (Bolam et al. 1988) and most directly with intracellular labeling of individual neurons (Kawaguchi et al. 1989). These latter studies have demonstrated that the dendrites may take tortuous paths to remain confined within a particular compartment. In particular, patch neurons are often seen to have recurved dendrites that dutifully respect the borders between the patch and matrix compartments. This organization of the dendrites of medium spiny neurons suggests that afferents from outside the striatum that target a particular compartment 10.3. CORTICAL INPUTS Cortical inputs to the patch and matrix compartments originate in different sublayers of layer 5, from most cortical areas (Gerfen 1989). Cortical inputs were amongst the first to be described as being compartmentally organized. Initial studies suggested that cortical areas with limbic connections provide inputs directed to the patch compartment, whereas neocortical areas provide inputs to the matrix compartment (Donoghue and Herkenham 1986; Gerfen 1984). However, more detailed analysis revealed that although different cortical areas provide inputs that differ in magnitude to the two compartments, most cortical areas appear to provide inputs to both compartments (Gerfen 1989). For example, the prelimbic cortex in the rat, which is on the medial bank of the frontal cortical hemisphere, provides a dense input to the patch compartment in the medial striatum from neurons in the deep part of layer 5 and an input to the matrix compart431

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E I= 1 mm Fig. 26. The relationship between the laminar organization of the cortex and the striatal patch-matrix compartments is diagrammed showing inputs from the prelimbic (A) and cingulate (D) cortices to the striatum. Corticostriatal neurons located in the deeper part of layer 5 (black cells in A and B) in each cortical area provide inputs directed to the patch compartment (black stippling in B,C, E and F), whereas corticostriatal neurons located in the superficial part of layer 5 (white cells in A and D) provide inputs directed to the matrix compartment (white stippling in B,C, E and F). Inputs from these cortical areas are somewhat greater to the patch compartment as compared to their inputs to the matrix compartment. The prelimbic and cingulate cortical areas provide inputs to a topographically related region in the striatum which overlaps to some extent for these two corticostriatal projections.

ment surrounding these patches from the superficial part of layer 5. This organization has subsequently been confirmed to also apply to cortical inputs to the ventral striatum and nucleus accumbens (Berendse et al. 1992a). The determination of the compartmental target of neurons in different sublaminae of the prelimbic cortex was based on a large number of cases of injections of PHA-L 432

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Fig. 27. The relationship between the laminar organization of the cortex and the striatal patch-matrix compartments is diagrammed showing inputs from the medial agranular cortex (AGm: A) and lateral agranular cortex (AGI: D) to the striatum. Corticostriatal neurons located in the deeper part of layer 5 (black cells in A and B) in each cortical area provide inputs directed to the patch compartment (black stippling in B,C, E and F), whereas corticostriatal neurons located in the superficial part of layer 5 (white cells in A and D) provide inputs directed to the matrix compartment (white stippling in B,C, E and F). Inputs from these cortical areas are relatively greater to the matrix as compared to the patch compartment. Also of note is the discontinuous pattern of inputs that arise from these injections to the striatum.

into a specified cortical area, such as the prelimbic area (Gerfen 1989). In order to assure that an injection was confined to the prelimbic cortex, that is, labeled cortical neurons whose efferent axons were labeled by the tracer, and did not include injected neurons in adjacent cortical areas several criteria were applied. The first was by inspection of the injection site to determine that labeled neurons were confined within a single cortical 433

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area. The second criterion was the pattern of thalamic labeling. Thus, the pattern of thalamic labeling of injections into the prelimbic area was compared with injections into adjacent cortical areas. Cases were selected for inclusion in a set of injections only if the pattern of thalamic labeling could be distinguished between that of the anterior cingulate and medial agranular cortices, the areas adjacent to the prelimbic cortex. The third criterion was that the pattern of the crossed cortico-cortical labeling displayed a pattern in which the crossed projection system was concentrated over the contralateral homologous cortical area. Using these criteria it was found that injections that were confined to a single cortical area such as the prelimbic area could be grouped into three types, those with projections to the striatal patch compartment, those with projections concentrated in the striatal matrix compartment and those with projections to both compartments. In these experiments the patch and matrix compartments were identified with either naloxone binding or calbindin immunoreactivity. In all types the area of the striatum innervated was comparable, although small differences reflecting microtopographic organization were apparent. Several features of the patterns of cortical labeling distinguished the injections which labeled projections to the patch compartment as compared to those which labeled inputs to the matrix compartment. Injections that labeled inputs preferentially distributed in the patch compartment labeled neurons that were situated in deeper parts of layer 5. In addition, the labeling of axon collaterals of these labeled neurons was distributed in the prelimbic area in layer 5 and 6 with little labeling of axons in superficial layers. A comparable pattern of labeling was also observed in the contralateral homologous cortical area. Contrasted with this pattern of labeling was that of injections which labeled inputs directed preferentially to the matrix compartment. In these cases labeled neurons were located more superficially, in upper layer 5 and also in layers 2 and 3. The pattern of axonal labeling surrounding the injection site showed dense labeling in superficial cortical areas. A comparably dense distribution of labeled fibers was also observed in the superficial layers of the contralateral cortex. While interpretations are limited by methodological considerations, the pattern of labeled projections suggested that neurons projecting to the striatal patch compartment are located more deeply in the cortex than those which provide projections to the matrix compartment. A similar organization was also found with injections into the infralimbic, anterior cingulate, medial agranular and lateral agranular cortices (Berendse et al. 1992a; Gerfen 1989). In each of these other cortical areas, the same criteria were applied for assuring that injections were confined to a single cortical area. In addition, the same pattern of cortical labeling was also observed. Differences between these cortical areas were mainly related to the relative density of inputs to the patch compartment. Infralimbic and prelimbic cortical injections provided denser inputs to the patch compartment, while cingulate and medial agranular cortical areas showed a slightly less dense input to the patch compartment. Inputs from lateral agranular cortical injections showed only very sparse inputs to the patch compartment. In addition, projections from the prelimbic, infralimbic, and cingulate cortices were each distributed to a rather continuous region within the striatum, including both the patch and matrix compartments. On the other hand, the pattern of striatal labeling after injections into the lateral agranular cortex were decidedly discontinuous, with separated dense zones of labeling within the matrix. Of note is the fact that the patterns of cortical labeling from such cortical injections also show marked discontinuities. This aspect of cortico-cortical and cortico-striatal labeling is of interest in the context of the relationship between cortico-cortical and corticostriatal organization. 434

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Thus, it appears that many, and perhaps most, cortical areas provide inputs to both the patch and matrix compartments (Gerfen 1989). However, the relative density of inputs to the patch compartment is denser from periallocortical areas such as the infralimbic and prelimbic cortices. Conversely, neocortical areas such as the medial and lateral agranular cortices have a relatively greater input to the matrix as compared to the patch compartment. Differences in the relative inputs from different cortical areas have led to the suggestion that inputs from the cortex to the patch-matrix compartments is related to the cortical area of origin. In this view cortical areas may be viewed as a continuum of areas with inputs directed to the patch compartment from allo- and peri-allocortical areas and those with inputs to the matrix compartment from neocortical areas. However, such a view should not be confused with the realization that the inputs from a given cortical area are directed to both compartments, albeit to different extents. Studies in primates have revealed a predominance of inputs to the matrix compartment. However, most studies have examined inputs from neocortical areas, which would be predicted to have a relatively weak input to the patch compartment. Recent studies have reported inputs to the patch compartments from primate cortical areas comparable to those in rats which also have a predominant input to the patch compartment. This would suggest that a similar organization applies in primates as well. 10.4. THALAMIC AFFERENTS Thalamic afferents in the striatum from the parafascicular/intralaminar nuclei are organized relative to the patch matrix compartments (Beckstead 1985; Berendse et al. 1988; Herkenham and Pert 1981; Xu et al. 1991). Inputs from the parafascicular/ centromedian thalamic nuclei provide inputs directed to the matrix compartment. Inputs to the striatal patch compartment arise from more restricted parts of the intralaminar thalamic nuclei. 10.5. GENERAL PATCH-MATRIX ORGANIZATION The general organization of the patch-matrix compartments provides separate pathways from the cortex, through the striatum to differentially effect dopamine and other, basal ganglia feed-back circuits, or to affect basal ganglia GABAergic output neurons in the entopeduncular nucleus and substantia nigra pars reticulata. Thus, the cortical connections through the patch compartment appear to be related to regulation of the dopamine, and possibly serotonergic feedback systems to the striatum, whereas cortical connections through the matrix compartment appear to be related to regulation of the output neurons of the basal ganglia. This organization appears to be common to all parts of the striatum. There has been some confusion in the literature with suggestions that the cortical inputs and striatal outputs of the patch-matrix compartments in the ventral striatum differ from those in the dorsal striatum. However, the differences that have been suggested are related to the use of markers for identifying patch-matrix compartments. Some studies of the ventral striatal patch-matrix organization have used enkephalin immunoreactivity as a compartmental marker (Berendse et al. 1992a, 1992b). However, this marker shows a transition between the dorsal and ventral striatum that shifts relative to other neurochemical markers such as calbindin and opiate receptor binding (Voorn et al. 1989), which are more consistent with connectional definitions of patch-matrix compartmental 435

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organization (Gerfen et al. 1985). When patch-matrix compartments are defined on the basis of input-output connectional organization the organization in the dorsal and ventral striatum is identical. 436

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10.6. CORTICAL ORGANIZATION RELATED TO STRIATAL PATCH-MATRIX COMPARTMENTS The relationship between the cortical laminar organization and striatal patch-matrix compartments suggests that the cortical output systems may be organized to regulate the dopamine feedback system to the striatum, which in turn regulates the cortical projection through the matrix compartment to the basal ganglia output neurons. This concept was originally formulated in terms of limbic cortical inputs to the patch compartment (Gerfen 1984). However, with the finding that all cortical areas may provide inputs to the patch compartment (Gerfen 1989), albeit to varying extents, the idea of a preferential connection between 'limbic' cortices and the patch compartment needs to be reexamined. We have suggested that the relationship between the cortex and the striatal patch-matrix compartments is related to the laminar organization of the cortex. This then raises the question as to the functional organization of cortical lamination. Neurons in the cortex are segregated into laminae in which neurons with similar projections are grouped (Jones 1984). For example, pyramidal neurons in superficial layers 2 and 3 provide axonal connections within the cortex, pyramidal neurons in layer 6 are the source of projections to the thalamus, and pyramidal neurons in layer 5 provide other subcortical projections, including those to the striatum. These patterns of cortical efferents related to the cortical layer of origin are by no means absolute. Moreover, there is considerable heterogeneity amongst the classes of cortical projections from a given layer. Relevant to the topic of this discussion are the different types of neurons in layer 5 and particularly the different types of corticostriatal neurons. As described above there are at least 3 types of corticostriatal neurons, pyramidal tract neurons with collaterals into the striatum, cortico-thalamic neurons with collaterals into the striatum, and bilaterally projecting cortico-striatal neurons. One possibility is that these different types of corticostriatal neurons contribute differentially to the projections to the patch and matrix compartments. However, at this time there is not sufficient data to determine whether such a distinction exists. Another possibility is that different subsets of each of these different corticostriatal types project to both compartments. The question therefore remains open as to what might distinguish cortical neurons that project to the striatal patch and matrix compartments. One of the determining features of PHA-L injections into the cortex which distinguished patch from matrix projections was the pattern of cortico-cortical projections of the injected neuron population. Injections which selectively labeled inputs to the patch compartment labeled both local and contralateral cortico-cortical connections that were preferentially distributed in deeper cortical layers. Conversely, injections which selectively labeled inputs to the matrix compartment labeled both local and contralateral cortico-cortical connections that were preferentially distributed to superficial cortical layers. With this method it is not possible to attribute the cortico-cortical pattern of labeling to neurons that project also Io the striatum. However, it is possible to speculate that a difference in the corticocortical connections of patch and matrix projecting corticostriatal neurons might distinguish these two neuron types. There do exist layer 5 neurons that show such patterns of cortico-cortical connectivity. For example, at least two distinct types of layer 5 neurons have been distinguished on the basis of their local axon collateras, one type which has axon collaterals which distribute longitudinally in layer 5 and 6, whereas another neuron type has axon collaterals that distribute to superficial layers, 2 and 3 (Chagnac-Amitai et al. 1990). These latter axon collaterals display a much more restricted distribution in the longitudinal axes. If such differences in local cortical axon 437

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collaterals apply to patch- and matrix-directed corticostriatal neurons the implication is that patch-directed corticostriatal neurons influence a larger domain of the cortical area of origin than do matrix-directed corticostriatal neurons. The resolution of this speculation awaits single cell labeling analysis. A possible function of the laminar organization of the cortex and the patch-matrix compartmentation of the striatum might be inferred from the apparent transition in the relative contribution to the striatal compartments from allo- (or periallo-) cortical compared to neocortical areas. As discussed above, early studies had suggested a preferential input from cortical areas connected with the limbic system to the striatal patch compartment, which in turn provides a direct input to dopamine neurons that project back to the striatum. This concept was a modification of the ideas put forward by Nauta and his co-workers that the basal ganglia was a site of integration of limbic and non-limbic systems. They suggested that the limbic parts of the striatum, the ventral striatum including the nucleus accumbens, which is the target of 'limbic' inputs from the amygdala, hippocampus, and olfactory related cortical areas, provided the main input to the dopamine neurons in the substantia nigra pars compacta, which projected back to both ventral, 'limbic'- and also dorsal, non-limbic-striatal regions. Initial studies of the input-output organization of the patch-matrix compartments, modified the ideas of Nauta with the finding that it was the patch compartment neurons, in both the ventral and dorsal striatum, which are the source of inputs to the dopamine feedback neurons to the striatum. Our early analysis retained the concept of Nauta, by suggesting that the source of the input to the patch compartment was exclusively from limbic connected cortical areas. This idea was further modified with more recent findings that the source of inputs to the patch compartment was not restricted only to limbic-connected cortical areas. Thus, given the fact that the patches in the dorsal striatum receive inputs from neocortical, non-limbic, areas of cortex, and that these patches nonetheless provide inputs to the dopamine nigrostriatal feedback system requires a further modification of the concept of the integration of so-called 'limbic' and 'non-limbic' integration within the basal ganglia. Rather than consider that the striatal patch-matrix systems are related to limbic and non-limbic cortical areas defined on the basis of the former's connections with olfactory related structures, these cortical areas might be considered on the basis of the differences in their organization. For this discussion it is best to refer to allo- and peri-allocortical and neocortical areas because of the obvious conceptual difficulties of defining limbic and non-limbic cortices. Allo-, peri-allo- and neo-cortical areas appear to process information in distinct ways. For example, in the piriform cortex, which may be viewed as a prototypic allocortical area, information coding of specific odors is distributed throughout the cortical area. Different odors are encoded in the same cortical space such that specific odors are encoded by different patterns of activity distributed across that cortical area. On the other hand, in neocortical areas such as the somatosensory or motor cortex, the encoding of information is somatotopically organized within the cortical fields. The computational differences required for encoding these different modalities, olfaction on the one hand, and somatotopically organized information on the other, is reflected in the organization of cortico-cortical connections within each of these cortical areas. Thus in the piriform cortex each neuron is broadly connected with other neurons in this cortical area, whereas in neocortical areas there appears to be considerable local specificity of cortico-cortical connections. Thus, allocortical areas appear to process information with relatively uniformly distributed connectional patterns, whereas neocortical areas parse information on the basis of somatotopic or retinotopic maps. Alheid and Heimer (1988) have also proposed that the subcortical 438

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connections of allo- and neocortical areas share common general organizational schemes whose specific elements reflect a transition in the final targets of these systems and in the feedback mechanisms they employ. In general they suggest that the projections of allo-cortical areas target more direct subcortical feedback systems, whereas neocortical areas target indirect subcortical feedback systems that are organized to provide more specific feedback to the cortex through the thalamus. We would argue that the transition from distributed information processing typical of allocortex to spatially compartmentalized information processing typical of neocortex is relevant to the function of the striatal patch-matrix compartments. The patch compartment, appears to have connections analogous to those of allocortex, providing inputs to a more direct feedback system, the nigrostriatal dopamine system. Conversely, the matrix compartment, appears to have connections analogous to the neocortex, which target indirect feedback pathways to the cortex through the thalamus. Whereas the connections of allocortical areas and somatosensory and visual cortical areas represent the extremes of the two forms of information processing, most cortical areas encompass both schemes, but to varying degrees. Thus, it is suggested that the the striatal targets of allocortical areas, which may be the shell region of the nucleus accumbens, whereas, the striata| target of the most extreme neocortical areas, which target striatal areas that are relatively devoid of the patch compartment, represent extreme cases. In most of the striatum both patch and matrix compartments exist for these two types of information processing. This would suggest that there is a retention of some organizational elements of allocortex in the transition to neocortex. It is proposed from all cortical areas providing inputs to both compartments, that cortical neurons projecting to the patch compartment have allocortical type connectional features, whereas those projecting to the matrix have 'neocortical' type connectional features. The relative numbers of each type varies according to the cortical area of origin. Regardless of the speculative proposals for the functional significance of the relationship between the cortex and the patch-matrix compartments several determinants of this relationship may be stated with some certainty. First, there is a differential projection of different cortical neurons to the patch and matrix compartments. Second, both patch and matrix corticostriatal projection neurons are located within a single cortical area. A corollary of this is that most cortical areas appear to contain both patch and matrix projection neurons but the relative number of each varies according to the type of cortical area. Third, within a single cortical area patch and matrix corticostriatal neurons are preferentially located in different sublaminae. As laminar organization varies across cortical areas the precise distribution of the patch and matrix corticostriatal projecting neurons may also vary. The laminar organization of patch-matrix corticostriatal neurons is distinguished from other aspects of cortical organization, such as the columnar organization. Fourth, the organization of separate cortical pathways into the patch and matrix compartments are carried through the striatum to provide segregated inputs to dopamine neurons and GABA output neurons in the substantia nigra.

11. DIRECT/INDIRECT STRIATAL OUTPUT SYSTEMS 11.1. C O N N E C T I O N A L BASIS Medium spiny neurons have a common morphology in terms of their size, dendritic organization and local axon collaterals. Within the striatum these neurons have an axon 439

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Fig. 29. Coronal sections through the striatum showing mu-opiate receptor with 3H-naloxone binding of patches (A and B) and in adjacent sections spiny projection neurons labeled by in situ hybridization histochemistry with probes directed against substance P mRNA (A') and enkephalin mRNA (B'). Substance P and enkephalin are expressed by different populations of spiny projection neurons, each comprising about half of the population and each evenly distributed in both patch and matrix compartments (arrows show patches in the corresponding sections). From Gerfen and Young (1987).

collateral that extends within varying domains around the parent neuron. Each of these neurons provides an axon that projects out of the striatum. Studies in which individual striatal medium spiny neurons were filled with the marker biocytin revealed subsets of neurons on the basis of the projection axons (Kawaguchi et al. 1990). One type, referred to as a striatopallidal neuron, provides an axon that extends into the globus pallidus and arborizes extensively, usually in two separate domains within this nucleus. These neurons do not have an axon that extends beyond the globus pallidus. A second type extends an axon collateral into the globus pallidus, which does not arborize extensively, and extends other collaterals that extend into either the entopeduncular nucleus and/or the substantia nigra. In order to simplify the terminology this second type of neuron is 440

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ENK

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Fig. 30. In situ hybridization histochemical localization of mRNAs to identify peptides and dopamine receptor subtypes in striatal spiny projection neurons. Striatonigral neurons contain both D 1 and substance P-mRNAs, whereas striatopallidal neurons contain both D2 and enkephalin mRNAs. A-C) Neurons that project to the substantia nigra have been retrogradely labeled with the fluorescent dye fluorogold (whitish labeled cell bodies). In situ hybridization labeling of specific mRNAs is shown by white grains. A) D 1 dopamine receptor mRNA is localized in labeled striatonigral neurons (arrows). B) Substance P mRNA is also localized in labeled striatonigral neurons(arrows). C) D2 dopamine receptor mRNA is not contained in labeled striatonigral neurons but in unlabeled striatopallidal neurons (open arrows). D) Enkephalin mRNA is also contained in unlabeled striatopallidal neurons (open arrows). E) Both D 1 and D2 mRNAs are labeled in the same section, D1 mRNA with an S35-riboprobe that is marked by white silver grains over neurons and D2 mRNA with a digoxigenin-riboprobe that is labeled with a dark immunoreactive reaction. D1 and D2 mRNAs are segregated in separate neurons, with less than 5% of the entire population of striatal spiny projection neurons containing appreciable amounts of both receptor subtypes. A-C) from Gerfen et al. 1990.

441

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~ntia ra Fig. 31. Summary diagram of the 'direct' and 'indirect' striatal output pathways. Layer 5 cortical neurons provide excitatory input (+) to the striatum. The direct striatal projection is provided by D1/substance P/dynorphin-containing neurons to the substantia nigra and entopeduncular nucleus, and to a lesser degree to the globus pallidus. The indirect striatal projection is provided by D2/enkephalin-containing neurons that project to the globus pallidus. The globus pallidus in turn provides an inhibitory projection to the substantia nigra and to the subthalamic nucleus. The subthalamic nucleus provides an excitatory input to the substantia nigra. Thus, the 'direct' and 'indirect' pathways provide antagonistic input to the substantia nigra. The GABA neurons in the substantia nigra provides an inhibitory projection to the superior colliculus, pedunculopontine nucleus (not shown) and thalamus. The thalamic nuclei receiving this output project back upon the frontal cortex. The entopeduncular nucleus is connected in a similar manner to the substantia nigra but is not shown.

442

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referred to as a striatonigral neuron. This simplification is used for several reasons, but the fact that it is a simplification should be kept in mind when considering the functional significance of these projection systems. First, as demonstrated, these neurons do extend an axon into the globus pallidus. Although the extent of arborization of this axon collateral is less than that of the striatopallidal neuron, it exists, and may make functional synapses with pallidal neurons. The numbers of neurons so contacted and the relative input of this neuron relative to that of the striatopallidal neuron input is not yet known. However, in terms of the numbers of synapses, striatonigral axon collaterals in the globus pallidus make as many as half the number of synaptic contacts as the axons of striatopallidal neurons. Second, the entopeduncular nucleus (as well as the internal segment of the globus pallidus in primates) and the substantia nigra may be considered to be part of a single nuclear complex in terms of both their inputs and outputs. Both structures receive direct inputs from the striatum and both contain GABA neurons that may be considered to be part of the output system of the basal ganglia in that they project to the thalamus. The targets in the thalamus are distinct (Gerfen et al. 1982; Van der Kooy and Carter 1981). The entopeduncular nucleus projects to the ventral lateral thalamic nucleus and lateral habenula, whereas the substantia nigra pars reticulata provides inputs to the ventral medial and intralaminar thalamus. These different targets of the two output components of the basal ganglia reflect that topographic organization of striatal outputs. Intracellular staining studies confirmed prior retrograde tracing experiments, in which tracers were injected into the target nuclei, which demonstrated that striatal neurons projected to either the globus pallidus or substantia nigra (Beckstead and Cruz 1986; Gerfen and Young 1988; Loopuijt and Kooy 1985). Such studies established several features of the striatal organization of such neurons. First, there appear to be distinct neuron subpopulations. In addition to the direct demonstration of this from Kawaguchi's work, this is also suggested from retrograde studies. Studies employing two fluorescent markers, one injected into the substantia nigra and the other into the globus pallidus, have shown most neurons to be labeled from only one injection site (Beckstead and Cruz 1986; Loopuijt and Kooy 1985). Even accounting for the possibility of injections that are not perfectly matched topographically in the two structures, such a labeling pattern points to an inherent limitation of the technique, as, based on the existence of a collateral of striatonigral nuerons in the globus pallidus the pattern of labeling is almost certainly revealing the precise organization of axonal projections. In this case such a limitation is an asset in that it does reveal two connectionally distinct neuron types. Second, the numbers of each projection type appear to be approximately equal. Given that over 90% of striatal neurons are projection neurons, estimates based on retrograde labeling suggest that approximately 40-45% project principally to the globus pallidus and another 40-45% project principally to the substantia nigra. Third, striatopallidal and striatonigral neurons are interspersed with one another. In some cases they may form small clusters of 2-5 neurons projecting to one site. In other cases, neurons projecting to separate sites may be nearest neighbors, often appearing to be in close apposition. 11.2. PEPTIDE BASIS The segregation of striatal output neurons on the basis of their differential targetting of the globus pallidus and substantia nigra was first suggested by the immunohistochemical labeling of opiate and tachykinin peptides in striatal terminals in these nuclei. 443

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Fig. 32. Data from an experiment demonstrating D 1- and D2-receptor selective gene regulation in 'direct' and 'indirect' striatal projection neurons. Images are of coronal sections of film autroadiographs labeled with in situ hybridization histochemical localization of enkephalin mRNA (top row), substance P mRNA (middle row) and dynorphin mRNA (bottom row) from an intact rat striatum (control striatum: first column), from a striatum depleted of dopamine (6-OHDA lesion: second column), from a dopamine depleted striatum of an animal treated with the D1 agonist SKF38393 (single daily injections 5 mg/kg for 21 days), and from a dopamine depleted striatum of an animal treated with a D2 agonist quinpirole (continuous treatment of lmg/kg for 21 days). Dopamine depletion elevates enkephalin, decreases substance P and has little effect on dynorphin. Subsequent D 1 agonist treatment has no effect on enkephalin (contained in D2 bearing neurons) but reverses the lesion induced decrease in substance P and causes a large increase in dynorphin mRNA both of which are contained in D 1 bearing neurons. On the other hand, subsequent to dopamine depletion of the striatum, D2 agonist treatment reverses the lesion-induced elevation of enkephalin mRNA in neurons bearing D2 receptors, but has no effect on substance P or dynorphin in D1 bearing neurons. From Gerfen et al. 1990.

Striatal neurons projection neurons all contain GAD (Aronin et al. 1984; Kita and Kitai 1988; Ribak et al. 1979), although subpopulations contain different neuropeptides including the opiate peptides enkephalin (Beckstead 1985; DiFiglia et al. 1982; Haber and Watson 1983; H6kfelt et al. 1977; Pickel et al. 1980) and dynorphin (Vincent et al. 1982a; Vincent et al. 1982b), or the tachykinin substance P (Brownstein et al. 1977; Hong et 444

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A diagram of the model of Parkinson's disease that suggests that dopamine (DA) depletion in the disease results in an elevated output of the indirect pathway (enkephalin, ENK, D2 containing neurons), which results in increased excitatory input from the subthalamic nucleus (stn) to the internal globus pallidus (GPi) and substantia nigra and a decreased output of the direct pathway (substance P: SP, D1 containing neurons). See text for further details.

al. 1977; Kanazawa et al. 1977). Immunohistochemical studies showed that these peptides are localized in connectionally defined striatal output neurons (Beckstead and Kersey 1985; Haber and Watson 1983). Enkephalin-immunoreactive terminals, originating from axons of striatal neurons, are concentrated in the globus pallidus, with only sparse distributions in the substantia nigra pars compacta (Beckstead and Kersey 1985; Haber and Watson 1983). Conversely, both dynorphin and substance P show dense terminal immunoreactivity in the substantia nigra (and entopeduncular nucleus), and only a sparse distribution in the globus pallidus (Brownstein et al. 1977; Hong et al. 1977; Kanazawa et al. 1977; Vincent et al. 1982b).. Whereas such studies had established 445

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the striatal origins of the terminal labeling in these structures, early immunohistochemical techniques were unable to identify the cells of origin without the use of colchicine. Moreover, peptide immunoreactivity in the striatum revealed complex patterns of heterogeneity being highly concentrated in the patch compartment (to be discussed in detail later) (Graybiel et al. 1981). However, these patterns varied from region to region which led to some ambiguity concerning the compartmental relationships of the neurons containing the different peptides. In part these patterns of immunohistochemical localization reflect technical aspects of the method in that different fixatives revealed different patterns of labeling (Graybiel and Chesselet 1984). As has become evident the varied levels of peptides in different striatal compartments and in different regions reflects regulatory mechanisms that underlie the functional organization of the striatum (Gerfen 1991). That the relative peptide levels in striatal neurons may be considered distinct from the localization of peptides in connectionally defined striatal neurons is evident from studies that combine axonal tracing techniques with in situ hybridization histochemical localization of the messenger RNAs that encode the various peptides (Gerfen and Young 1988). Using these techniques it has been established that striatopallidal neurons contain mRNA encoding enkephalin and striatonigral neurons contain mRNAs encoding both dynorphin and substance P. Moreover, these studies show that these two connectionally defined neuron types each constitute approximately half of the striatal projection neuron population, that the two populations are intermingled with each other throughout all regions of the striatum and that they are equally distributed in both the patch and matrix compartments. This pattern of localization is shown in Figures 29 and 30. 446

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11.3. DOPAMINE RECEPTOR-MEDIATED REGULATION Levels of peptides in striatal neurons are regulated by dopamine receptor-mediated mechanisms. Work by several groups demonstrated that levels of enkephalin and substance P are oppositely modulated by dopamine (Gerfen et al. 1991; Hong et al. 1978a; Hong et al. 1978b; Young et al. 1986). Dopamine depletion of the striatum or neuroleptic blockade of D2 dopamine receptors result in an elevation of enkephalin peptide and mRNA levels in striatopallidal neurons (Hong et al. 1978b, 1985; Mocchetti et al. 1985; Tang et al. 1983) and a decrease in substance P levels (Bannon et al. 1986; Hanson et al. 1981; Hong et al. 1978a). Conversely, pharmacologic treatments that enhance dopamine neurotransmission result in elevated substance P and dynorphin peptide and mRNA levels in striatonigral neurons (Gerfen et al. 1990, 1991; Hanson et al. 1987; Li et al. 1986, 1988). The opposite effects that dopamine has on the peptides in striatal output neurons appear to be related to the differential expression of the D 1 and D2 dopamine receptor subtypes by the neurons that express these peptides (Gerfen et al. 1990). Thus, mRNA encoding the D 1 dopamine receptor subtype is localized in striatonigral neurons and the mRNA encoding the D2 dopamine receptor subtype is localized in striatopallidal neurons. This distribution of receptors has been established in numerous ways. First, similar to the immunohistochemical localization of peptides to the different output pathways, receptor binding studies demonstrate a differential localization of D2 and D 1 receptor binding, of striatal origin, in terminals in the globus pallidus and substantia nigra, respectively (Beckstead 1988; Richfield et al. 1989). Second, combined axonal tracing and in situ hybridization studies localize D2 and enkephalin m R N A in striatopallidal neurons and D1 and substance P m R N A in striatonigral neurons (Gerfen et al. 1990). Third, double in situ hybridization studies reveal the exclusive co-localization of D2 mRNA in neurons with enkephalin mRNA and D1 mRNA in neurons with substance P mRNA (Le Moine et al. 1990, 1991). Fourth, dual visualization of D 1 and D2 mRNAs in the same histologic sections with in situ hybridization demonstrate a near complete segregation of neurons expressing each receptor subtype. It should be noted that, while the in situ hybridization studies seem conclusive when considered alone, they are not in agreement with the results from a number of physiological and biochemical studies, and so the differential expression of D 1 and D2 receptors continues to be controversial. Most striatal spiny neurons, including most identified striatonigral neurons, respond to both D1 and D2 receptor agonists and antagonists, even when isolated from all synaptic input (Surmeier et al. 1992). Similarly D 1 and D2 agonists act synergistically in suppressing Na+-K + ATPase activity in isolated striatal neurons (Bertorello et al. 1990). Gene amplification techniques have been used to demonstrate the co-localization of D1 and D2 dopamine receptor subtype mRNAs in striatonigral neurons (Surmeier et al. 1992). These data are at odds with in situ hybridization techniques. One possiblity is that even though in situ hybridization techniques show a segregation of D 1 and D2 dopamine receptors in different striatal neurons, there may be low levels of expression of D1 mRNA in striatopallidal neurons that express relatively high levels of D2 m R N A and conversely there may be low levels of expression of D2 m R N A in striatonigral neurons that express relatively high levels of expression of D 1 mRNA. The question is whether the disparity of different levels of these receptor subtypes in individual neurons is related to the function of these neurons. Physiologic studies have suggested at least that individual neurons show physiologic changes in ion conductances in response to activation of both receptor subtypes. However, as will be 447

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detailed below studies employing selective D 1 and D2 receptor agonists and antagonists suggest that striatopallidal and striatonigral output neurons are differentially and selectively affected by pharmacological manipulation of these dopamine receptor subtypes when changes in gene regulation are measured (Dragunow et al. 1990; Gerfen et al. 1990; Robertson and Fibiger 1992; Robertson et al. 1990). In animals with 6-hydroxydopamine lesions of the nigrostriatal pathway, it is possible to selectively activate receptor subtypes without the effects of endogenous transmitter (Gerfen et al. 1990, 1991). In such dopamine depleted striata, levels of genes contained in striatopallidal neurons are increased, including mRNAs encoding enkephalin and the D2 receptor. Conversely, in striatonigral neurons various mRNAs are decreased, including those encoding the peptides substance P and dynorphin and the D1 dopamine receptor. These lesion-induced alterations are selectively reversed, in each neuron type, by treatment with agonist directed against the recpetor expressed by that neuron type. Thus, increased enkephalin and D2 receptor mRNA levels are reversed by administration of the D2 agonist quinpirole, and the decreased substance P and D1 receptor mRNA levels are reversed by D1 agonist (SKF38393) treatment. Significantly, the schedule of treatment with these agonists was a critical factor in the effect on peptide mRNA levels. Two treatment schedules were used to administer dopamine receptorselective agonists to animals with unilateral lesions of the nigrostriatal dopamine system. The first was a continuous infusion schedule, in which the drugs were administered for 21 days with osmotic minipumps implanted intraperitoneally. The second was an intermittent schedule, in which drugs were administered once daily for 21 days. Reversal of the lesion induced increase of enkephalin and D2 receptor mRNA was effected with continuous (1 mg/day) but not intermittent (1 x 1 rag/day) quinpirole treatment. Conversely, reversal of the lesion-induced decrease in substance P and D1 receptor mRNA was effected with intermittent (1 x 10 mg/kg) but not continuous (10 mg/day) SKF38393 treatment. In addition, intermittent SKF-38393 treatment resulted in a large increase above baseline levels of the mRNA encoding the peptide dynorphin in striatonigral neurons. These results suggest that gene regulation in striatopallidal and striatonigral neurons are regulated in different ways by the activation of the dopamine receptor subtypes (Gerfen et al. 1990). Changes in peptide/protein or mRNA levels in neurons in response to pharmacologic activiation or blockade of receptor subtypes does not substitute for measurements of physiologic response. Moreover, as changes in peptide levels occur over a prolonged time period, these may be secondary to the direct effect of dopamine receptor activation. However, other markers of gene regulation, such as the induction of transcription factors including the immediate early gene c-fos, which occur immediately following drug treatments, reveal a similar pattern of selective effect of D1 and D2 dopamine receptor subtype effects on striatonigral and striatopallidal neurons. For example, in the unilateral nigrostriatal dopamine lesion model, a single injection of the D1 agonist SKF-38393, results in the rapid induction of c-fos in striatonigral and not in striatopallidal neurons (Robertson et al. 1989, 1990). Thus, the immediate effect of activation of D1 receptor activation appears to have a selective effect on striatonigral neurons. While the dopamine depleted striatum provides a good model for study of the selective effects of D1 and D2 receptor stimulation these effects are abnormal in the sense that the pharmacologic treatments that alter gene regulation in the lesioned striatum are not paralleled in the unlesioned striatum. These differences in effect are not due to a redistribution of the receptor subtypes, as the segregated localization of the D 1 and D2 receptor subtypes to striatonigral and striatopallidal neurons occurs in both the lesioned 448

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and unlesioned striatum (Gerfen et al. 1990; Le Moine et al. 1990, 1991). More likely, such differences reflect altered receptor-mediated signal transduction processes that result in supersensitive responses to receptor activation. However, there are some drug treatments that elicit responses in the normal striatum that are similar to those in the lesioned striatum. For example, systemic administration of the D2 receptor antagonist haloperidol results in the immediate induction of c-fos selectively in striatopallidal neurons (Dragunow et al. 1990; Robertson and Fibiger 1992). Longer-term treatment with such neuroleptics result in elevated enkephalin (Hong et al. 1978b, 1985; Mocchetti et al. 1985; Tang et al. 1983). These effects, in normal striatum, are the converse of changes caused by striatal dopamine depletion and subsequent D2 agonist treatments that selectively effect striatopallidal neurons. In normal rats induction of immediate early genes and changes in peptide levels occur within the striatum after single and repeated administration of drugs that enhance dopamine function. Both amphetamine administration, which acts to enhance dopamine release, and cocaine administration, which acts to prolong the effects of dopamine by blocking catecholamine reuptake, result in c-fos induction in the striatum (Cenci et al. 1992; Graybiel et al. 1990; Steiner and Gerfen 1993; Young et al. 1991). The regional patterns of induction produced by these two drug treatments differ, with amphetamine producing induction that is most prevalent in the striatal patch compartment, whereas cocaine produces induction in both patch and matrix compartments that is regionally localized to the dorsal striatum. In the case of cocaine administration c-fos is induced selectively in striatonigral neurons and this induction is blocked by D1 receptor antagonists (Cenci et al. 1992; Graybiel et al. 1990; Young et al. 1991). These effects provide several insights into dopamine regulation of striatal function. First, they provide evidence that the same underlying dopamine receptor-mediated regulatory processes that occur in the dopamine depleted striatum function in the normal striatum. Second, the compartmental and regional variations in the response of striatal neurons to different manipulations of dopamine function in the striatum suggest heterogeneity in the organization of nigrostriatal dopamine system and other striatal afferent systems, most notably the corticostriatal and thalamostriatal systems. 11.4. OTHER (NON-DOPAMINERGIC) REGULATORY RECEPTOR SYSTEMS IN STRIATUM The organization of D1 ad D2 dopaminergic receptors among the striatonigral and striatopallidal neuron populations is relatively uniform throughout all regions of the striatum. Moreover, the opposite regulation of these two populations of neurons, at least in terms of gene regulatory responses of the neurons to dopamine receptor stimulation, is also rather uniform. However, in addition to the direct effects of dopamine on striatal output neurons, there are multiple other receptors and neuronal systems that are involved in the modulation of striatal output function. These other mechanisms produce differences in the relative responses of neurons to various inputs, including differences in the modulation mediated by the D1 and D2 dopamine receptors. The distribution of different receptors and/or their subtypes show various distributions amongst connectionally defined subpopulations of striatal neurons. In some cases the distribution patterns are similar to those of dopamine receptor subtypes, but in other cases the distribution patterns are different. An example of a receptor subtype that shows a similar pattern to the dopamine receptor distribution is the a2 adenosine receptor. The mRNA encoding this receptor 449

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has been shown to be localized specifically in neurons that also contain enkephalin mRNA, and are thus striatopallidal neurons (Ferre et al. 1993; Schiffmann and Vanderhaeghen 1993). Moreover, pharmacologic treatment with adenosine agonists has shown a specific regulation of enkephalin mRNA levels in these neurons (Ferre et al. 1993; Schiffmann and Vanderhaeghen 1993), causing similar changes in peptide as occurs through D2 dopamine receptors. Consistent with the restricted localization of this receptor to striatopallidal neurons, changes in levels of substance P, in striatonigral neurons, are not observed with the same treatments (Schiffmann and Vanderhaeghen 1993). Thus, the localization of the a2-adenosine and D2-dopamine receptor subtypes are both expressed in a similar restricted set of striatal output neurons, and activation of these receptors produce selective changes in gene regulation in these neurons. Although the changes produced by a2-adenosine and D2-dopamine receptor stimulation appear to be similar as regards changes in gene regulation of peptides in these neurons, the effects of co-stimulation of these receptors appears to be antagonistic (Ferre et al. 1993). This suggests that these two receptor systems, acting on an individual neuron, may modulate the responsiveness of these neurons to activation of the other receptor. In other cases receptors are distributed either in all striatal output neurons or in subsets of neurons that do not conform with the simple segregation of striatopallidal and striatonigral neurons. Both receptor binding studies (Herkenham et al. 1991) and in situ hybridization localization of mRNA encoding the cannabinoid receptor show that this receptor is (Mailleux and Vanderhaeghen 1992; Matsuda et al. 1993) contained in both striatal output neuron populations. Moreover, there appears to be an interaction between the activation of dopamine and cannabinoid receptors in striatal output neurons in terms of the regulation of receptor gene products (Mailleux and Vanderhaeghen 1993). Opiate receptors in the striatum have been studied for some time using receptor binding techniques (Eghbali et al. 1987; Herkenham and Pert 1982; Mansour et al. 1987; McLean et al. 1986; Tempel and Zukin 1987). Recently, the genes encoding these receptors have been identified and the coding regions sequenced, which has enabled their localization with in situ histochemistry (Evans et al. 1992; Meng et al. 1993; Thompson et al. 1993). Acetylcholine, released from interneurons within the striatum, has an important role in the regulation of striatal function. Such regulation is in part mediated through acetylcholine muscarinic receptors, which show a complex distribution pattern in striatal neuron populations. With the cloning of the family of muscarinic receptor subtypes (Bonner et al. 1987) it has been possible to localize different receptor subtypes in striatal neuron populations (Bernard et al. 1992; Weiner et al. 1990). One subtype, the m l muscarinic receptor subtype appears to be expressed by nearly all striatal medium spiny neurons. Another subtype, the m2 receptor, is expressed selectively by striatal cholinergic neurons, and may thus be an autoreceptor. Another subtype, the m4 receptor is expressed in a subpopulation that straddles the two striatal neuron populations that express D1 and D2 receptors, being contained in approximately 40% of the D2-dopamine receptor (striatopallidal) and 80% of the D l-dopamine receptor (striatonigral) neurons. Unfortunately, at this time pharmacologic agents that allow for the selective activation of the various muscarinic receptor subtypes are not available. However, it does appear that activation of these receptors has an important function in the regulation of striatal neuron activity. This may prove a complicated problem to study, as electrophysiologic studies suggest that muscarinic receptor activation may differentially alter the membrane potential of medium spiny neurons dependent on the membrane 450

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potential at the time of activation (Akins et al. 1990). Gene regulation studies also show that muscarinic agonist and antagonist treatments lead to induction of immediate early genes in subpopulations of striatal output neurons (Bernard et al. 1993). GABA and glutamate receptors are two classes of neurotransmitter receptors that are critically important to striatal function. Adequate description of these systems within the basal ganglia warrants a review that is beyond the scope of this chapter. Recent description of the distribution of the genes encoding the different subunits of both GABA and glutamate receptors are listed for reference. The GABAa receptor is composed of a combination of subunits which have been cloned and characterized (Araki et al. 1992; Seeburg et al. 1990; Shivers et al. 1989; Wisden et al. 1992; Zhang et al. 1991). The differential distribution of different subunits within the striatum suggests that this receptor system plays a complex role in striatal function. Similarly the different subtypes of glutamate receptors have been cloned, characterized and mapped within the cortex and striatum (Albin et al. 1992; Dure et al. 1992; Martin et al. 1992, 1993a, 1993b, 1993c; Petralia et al. 1994). 11.5. CELLULAR INTERACTIONS WITHIN THE STRIATUM As described above, regulation of the relative activity in striatopallidal and striatonigral neurons may be effected through the direct actions of dopamine on receptor subtypes that are differentially expressed by these two output neuron populations. However, there are multiple other neurotransmitter/receptor systems that may also function to regulate the activity of these neurons. At this time the multiplicity of interactions that presumably occur during the normal functioning of the striatum have not been worked out in any detail. Some plausible cellular interactions may be suggested based on both neuroanatomical and receptor localization studies. As described above, spiny projection neurons possess axon collaterals that extend within the striatum. Most of these appear to be distributed in a domain slightly larger than the domain of the dendritic arbors of the parent neuron. However, as seen in Figure 6 and 7, the distribution of such collaterals does not appear to cover the same area as the dendrites of its parent, and in some cases the distribution is complementary. This would suggest that one neurons axon makes contact with a neighboring spiny projection neuron, for which there is morphologic evidence (Wilson and Groves 1980). The question of whether contacts between neighboring spiny projection neurons are between neurons belonging to a similar connectionally/neurochemically defined subset of neurons or between neurons of different subsets is of some interest. Based on ultrastructural studies of the localization of peptides in boutons presynaptic to medium spiny neurons it might be suggested at least in a very preliminary way, that contacts occur between neurons belonging to the same and to different subpopulations (Bolam and Izzo 1988). Further study of this will be critical to understanding the functional significance of these local collaterals within the striatum. The neurotransmitter(s) used in these connections is also of significant interest. GABA is a likely candidate since all spiny projection neurons not only use this neurotransmitter but also possess GABA receptors. Whether the peptides that are co-localized with GABA in these neurons are employed as neurotransmitters in the connections between medium spiny neurons remains an open question. While substance P has been shown to be contained in boutons presynaptic to medium spiny neurons and to striatal cholinergic neurons, the receptor for substance P has only been localized, at this date, in cholinergic neurons (Gerfen 1991). This suggests that a single neuron might have different effects on neurons with which it makes 451

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synaptic contact dependent on the receptors on the post-synaptic neuron. In this case it is suggested that medium spiny neurons might effect cholinergic neurons through substance P-mediated mechanisms (Arenas et al. 1991), and other medium spiny neurons through other neurotransmitters, possibly GABA. The domains of the axon collaterals of medium spiny neurons are of interest in how populations of medium spiny neurons might be connected together. Most medium spiny neurons are thought to possess axon collaterals that spread within a domain roughly 200-300/zm in diamter. However, as described by Kawaguchi et al (1990), there is a subset of medium spiny neurons which have axon collaterals that spread over a considerably larger domain, up to 2 mm in diameter (see Figure 7). Such a subset of neurons has important implications for understanding the domains of populations of striatal neurons that might be functionally linked together. These neurons which have been found with such extensive local collaterals have been found to belong to the subset of striatopallidal neurons. Other characteristics of these neurons will be of great interest. Striatal interneurons undoubtedly have a major influence on the regulation of striatal medium spiny neurons, based on their synaptic contacts onto these neurons. Whether regulation of the activity in interneurons is distributed to connectionally/neurochemically defined subsets of medium spiny neurons, or are distributed more homogeneously is of interest. Most likely many combinations of interactions occur. Rather than list all the possibilities one will be suggested for which there is some experimental evidence. As described, boutons containing substance P, presumably from axon collaterals of striatonigral medium spiny neurons, make synaptic contact with cholinergic neurons, which possess the receptor for substance P (Gerfen 1991). Studies have reported substance P-mediated increase in acetylcholine release (Arenas et al. 1991) supporting the functional relevance of the neuroanatomical connections described. In addition, it has been reported that D1 receptor agonist treatment results in acetylcholine release that is mediated by substance P-receptor mediated mechanisms. Together these studies suggest that one possible cellular basis of the interaction between striatonigral and striatopallidal neurons might be mediated via connections of the striatonigral neurons with striatal cholinergic interneurons, provided that acetylcholine effects striatopallidal neurons. The select effect that stimulation of D 1 receptors has on gene regulation in striatonigral neurons and conversely that stimulation of D2 receptors has on striatopallidal neurons occurs in animal models in which dopamine is depleted from the striatum and these receptors may be stimulated independently. Of course, in the normal striatum, these receptors are most likely activated concurrently. While some models of striatal function have suggested that the interactions that occur when D 1 and D2 receptors are co-activated result from receptors co-expressed by single striatal neurons, an alternative model is that such interactions occur by way of interactions between neurons, which express predominantly one or the other dopamine receptor subtype. We have suggested some possible intercellular connections that might be involved. Moreover, these receptors are being activated in concert with other neurotransmitter/receptors expressed by striatal output neurons. Thus the effect that stimulation of any one receptor subtype, such as one of the dopamine receptor subtypes, may depend on the state of the neuron in terms of other inputs, such as glutamate inputs from the cortex, or muscarinic cholinergic inputs from striatal interneurons.

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11.6. FUNCTIONAL SIGNIFICANCE A model of basal ganglia function has been proposed based on a synthesis of experimental data which suggests that normal behavior is dependent on a balance in the output of the direct striatonigral system and the indirect, striatopallidal system (Albin et al. 1989; DeLong 1990; Mitchell et al. 1989). As described above, this model is supported by the differential effects that dopamine receptor subtype stimulation has on gene regulation in these two output systems (Gerfen et al. 1990). The model of neurologic dysfunction of the basal ganglia suggests that increased output of the indirect pathway (striatopallidal), relative to that in the direct pathway (striatonigral), results in akinesia as occurs in Parkinson's disease. Conversely, increased output of the striatonigral pathway, relative to the striatopallidal pathway, is thought to result in hyperkinetic syndromes, such as occurs in dystonia, Huntington's chorea and Tourette's syndrome, each of which is characterized by uncontrolled movement. In the case of the model of Parkinson's disease, the idea that there is an increase in the function of the striatopallidal pathway emerged from 2-deoxyglucose studies in both primates and rats which had lesions of the nigrostriatal pathway to deplete dopamine in the striatum (Mitchell et al. 1989; Trugman and Wooten 1987). In this condition, there was seen to be an increase in the glucose utilization in basal ganglia nuclei that are targets of the subthalamic nucleus, that is in the two segments of the globus pallidus (in primates) and in the substantia nigra. This suggested that increased inhibition of the globus pallidus (external segment in primates) resulting from increased striatopallidal output resulted in a disinhibition of the subthalamic nucleus and consequently increased excitatory input to the output neurons of the basal ganglia. As the output of the basal ganglia provides inhibition to the thalamus, and other targets such as the superior colliculus and pedunculopontine nucleus, increased inhibitory output was suggested to be the cause of the slowed or absent movements typical in primate models of Parkinson's disease. A test of this hypothesis was carried out by DeLong and co-workers (Bergman et al. 1990). In monkeys that showed profound bradykinesia resulting from MPTP lesions of the nigrostriatal pathway they performed lesions of the subthalamic nucleus, with the intent to block the hypothesized abnormally high output of this nucleus. Results of these lesions were dramatic in that they resulted in an immediate reversal of the lesion-induced bradykinesia. Thus, at least as far as the bradykinesia of Parkinson's disease there has been a good correlation between the connectional and neurochemical organization of striatal output pathways and dysfunctional motor behavior. As might be predicted, a simple model of basal ganglia function in the control of movement (and behavior) in terms of increased or decreased output of the striatopallidal and striatonigral pathways does not provide a full explanation of the activity in different parts of the basal ganglia during the performance of normal behaviors. On the one hand, studies of eye movements are generally referred in support of the model. Studies by Hikosaka and Wurtz (Hikosaka and Wurtz 1983a, 1983b), demonstrated that disruption of the tonic activity of the substantia nigra pars reticulata and the resultant disinhibition of neurons in the superior colliculus were tightly coupled to eye movements. However, studies of the relationship between activity in the other output nucleus of the basal ganglia, the internal segment of the globus pallidus, and movements of limb or axial musculature, do not provide such direct correlation (Hikosaka and Wurtz 1983a, 1983b; Mink and Thach 1991a, 1991b, 1991c). In some studies, most neurons recorded from the internal segment of the globus pallidus during movements show increased activity. Changes in the patterns of activity, not simple increases or decreases in the 453

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regional organization of dopamine response dynorphin

cocaine-induced c-fos 9 :i. ::5

"

)",:.i:i

: .ii: I;- . 9

:..

repeated cocaine treatment 9 . . . .

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~ :)i ~;: ~:)i~ ~~~; :~: ~:::~: : ........

Fig. 35. Diagram of the regional response within the striatum to the indirect dopamine agonist cocaine demonstrating the functional role of dynorphin in modulating this response. The basal level of dynorphin expression shows a higher level in ventral and medial striatal regions. A single injection of cocaine induces the immediate early gene c-fos by a D 1 mediated mechanism in the dorsal lateral striatal region, complementary to the area showing high levels of dynorphin. Repeated treatment with cocaine ( single daily injections of 30 mg/kg for 3 days) results in an increase in dynorphin levels in the dorsal striatal region, which has low basal expression, and a marked reduction of c-fos induction in this area, in which c-fos had previously been induced. These data suggest that dynorphin blunts the response of neurons to D 1 receptor stimulation. Further studies have shown that this effect of dynorphin is mediated through kappa opiate receptors. From Steiner and Gerfen (1993). 454

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output of the basal ganglia output are commonly reported (Filion and Tremblay 1991). In other studies, there appears to be both increased activity in the pallido-thalamic neurons, and increased activity in the target neurons of these neurons, despite the fact that stimulation of these same pallido-thalamic neurons results in inhibition in the thalamus (Anderson and Turner 1991). This finding suggests that the major target of the basal ganglia outputs in the thalamus is under the influence of other inputs that may over-ride those from the basal ganglia, possibly from the cortex. The purpose of introducing such studies is to point out that extrapolating from models of the abnormal basal ganglia to the normal function of the system requires some caution. Nonetheless, the fact that the direct and indirect striatal output pathways may, in certain conditions, be rather uniformly regulated by dopamine receptor mediated mechanisms, provides at least some insight into the functional organization of the striatum. 11.7. REGIONAL DIFFERENCES A common feature of the organization of the striatum is distinct regional and local variations in the relative expression of different neurochemical markers. The fact that these regional variations in relative expression occur in defined neuron populations that are homogeneously distributed in the striatum sets up a dichotomy that is important for understanding the functional organization of the striatum. On the one hand there are features of striatal organization that are common to all striatal regions. On the other hand, differences in the ongoing activity of inputs to different striatal regions result in differences in the level of expression of various neurochemicals that most likely reflect differential activation of the mechanisms that regulate their expression. Thus, it is important to distinguish between differences in the relative level of expression of neurochemical markers that reflect the level of activation of regulation of those markers, from the underlying mechanisms of regulation. An example of this dichotomy is the distribution of peptide markers in striatal spiny projection neurons. Striatopallidal neurons expressing enkephalin, and striatonigral neurons expressing dynorphin and substance P are fairly uniformly intermingled and evenly distributed across all regions of the striatum. This is most clearly seen using in situ hybridization histochemistry (Gerfen and Young 1988). However, even with in situ hybridization it is apparent that the relative levels of expression of the mRNAs encoding these peptides vary in different regions and in the patch-matrix compartments (discussed below). The uneveness of peptide levels is readily apparent with immunohistochemical methods. For example, the immunohistochemical localization of the peptides substance P and enkephalin are enriched in the striatal patch compartment in the dorsal parts of the striatum, and in the ventral striatum show either a more homogeneous distribution or even enriched labeling in the matrix compartment (Graybiel et al. 1981). Thus, in the normal striatum, there are distinct regional differences in the basal levels of peptide expression in striatal projection neurons. In studies in the dopamine depleted striatum, dopamine agonist treatments alter peptide levels rather uniformly in all striatal regions, independent of the regional heterogeneity that marks the normal striatum (Gerfen et al. 1990). This suggests that normal regional heterogeneity of peptide expression may reflect differences in the patterns of ongoing afferent input that regulate peptide expression, and that these patterns differ in different regions. Studies employing the indirect dopamine agonist cocaine to effect changes in striatal gene regulation reveal a possible mechanism responsible for the heterogeneity of striatal peptide expression (Steiner and Gerfen 1993). Basal dynorphin levels are relatively high 455

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in the ventral striatum, including the nucleus accumbens, and in the dorsal striatal patches. A single high dose of cocaine (30 mg/kg) results in the induction of immediate early genes, such as c-fos, in striatonigral neurons via a D1 receptor-mediated process in the dorsal striatal region that is complementary to that in which dynorphin levels are relatively high. Repeated cocaine treatment results in an elevation of dynorphin in striatonigral neurons concomitant with a decreased induction of c-fos mRNA in these neurons. This observation led to the suggestion that dynorphin functions to suppress the response of striatonigral neurons to D1 receptor activation. Consistent with this hypothesis is the finding that agonists which bind to the kappa opiate receptor through which dynorphin acts block cocaine induced c-fos mRNA. These results suggest that dynorphin may function to suppress the response of striatal neurons to the effects of dopamine mediated through D1 receptor subtype. This may be a generalized function of peptides expressed by striatal neurons, namely to provide mechanisms that modulate the responsiveness of these neurons to other neurotransmitter inputs. Differences in the normal ongoing pattern of afferent activity to the striatum may be reflected in the compensatory responses of neurons to that input. Heterogeneity in peptide levels may be the reflection of such differences. Within the striatum, there appear to be distinct differences in the dorsal and ventral patterns of expression of different peptides. This may reflect differences in either the cortical or dopamine input to these two regions. It might seem most plausible that such differences reflect differences in the dopamine innervation systems, because they are, at least in part, responsible for regulation of the peptides in question. However, for several reasons we favor as a more likely candidate the cortical or other inputs to the striatum as being responsible for such regional heterogeneity. The dopamine input to these regions originates from a continuous group of neurons in the midbrain and there is no obvious transition zone in the neurons projecting to these striatal regions. On the other hand, there are distinct differences in the cortical areas projecting to the ventral and dorsal striatum. Those projecting to the ventral striatum are for the most part allocortical or peri-allocortical areas, and include also the amygdala. Those cortical areas projecting to the dorsal striatum are neocortical areas. There are a number of major differences in the organization of these different cortical areas, such as their laminar organization, the organization of their GABA interneuron systems, and the organization of their intrinsic cortical connections, which are probably responsible for differences in the pattern of their efferent output. Whereas many of the elements of the organization of cortical-basal ganglia circuits are common in all parts of the system, other elements show distinct regional variations. In particular, there are distinct differences in the relative distribution of neurons containing the calcium binding protein parvalbumin, that show consistent regional variations in the cortex, striatum, and substantia nigra. As described in an earlier section, parvalbumin is contained in a subset of striatal interneurons, the GABAergic medium aspiny class. These neurons are most abundant in dorsolateral striatal regions (Gerfen et al., 1985), areas that receive inputs from neocortical areas. In the substantia nigra, a subset of GABA neurons in pars reticulata contain parvalbumin neurons. These parvalbumin neurons are most abundant in the regions of the pars reticulata that receive inputs from the regions of the striatum that are enriched in parvalbumin neurons. In the cortex, parvalbumin is also contained in a particular subset of GABAergic interneurons. These neurons have been well characterized by Kawaguchi and Kubota (1993) in terms of electrophysiologic properties. The number and distribution of these neurons again varies in different cortical areas, with neocortical areas showing the greatest numbers in both deep and superficial layers. These cortical areas provide inputs to the striatal 456

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regions in which parvalbumin interneurons are most abundant (Gerfen et al. 1985). Conversely, peri- and allocortical areas show a marked paucity of these neurons, as do striatal regions that receive inputs from these cortical areas, as well as regions of the substantia nigra that receive inputs from these striatal regions (Gerfen et al. 1985). Thus, it might be suggested that differences in the pattern of cortical efferent activity that is transmitted through dorsal and ventral cortico-basal ganglia circuits is related to the relative abundance of parvalbumin interneurons at each level of the system.

12. ACKNOWLEDGEMENTS

We wish to thank and give credit to H. Kita for providing examples of intracellularly filled striatal and globus pallidal neurons and to J. Tepper for similarly providing substantia nigra neurons that were used for illustrations in this paper.

13. REFERENCES Akins PT, Surmeier DJ, Kitai ST (1990): Muscarinic modulation of a transient K + conductance in rat neostriatal neurons. Nature, 344, 240-242. Albin RL, Young AB, Penney JB (1989): The functional anatomy of basal ganglia disorders. Trends Neurosci., 12, 366-375. Albin RL, Makowiec RL, Hollingsworth ZR, Dure L, Penney JB, Young AB (1992): Excitatory amino acid binding sites in the basal ganglia of the rat: a quantitative autoradiographic study. Neuroscience, 46, 35-48. Alexander GE, Crutcher MD (1990): Functional architecture of basal ganglia circuits: neural substrates of parallel processing. Trends Neurosci., 13, 266-271. Alexander GE, DeLong MR, Strick PL (1986): Parallel organization of functionally segregated circuits linking basal ganglia and cortex. Ann. Rev. Neurosci., 9, 357-381. Alexander GE, Crutcher MD, DeI~ong MR (I 990): Basal ganglia-thalamocortical circuits: parallel substrates for motor, oculomotor, prefrontal and limbic functions. Progr. Brain Res., 85, 119-146. Alheid GF, Heimer L (1988): New perspectives in basal forebrain organization of special relevance for neuropsychiatric disorders: the striatopallidal, amygdaloid, and corticopetal components of the substantia innominata. Neuroscience, 27, 1-39. Andersen R Asanuma, C, Essick, G, Siegel, RM (1990): Corticocortical connections of anatomically and physiologically defined subdivisions within the inferior parietal lobule. J. Comp. Neurol., 296, 65-113. Anderson ME, Turner RS (1991): Activity of neurons in cerebellar-receiving and pallidal-receiving areas of the thalamus of the behaving monkey. J. Neurophysiol., 66, 879-893. Araki T, Sato M, Kiyama H, Manabe Y, Tohyama M (1992): Localization of GABAA-receptor ~ 2-subunit mRNA-containing neurons in the rat central nervous system. Neuroscience, 47, 45-61. Arenas E, Alberch J, Perez-Navarro E, Solsona C, Marsal J (1991): Neurokinin receptors differentially mediate endogenous acetycholine release evoked by tachykinins in the neostriatum. J. Neurosci., 11, 2332-2338. Arikuni T, Kubota K (1986): The organization of prefrontocaudate projections and their laminar origin in the macaque monkey: A retrograde study using HRP-gel. J. Comp. Neurol., 244, 492-510. Arluison M, Dietl M, Thibault J (1984): Ultrastructural morphology of dopaminergic nerve terminals and synapses in the striatum of the rat using tyrosine hydroxylase immunoreactivity: a topographical study. Brain Res. Bull., 13, 269-285. Aronin N, Difiglia M, Graveland GA, Schwartz WJ, Wu J-Y (1984): Localization of immunoreactive enkephalins in GABA synthesizing neurons of the rat neostriatum. Brain Res., 300, 376-380. Bannon MJ, Lee J-M, Girand P, Young A, Affolter J-U, Bonner TI (1986): Dopamine antagonist haloperidol decreases substance P, substance K and preprotachykinin mRNAs in rat striatonigral neurons. J. Biol. Chem., 261, 6640-6642. Beckstead RM (1979): An autoradiographic examination of corticocortical and subcortical projections of the mediodorsal-projection (prefrontal) cortex in the rat. J. Comp. Neurol., 184, 43-62. Beckstead RM (1983): A pallidostriatal projection in the cat and monkey. Brain Res. Bull., 11,629-632. Beckstead RM (1984): The thalamostriatal projection in the cat. J. Comp. Neurol., 223, 313-346.

457

Ch. H

C R. G e r f en a n d C J. Wilson

Beckstead RM (1985): Complementary mosaic distributions of thalamic and nigral axons in the caudate nucleus of the cat: double anterograde labeling combining autoradiography and wheat germ-HRP histochemistry. Brain Res., 335, 153-159. Beckstead RM (1988): Association of dopamine D1 and D2 receptors with specific cellular elements in the basal ganglia of the cat: the uneven topography of dopamine receptors in the striatum is determined by intrinsic striatal cells, not nigrostriatal axons. Neuroscience, 27, 851-863. Beckstead RM, Cruz CJ (1986): Striatal axons to the globus pallidus, entopeduncular nucleus and substantia nigra come mainly from separate cell populations in cat. Neuroscience, 19, 147-158. Beckstead RM, Kersey KS (1985): Immunohistochemical demonstration of differential substance P-, metenkephalin-, and glutamic-acid-decarboxylase-containing cell body and axon distributions in the corpus striatum of the cat. J. Comp. Neurol., 232, 481-498. Berendse HW, de Galis GY, Groenewegen HJ (1992a): Topographical organization and relationship with ventral striatal compartments of prefrontal corticostriatal projections in the rat. J. Comp. Neurol., 316, 314-47. Berendse HW, Groenewegen HJ, Lohman AH (1992b): Compartmental distribution of ventral striatal neurons projecting to the mesencephalon in the rat. J. Neurosci., 12, 2079-2103. Berendse HW, Voorn P, te Kortschot A, Groenewegen HJ (1988): Nuclear origin of thalamic afferents of the ventral striatum determines their relation to patch/matrix configurations in enkephalin-immunoreactivity in the rat. J. Chem. Neuroanat., 1, 3-10. Bergman H, Wichmann T, DeLong MR (1990): Reversal of experimental parkinsonism by lesions of the subthalamic nucleus. Science, 249, 1436-1438. Bernard V, Normand E, Bloch B (1992): Phenotypical characterization of the rat striatal neurons expressing muscarinic receptor genes. J. Neurosci., 12, 3591-3600. Bernard V, Dumartin B, Lamy E, Bloch B (1993): Fos immunoreactivity after stimulation or inhibition of muscarinic receptors indicates anatomical specificity for cholinergic control of striatal efferent neurons and cortical neurons in the rat. Eur. J. Neurosci., 5, 1218-1225. Bertorello AM, Hopfield JF, Aperia A, Greengard P (1990): Inhibition by dopamine of (Na § +K+)ATPase activity in neostriatal neurons through D1 and D 2 dopamine receptor synergism. Nature, 347, 386-388. Bishop GA, Chang HT, Kitai ST (1982): Morphological and physiological properties of neostriatal neurons: an intracellular horseradish peroxidase study in the rat. Neuroscience, 7, 179-191. Bj6rklund A, Lindvall O (1984): Dopamine-containing systems in the CNS. In: Bj6rklund A, H6kfelt T (Eds), Handbook of Chemical Neuroanatomy, Vol. 2." Classical Transmitters in the CNS, Part I, pp. 55-122. Elsevier, Amsterdam. Bolam JP, Izzo PN (1988): The postsynaptic targets of substance P-immunoreactive terminals in the rat neostriatum with particular reference to identified spiny striatonigral neurons. Exp. Brain. Res., 70, 361-377. Bolam JR Somogyi P, Totterdell S, Smith AD (1981): A second type of striatonigral neuron: a comparison between retrogradely labelled and Golgi-stained neurons at the light and electron microscopic levels. Neuroscience, 6, 2141-2157. Bolam JP, Clarke DJ, Smith AD, Somogyi P (1983): A type of aspiny neuron in the rat neostriatum accumulates [3H]gamma-aminobutyric acid: combination of Golgi-staining, autoradiography, and electron microscopy. J. Comp. Neurol., 213, 121-134. Bolam JR Wainer BH, Smith AD (1984): Characterization of cholinergic neurons in the rat neostriatum. A combination of choline acetyltransferase immunocytochemistry, Golgi-impregnation and electron microscopy. Neuroscience, 12, 711-718. Bolam JR Powell JF, Wu JY, Smith AD (1985): Glutamate decarboxylase-immunoreactive structures in the rat neostriatum: a correlated light and electron microscopic study including a combination of Golgi impregnation with immunocytochemistry. J. Comp. Neurol., 237, 1-20. Bolam JR Ingham CA, Izzo PN, Levey AI, Rye DB, Smith AD, Wainer BH (1986): Substance P-containing terminals in synaptic contact with cholinergic neurons in the neostriatum and basal forebrain: a double immunocytochemical study in the rat. Brain Res., 397, 279-289. Bolam JP, Izzo PN, Graybiel AM (1988): Cellular substrate of the histochemically defined striosome/matrix system of the caudate nucleus: a combined Golgi and immunocytochemical study in cat and ferret. Neuroscience, 24, 853-875. Bonner TI, Buckley NJ, Young AC, Brann MR (1987): Identification of a family of muscarinic acetylcholine receptor genes. Science, 237, 527-532. Bouyer JJ, Park DH, Joh TH, Pickel VM (1984): Chemical and structural analysis of the relation between cortical inputs and tyrosine hydroxylase-containing terminals in rat neostriatum. Brain Res., 302, 267-275.

458

The basal ganglia

Ch. H

Brown LL (1992): Somatotopic organization in rat striatum: evidence for a combinational map. Proc. Nat. Acad. Sci. USA, 89, 7403-7407. Brown LL, Feldman SM (1993): The organization of somatosensory activity in dorsolateral striatum of the rat. Prog. Brain Res., 99, 237-250. Brown RG, Jahanshahi M, Marsden CD (1993): Response choice in Parkinson's disease. The effects of uncertainty and stimulus-response compatibility. Brain, 116, 869-885. Brown VJ, Robbins TW (1991): Simple and choice reaction time performance following unilateral striatal dopamine depletion in the rat. Impaired motor readiness but preserved response preparation. Brain, 114 (1B), 513-525. Brownstein MJ, Mroz EA, Tappaz ME, Leeman SE (1977): On the origin of substance P and glutamic acid decarboxylase (GAD) in the substantia nigra. Brain Res., 135, 315-323. Carman JB, Cowan WM, Powell TPS (1965): The organization of cortico-striate connexions in the rabbit. Brain, 86, 525-562. Cavada C, Goldman RP (1989a): Posterior parietal cortex in rhesus monkey: I. Parcellation of areas based on distinctive limbic and sensory corticocortical connections. J. Comp. Neurol., 287, 393-421. Cavada C, Goldman RP (1989b): Posterior parietal cortex in rhesus monkey: II. Evidence for segregated corticocortical networks linking sensory and limbic areas with the frontal lobe. J. Comp. Neurol., 287, 422-445. Cavada C, Goldman RP (1991): Topographic segregation of corticostriatal projections from posterior parietal subdivisions in the macaque monkey. Neuroscience, 42, 683-696. Cenci MA, Campbell K, Wictorin K, Bj6rklund A (1992): Striatal c-fos induction by cocaine or apomorphine occurs preferentially in output neurons projecting to the substantia nigra in the rat. Eur. J. Neurosci., 4, 376-380. Chagnac-Amitai Y, Luhmann H, Prince D (1990): Burst generating and regular spiking layer 5 pyramidal neurons of rat neocortex have different morphological features. J. Comp. Neurol., 296, 598-613. Chang HT, Wilson C J, Kitai ST (1981): Single neostriatal efferent axons in the globus pallidus: a light and electron microscopic study. Science, 213, 915-918. Chang HT, Wilson C J, Kitai ST (1982): A Golgi study of rat neostriatal neurons: light microscopic analysis. J. Comp. Neurol., 208, 107-126. Chesselet MF, Robbins E (1989): Characterization of striatal neurons expressing high levels of glutamic acid decarboxylase messenger RNA. Brain Res., 492, 237-244. Chevalier G, Vacher S, Deniau JM, Desban M (1985): Disinhibition as a basic process in the expression of striatal functions. I. The striato-nigral influence on tecto-spinal/tecto-diencephalic neurons. Brain Res., 334, 215-226. Christoph GR, Leonzio RJ, Wilcox KS (1986): Stimulation of the lateral habenula inhibits dopamine-containing neurons in the substantia nigra and ventral tegmental area of the rat. J. Neurosci, 6, 613-619. Cowan RE, Wilson CJ (1994): Spontaneous firing patterns and axonal projections of single corticostriatal neurons in the rat medial agranular cortex. J. Neurophysiol., 71, Cowan RE, Wilson C J, Emson PC, Heizmann CW (1990): Parvalbumin-containing GABAergic interneurons in the rat neostriatum. J. Comp. Neurol., 302, 197-205. Cowan WM, Powell TPS (1966): Strio-pallidal projection in the monkey. J. Neurol. Neurosurg. Psychiatry, 29, 426-439. Dawson TM, Bredt DS, Fotuhi M, Hwang PM, Snyder SH (1991): Nitric oxide synthase and neuronal NADPH diaphorase are identical in brain and peripheral tissues. Proc. Nat. Acad. Sci. USA, 88, 7797-7801. DeLong MR (1990): Primate models of movement disorders of basal ganglia origin. Trends Neurosci., 13, 281-285. Deniau JM, Chevalier G (1985): Disinhibtion as a basic process in the expression of striatal functions. II. the striato-nigral influence on thalamocortical cells of the ventromedial thalamic nucleus. Brain Res., 334, 227-233. Deniau JM, Chevalier G (1992): The lamellar organization of the rat substantia nigra pars reticulata: distribution of projection neurons. Neuroscience, 46, 361-377. Deniau JM, Feger J, LeGuyader C (1976): Striatal evoked inhibition of identified nigro-thalamic neurons. Brain Res., 104, 152-156. DeVito JL, Anderson ME (1982): An autoradiographic study of efferent connections of the globus pallidus in macaca mulatta. Exp. Brain Res., 46, 107-117. DeVito JL, Anderson ME, Walsh KE( (1980): A horseradish peroxidase study of afferent connections of the globus pallidus in macaca mulatta. Exp. Brain Res., 33, 65-73. DiFiglia M (1987): Synaptic organization of cholinergic neurons in the monkey neostriatum. J. Comp. Neurol., 255, 245-258.

459

Ch. H

C. R. G e r f en a n d C. J. Wilson

DiFiglia M, Carey J (1986): Large neurons in the primate neostriatum examined with the combined Golgielectron microscopic method. J. Comp. Neurol., 244, 36-52. Difiglia M, Rafols JA (1988): Synaptic organization of the globus pallidus. J. Electron Microsc. Tech., 10, 247-263. DiFiglia M, Pasik P, Pasik T (1976): A Golgi study of neuronal types in the neostriatum of monkeys. Brain Res., 114, 245-256. DiFiglia M, Aronin N, Martin JB (1982): Light and electron microscopic localization of immunoreactive Leu-enkephalin in the monkey basal ganglia. J. Neurosci., 2, 303-320. Difiglia M, Pasik P, Pasik T (1982): A Golgi and ultrastructural study of the monkey globus pallidus. J. Comp. Neurol., 212, 53-75. Donoghue JP, Herkenham M (1986): Neostriatal projections from individual cortical fields conform to histochemically distinct striatal compartments in the rat. Brain Res., 365, 397-403. Donoghue JP, Kitai ST (1981): A collateral pathway to the neostriatum from corticofugal neurons of the rat sensory-motor cortex: an intracellular HRP study. J. Comp. Neurol., 210, 1-13. Dragunow M, Robertson GS, Faull RL, Robertson HA, Jansen K (1990): D2 dopamine receptor antagonists induce fos and related proteins in rat striatal neurons. Neuroscience, 37, 287-294. Dube L, Smith AD, Bolam JP (1988): Identification of synaptic terminals of thalamic or cortical origin in contact with distinct medium-size spiny neurons in the rat neostriatum. J. Comp. Neurol., 267, 455-471. Dure L, Young AB, Penney JJ (1992): Compartmentalization of excitatory amino acid receptors in human striatum. Proc. Nat. Acad. Sci. USA, 89, 7688-7692. Eghbali M, Santoro C, Paredes W, Gardner EL, Zukin RS (1987): Visualization of multiple opioid-receptor types in rat striatum after specific mesencephalic lesions. Proc. Nat. Acad. Sci. USA, 84, 6582-6586. Elde R, Schalling M, Ceddatelli S, Nakanishi S, H6kfelt T (1990): Localization of neuropeptide receptor mRNA in rat brain: initial observations using probes for neurotensin and substance P receptors. Neurosci. Lett., 120, 134-138. Evans CJ, Keith DJ, Morrison H, Magendzo K, Edwards RH (1992): Cloning of a delta opioid receptor by functional expression [see comments] Science, 258, 1952-1955. Falls WM, Park MR, Kitai ST (1982): An intracellular HRP study of the rat globus pallidus. II. Fine structural characteristics and synaptic connections fo medially located large GP neurons. J. Comp. Neurol., 220, 229-245. Fen61on G, Francois C, Percheron G, Yelnik J (1990): Topographic distribution of pallidal neurons projecting to the thalamus in macaques. Brain Res., 520, 27-35. Ferre S, O'Connor WT, Fuxe K, Ungerstedt U (1993): The striopallidal neuron: a main locus for adenosinedopamine interactions in the brain. J. Neurosci., 13, 5402-5406. Fibiger HC (1982): The organizatoin and some projections of cholinergic neurons of the mammalian forebrain. Brain Res. Rev., 4, 327-338. Filion M, Tremblay L (1991): Abnormal spontaneous activity of globus pallidus neurons in monkeys with MPTP-induced parkinsonism. Brain Res., 547, 142-151. Flaherty AW, Graybiel AM (1991): Corticostriatal transformations in the primate somatosensory system. Projections from physiologically mapped body-part representations. J. Neurophysiol., 66, 1249-1263. Flaherty AW, Graybiel AM (1993a): Output architecture of the primate putamen. J. Neurosci., 13, 3222-3237. Flaherty AW, Graybiel AM (1993b): Two input systems for body representations in the primate striatal matrix: experimental evidence in the squirrel monkey. J. Neurosci., 13, 1120-1137. Fox CA, Rafols JA (1976): The striatal efferents in the globus pallidus and substantia nigra. In: Yahr MD (Ed.) The Basal Ganglia, pp 37-55. Raven Press, New York. Fox CA, Andrade AN, Hillman DE, Schwyn RC (1971): The spiny neurons in the primate striatum: A Golgi and electron microscopic study. J. Hirnforsch., 13, 181-201. Francois C, Percheron G, Yelnik J, Heyner S (1984): A Golgi analysis of the primate globus pallidus. I. Inconstant processes of large neurons, other neuronal types, and afferent axons. J. Comp. Neurol., 227, 182-199. Francois C, Yelnik J, Percheron G (1987): Golgi study of the primate substantia nigra. II. Spatial organization of dendritic arborizations in relation to the cytoarchitectonic boundaries and to the striatonigral bundle. J. Comp. Neurol., 265, 473-493. Freund TF, Powell JF, Smith AD (1984): Tyrosine hydroxylase-immunoreactive boutons in synaptic contact with identified striatonigral neurons, with particular reference to dendritic spines. Neuroscience, 13, 1189- 1215. Gerfen CR (1984): The neostriatal mosaic: compartmentalization of corticostriatal input and striatonigral output systems. Nature, 311,461-464. Gerfen CR (1985): The neostriatal mosaic. I. Compartmental organization of projections from the striatum to the substantia nigra in the rat. J. Comp. Neurol., 236, 454-476.

460

The basal ganglia

Ch. H

Gerfen CR (1989): The neostriatal mosaic: striatal patch-matrix organization is related to cortical lamination. Science, 246, 385-388. Gerfen CR (1991): Substance P (neurokinin-1) receptor mRNA is selectively expressed in cholinergic neurons in the striatum and basal forebrain. Brain Res., 556, 165-170. Gerfen CR (1992): The neostriatal mosaic: multiple levels of compartmental organization. Trends Neurosci., 15, 133-139. Gerfen CR, Young WS (1988): Distribution of striatonigral and striatopallidal peptidergic neurons in both patch and matrix compartments: an in situ hybridization histochemistry and fluorescent retrograde tracing study. Brain Res., 460, 161-167. Gerfen CR, Staines WA, Arbuthnott GW, Fibiger HC (1982): Crossed connections of the substantia nigra in the rat. J. Comp. Neurol., 207, 283-303. Gerfen CR, Baimbridge KG, Miller JJ (1985): The neostriatal mosaic: compartmental distribution of calciumbinding protein and parvalbumin in the basal ganglia of the rat and monkey. Proc. Nat. Acad. Sci. USA, 82, 8780-8784. Gerfen CR, Baimbridge KG, Thibault J (1987): The neostriatal mosaic: III. Biochemical and developmental dissociation of patch-matrix mesostriatal systems. J. Neurosci., 7, 3935-3944. Gerfen CR, Herkenham M, Thibault J (1987): The neostriatal mosaic: II. Patch- and matrix-directed mesostriatal dopaminergic and non-dopaminergic systems. J. Neurosci., 7, 3915-3934. Gerfen CR, Engber TM, Mahan LC, Susel Z, Chase TN, Monsma FJ, Sibley DR (1990): D 1 and D2 dopamine receptor-regulated gene expression of striatonigral and striatopallidal neurons [see comments]. Science, 250, 1429-1432. Gerfen CR, McGinty JF, Young WS (1991): Dopamine differentially regulates dynorphin, substance P, and enkephalin expression in striatal neurons: in situ hybridization histochemical analysis. J. Neurosci., 11, 1016-1031. Goldman PS, Nauta WJH (1977): An intricately patterned prefronto-caudate projection in the rhesus monkey. J. Comp. Neurol., 171, 369-385. Gonzales C, Chesselet MF (1990): Amygdalonigral pathway: an anterograde study in the rat with Phaseolus vulgaris leucoagglutinin (PHA-L). J. Comp. Neurol., 297, 182-200. Graybiel AM, C.W. Ragsdale J (1978): Histochemically distinct compartments in the striatum of human, monkey and cat demonstrated by acetylcholinesterase staining. Proc. Nat. Acad. Sci. USA, 75, 57235726. Graybiel AM, Chesselet MF (1984): Compartmental distribution of striatal cell bodies expressing [Met]enkephalin-like immunoreactivity. Proc. Nat. Acad. Sci. USA, 81, 7980-7984. Graybiel AM, Ragsdale CJ, Yoneoka ES, Elde RP (1981): An immunohistochemical study of enkephalins and other neuropeptides in the striatum of the cat with evidence that the opiate peptides are arranged to form mosaic patterns in register with the striosomal compartments visible by acetylcholinesterase staining. Neuroscience, 6, 377-397. Graybiel AM, Moratalla R, Robertson HA (1990): Amphetamine and cocaine induce drug-specific activation of the c-fos gene in striosome-matrix compartments and limbic subdivisions of the striatum. Proc. Nat. Acad. Sci. USA, 87, 6912-6916. Groenewegen HJ (1988): Organization of the afferent connections of the mediodorsal thalamic nucleus in the rat, related to the mediodorsal-prefrontal topography. Neuroscience, 24, 379-431. Groenewegen HJ, Russchen FT (1984): Organization of the efferent projections of the nucleus accumbens to pallidal, hypothalamic, and mesencephalic structures: a tracing and immunohistochemical study in the cat. J. Comp. Neurol., 223, 347-367. Groenewegen HJ, Berendse HW, Haber SN (1993): Organization of the output of the ventral striatopallidal system in the rat: ventral pallidal efferents. Neuroscience, 57, 113-142. Grofov~ I (1975): The identification of striatal and pallidal neurons projecting to substantia nigra. An experimental study by means of retrograde axonal transport of horseradish peroxidase. Brain Res., 91, 286-291. Grofov~t I (1979): Types of striatonigral neurons labeled by retrograde transport of horseradish peroxidase. Appl. Neurophysiol., 42, 25-28. Grofova I, Deniau JM, Kitai ST (1982): Morphology of the substantia nigra pars reticulata projection neurons intracellularly labeled with HRE J. Comp. Neurol., 208, 352-368. Grove EA, Domesick VB, Nauta WJH (1986): Light microscopic evidence of striatal input to intrapallidal neurons of cholinergic cell group Ch4 in the rat: a study employing the anterograde tracer Phaseolus vulgaris leucagglutinin (PHA-L). Brain Res., 367, 379-384. Haber SN, Watson SJ (1983): The comparison between enkephalin-like and dynorphin-like immunoreactivity in both monkey and human globus pallidus and substantia nigra. Life Sci., 1, 33-36.

461

Ch. H

C R. G e r f en and C J. Wilson

Haber SN, Groenewegen HJ, Grove EA, Nauta WJ (1985): Efferent connections of the ventral pallidum: evidence of a dual striato pallidofugal pathway. J. Comp. Neurol., 235, 322-335. Haber SN, Lynd BE, Mitchell SJ (1993): The organization of the descending ventral pallidal projections in the monkey. J. Comp. Neurol., 329, 111-128. Hanson GR, Alphs L, Pradham S, Lovenberg W (1981): Haloperidol-induced reduction of nigral substance P-like immunoreactivity: a probe for the interactions between dopamine and substance P neuronal systems. J. Pharmacol. Exp. Ther., 218, 568-574. Hanson GR, Merchant KM, Letter AA, Bush L, Gibb JW (1987): Methamphetamine-induced changes in the striato-nigral dynorphin sytem: role of D-1 and D-2 receptors. Eur. J. Pharmacol., 144, 245-246. Hattori T, McGeer EG, McGeer PL (1978): Fine structural analysis of cortico-striatal pathway. J. Comp. Neurol., 185, 347-354. Hedreen JC, DeLong MR (1991): Organization of striatopallidal, striatonigral, and nigrostriatal projections in the macaque. J. Comp. Neurol., 304, 569-595. Heimer L, Wilson RD (1975): The subcortical projections of the allocortex: similarities in the neural associations of the hippocampus, the piriform cortex, and the neocortex. In: Santini M (Ed.), Golgi Centennial Symposium, pp 177-193. Raven Press, New York. Herkenham M (1979): The afferent and efferent connections of the ventromedial thalamic nucleus in the rat. J. Comp. Neurol., 183, 487-518. Herkenham M, Nauta WJH (1979): Efferent connections of the habenular nuclei in the rat. J. Comp. Neurol., 187, 19-48. Herkenham M, Pert CB (1981): Mosaic distribution of opiate receptors, parafascicular projections and acetylcholinesterase in rat striatum. Nature, 291,415-418. Herkenham M, Pert CB (1982): Light microscopic localization of brain opiate receptors: a general autoradiographic method which preserves tissue quality. J. Neurosci., 2, 1129-1149. Herkenham M, Lynn AB, Johnson MR, Melvin LS, Costa BRD, Rice K (1991): Characterization and localization of cannabinoid receptors in rat brain: a quantitative in vitro autoradiographic study. J. Neurosci., 11,563-583. Hikosaka O, Wurtz RH (1983a): Visual and oculomotor functions of monkey substantia nigra pars reticulata. I. Relation of visual and auditory responses to saccades. J. Neurophysiol., 49, 1230-1253. Hikosaka O, Wurtz RH (1983b): Visual and oculomotor functions of monkey substantia nigra pars reticulata. IV. Relation of substantia nigra to superior colliculus. J. Neurophysiol., 49, 1285-1301. H6kfelt T, Elde R, Johansson O, Terenius L, Stein L (1977): Distribution of enkephalin immunoreactive cell-bodies in the rat central nervous system. Neurosci. Lett., 5, 25-31. Holsapple JW, Preston JB, Strick PL (1991): The origin of thalamic inputs to the hand representation in the primary motor cortex. J. Neurosci., 11, 2644-2654. Hong JS, Yang H-YT, Costa E (1977): Projections of substance P containing neurons from neostriatum to substantia nigra. Brain Res., 121, 541-544. Hong JS, Yang H-YT, Costa E (1978a): Substance P content of substantia nigra after chronic treatment with antischizophrenic drugs. Neuropharmacol., 17, 83-85. Hong JS, Yang H-YT, Fratta W, Costa E (1978b): Rat striatal methionine-enkephalin content after chronic treatment with cataleptogenic and noncataleptogenic drugs. J. Pharmacol. Exp. Ther., 205, 141-147. Hong JS, Yoshikawa K, Kanamatsu T, Sabol SL (1985): Modulation of striatal enkephalinergic neurons by antipsychotic drugs. Fed. Proc., 44, 2535-2539. Hoover JE, Strick PL (1993): Multiple output channels in the basal ganglia. Science, 259, 819-821. Ilinsky IA, Jouandet ML, Goldman-Rakic PS (1985): Organization of the nigrothalamocortical system in the rhesus monkey. J. Comp. Neurol., 236, 315-330. Ingham CA, Bolam JP, Wainer BH, Smith AD (1985): A correlated light and electron microscopic study of identified cholinergic basal forebrain neurons that project to the cortex in the rat. J. Comp. Neurol., 239, 176-192. Ingham CA, Bolam JP, Smith AD (1988): GABA-immunoreactive synaptic boutons in the rat basal forebrain: comparison of neurons that project to the neocortex with pallidosubthalamic neurons. J. Comp. Neurol., 273, 263-282. Izzo PN, Bolam JP (1988): Cholinergic synaptic input to different parts of spiny striatonigral neurons in the rat. J. Comp. Neurol., 269, 219-234. Jahanshahi M, Brown RG, Marsden CD (1993): A comparative study of simple and choice reaction time in Parkinson's, Huntington's and cerebellar disease. J. Neurol. Neurosurg. Psychiatry, 56, 1169-1177. Jimenez CJ, Graybiel AM (1987): Subdivisions of the dopamine-containing A8-A9-A10 complex identified by their differential mesostriatal innervation of striosomes and extrastriosomal matrix. Neuroscience, 23, 223-242.

462

The basal ganglia

Ch. H

Jimenez CJ, Graybiel AM (1989): Compartmental origins of striatal efferent projections in the cat. Neuroscience, 32, 297-321. Jinnai K, Matsuda Y (1979): Neurons of the motor cortex projecting commonly on the caudate nucleus and the lower brainstem in the cat. Neurosci. Lett., 13, 121-126. Jones EG (1984). Laminar distribution of cortical efferent cells. In: Cerebral Cortex, Vol. 1: Cellular Components of the Cerebral Cortex. 521-553. Plenum Press, New York. Kanazawa I, Emson PC, Emson AC (1977): Evidence for the existence of substance P-containing fibers in the striato-nigral and pallido-nigral pathways in rat brain. Brain Res., 119, 447-453. Kawaguchi Y (1992): Large aspiny cells in the matrix of the rat neostriatum in vitro: physiological identification, relation to the compartments and excitatory postsynaptic currents. J. Neurophysiol., 67, 1669-1682. Kawaguchi Y (1993): Physiological, morphological, and histochemical characterization of three classes of ir,terneurons in rat neostriatum. J. Neurosci., 13, 4908-4923. Kawaguchi Y, Kubota Y (1993): Correlation of physiological subgroupings of nonpyramidal cells with parvalbumin- and calbindinD28k-immunoreactive neurons in layer V of rat frontal cortex. J. Neurophysiol., 70, 387-396. Kawaguchi Y, Wilson CJ, Emson PC (1989): Intracellular recording of identified neostriatal patch and matrix spiny cells in a slice preparation preserving cortical inputs. J. Neurophysiol., 62, 1052-1068. Kawaguchi Y, Wilson CJ, Emson PC (1990): Projection subtypes of rat neostriata! matrix ceils revealed by intracellular injection of biocytin. J. Neurosci., 10, 3421-3438. Kemp JM, Powell TPS (1970): The cortico-striate projection in the monkey. Brain, 93, 525-546. Kemp JM, Powell TPS (1971): The structure of the caudate nucleus of the cat: Light and electron microscopic study. Phil. Trans. R. Soc. Lond. (Biol.), 262, 383-401. Kievet J, Kuypers HGJM (1977): Organization of the thalamocortical connections to the frontal lobe in the rhesus monkey. Exp. Brain Res., 29, 229-322. Kita H (1993): GABAergic circuits of the striatum. Progr. Brain Res., 99, 51-72. Kita H, Kitai ST (1987): Efferent projections of the subthalamic nucleus in the rat: light and electron microscopic analysis with the PHA-L method. J. Comp. Neurol., 260, 435-452. Kita H, Kitai ST (1988): Glutamate decarboxylase immunoreactive neurons in rat neostriatum: their morphological types and populations. Brain Res., 447, 346-352. Kita H, Kitai ST (1991): Intracellular study of rat globus pallidus neurons: membrane properties and responses to neostriatal, subthalamic and nigral stimulation. Brain Res., 564, 296-305. Kita H, Kitai S (1994a): Parvalbuminin-immunoreactive neurons in rat globus pallidus: a light and electron microscopic study. Brain Res., 657, 31-41. Kita H, Kitai ST (1994b): The morphology of globus pallidus projection neurons in the rat: an intracellular staining study. Brain Res., 636, 308-319. Kita H, Chang HT, Kitai ST (1983a): The morphology of intracellularly labeled rat subthalamic neurons: a light microscopic analysis. J. Comp. Neurol., 215, 245-257. Kita H, Chang HT, Kitai ST (1983b): Pallidal inputs to subthalamus: intracellular analysis. Brain Res., 264, 255-265. Kita H, Kosaka T, Heizmann CW (1990): Parvalbumin-immunoreactive neurons in the rat neostriatum: a light and electron microscopic study. Brain Res., 536, 1-15. Kitai ST, Koscis JD, Preston RJ, Sugimori M (1976): Monosynaptic inputs to caudate neurons identified by intracellular injection of horseradish peroxidase. Brain Res., 109, 601-606. K611iker A (1896). Handbuch der Gewebelehre des Menschen. Bd. II.: Kubota Y, Kawaguchi Y (1993): Spatial distributions of chemically identified intrinsic neurons in relation to patch and matrix compartments of rat neostriatum. J. Comp. Neurol., 332, 499-513. Kubota Y, Mikawa S, Kawaguchi Y (1993): Neostriatal GABAergic interneurones contain NOS, calretinin or parvalbumin. Neuroreport, 5, 205-208. Kunzle H (1975): Bilateral projections from precentral motor cortex to the putamen and other parts of the basal ganglia. An autoradiographic study in Macaca fascicularis. Brain Res., 88, 195-209. Kunzle H (1977): Projections from the primary somatosensory cortex to basal ganglia and thalamus in the monkey. Exp. Brain Res., 30, 481-492. Kunzle H (1978): An autoradiographic analysis of the efferent connections from premotor and adjacent prefrontal regions (areas 6 and 9) in macaca fascicularis. Brain Behav. Evol., 15, 185-234. Kunzle H, Akert K (1977): Efferent connections of cortical, area 8 (frontal eye field) in Macaca fascicularis. A reinvestigation using the autoradiographic technique. J. Comp. Neurol., 173, 147-164. Landry P, Wilson CJ, Kitai ST (1984): Morphological and electrophysiological characteristics of pyramidal tract neurons in the rat. Exp. Brain Res., 177-190.

463

Ch. H

C R. G e r f en a n d C J. Wilson

Langer LF, Graybiel AM (1989): Distinct nigrostriatal projection systems innervate striosomes and matrix in the primate striatum. Brain Res., 498, 344-350. LeMoine C, Normand E, Guitteny AF, Fouque B, Teoule R, Bloch B (1990): Dopamine receptor gene expression by enkephalin neurons in rat forebrain. Proc. Nat. Acad. Sci. USA, 87, 230-234. Le Moine C, Normand E, Bloch B (1991): Phenotypical characterization of the rat striatal neurons expressing the D1 dopamine receptor gene. Proc. Nat. Acad. Sci. USA, 88, 4205-4209. Li SJ, Sivam SP, Hong JS (1986): Regulation of the concentration of dynorphin A(1-8) in the striatonigral pathway by the dopaminergic system. Brain Res., 398, 390-392. Li SJ, Sivam SP, McGinty JF, Douglass J, Calavetta L, Hong JS (1988): Regulation of the metabolism of striatal dynorphin by the dopaminergic system. J. Pharmacol. Exp. Ther., 246, 403-408. Loopuijt LD, Kooy Dvd (1985): Organization of the striatum: collateralization of its efferent axons. Brain Res., 348, 86-99. Mailleux P, Vanderhaeghen JJ (1992): Distribution of neuronal cannabinoid receptor in the adult rat brain: a comparative receptor binding radioautography and in situ hybridization histochemistry. Neuroscience, 48, 655-668. Mailleux P, Vanderhaeghen JJ (1993): Dopaminergic regulation of cannabinoid receptor mRNA levels in the rat caudate-putamen: an in situ hybridization study. J. Neurochem., 61, 1705-1712. Malach R, Graybiel AM (1986): Mosaic architecture of the somatic sensory-recipient sector of the cat's striatum. J. Neurosci., 6, 3436-3458. Mansour A, Khachaturian H, Lewis ME, Akil H, Watson SJ (1987): Autoradiographic differentiation of mu, delta, and kappa opioid receptors in the rat forebrain and midbrain. J. Neurosci., 7, 2445-2464. Martin LJ, Blackstone CD, Huganir RL, Price DL (1992): Cellular localization of a metabotropic glutamate receptor in rat brain. Neuron, 9, 259-270. Martin LJ, Blackstone CD, Huganir RL, Price DL (1993a): The striatal mosaic in primates: striosomes and matrix are differentially enriched in ionotropic glutamate receptor subunits. J. Neurosci., 13, 782-792. Martin LJ, Blackstone CD, Levey AI, Huganir RL, Price DL (1993b): AMPA glutamate receptor subunits are differentially distributed in rat brain. Neuroscience, 53, 327-358. Martin LJ, Blackstone CD, Levey AI, Huganir RL, Price DL (1993c): Cellular localizations of AMPA glutamate receptors within the basal forebrain magnocellular complex of rat and monkey. J. Neurosci., 13, 2249-2263. Matsuda LA, Bonner TI, Lolait SJ (1993): Localization ofcannabinoid receptor mRNA in rat brain. J. Comp. Neurol., 327, 535-550. McGeorge AJ, Faull RLM (1989): The organization of the projection from the cerebral cortex to the striatum of the rat. Neuroscience, 29, 503-537. McLean S, Rothman RB, Herkenham M (1986): Autoradiographic localization of mu- and delta-opiate receptors in the forebrain of the rat. Brain Res., 378, 49-60. Meng F, Xie GX, Thompson RC, Mansour A, Goldstein A, Watson SJ, Akil H (1993): Cloning and pharmacological characterization of a rat kappa opioid receptor. Proc. Nat. Acad. Sci. USA, 90, 9954-9958. Mercugliano M, Soghomonian JJ, Qin Y, Nguyen HQ, Feldblum S, Erlander MG, Tobin AJ, Chesselet MF (1992): Comparative distribution of messenger RNAs encoding glutamic acid decarboxylases (Mr 65,000 and Mr 67,000) in the basal ganglia of the rat. J. Comp. Neurol., 318, 245-254. Millhouse OE (1986): Pallidal neurons in the rat. J. Comp. Neurol., 254, 209-227. Mink JW, Thach WT (1991a): Basal ganglia motor control. I. Nonexclusive relation of pallidal discharge to five movement modes. J. Neurophysiol., 65, 273-300. Mink JW, Thach WT (1991 b): Basal ganglia motor control. II. Late pallidal timing relative to movement onset and inconsistent pallidal coding of movement parameters. J. Neurophysiol., 65, 301-329. Mink JW, Thach WT (1991 c): Basal ganglia motor control. III. Pallidal ablation: normal reaction time, muscle cocontraction, and slow movement. J. Neurophysiol., 65, 330-351. Mitchell IJ, Clarke CE, Boyce S, Robertson RG, Peggs D, Sambrook MA, Crossman AR (1989): Neural mechanisms underlying parkinsonian symptoms based upon regional uptake of 2-deoxyglucose in monkeys exposed to 1-methyl-4-phenyl- 1,2,3,6-tetrahydropyridine. Neuroscience, 32, 213-226. Mocchetti I, Schwartz JP, Costa E (1985): Use of mRNA hybridization and radioimmunoassay to study mechanisms of drug-induced accumulation of enkaphalins in rat brain structures. Mol. Pharmacol., 28, 86-91. Mogenson GJ, Ciriello J, Garland J, Wu M (1987): Ventral pallidum projections to mediodorsal nucleus of the thalamus: an anatomical and electrophysiological investigation in the rat. Brain Res., 404, 221-230. Munoz DE Wurtz RH (1992): Role of the rostral superior colliculus in active visual fixation and execution of express saccades. J. Neurophysiol., 67, 1000-1002.

464

The basal ganglia

Ch. H

Munoz DR Wurtz RH (1993): Fixation cells in monkey superior colliculus. I. Characteristics of cell discharge. J. Neurophysiol., 70, 559-575. Nakanishi H, Kita H, Kitai ST (1987a): Electrical membrane properties of rat subthalamic neurons in an in vitro slice preparation. Brain Res., 437, 35-44. Nakanishi H, Kita H, Kitai ST (1987b): Intracellular study of rat substantia nigra pars reticulata neurons in an in vitro slice preparation: electrical membrane properties and response characteristics to subthalamic stimulation. Brain Res., 437, 45-55. Nakanishi H, Kita H, Kitai ST (1988): An N-methyl-D-aspartate receptor mediated excitatory postsynaptic potential evoked in subthalamic neurons in an in vitro slice preparation of the rat. Neurosci. Lett., 95, 130-136. Nauta WJH, Mehler WR (1966): Projections of the lentiform nucleus in the monkey. Brain Res., 1, 3-42. Nauta WJH, Smith G, Faull RLM, Domesick VB (1978): Efferent connections and nigral afferents of the nucleus accumbens septi in the rat. Neuroscience, 3, 385-401. Oertel WH, Mugnaini E (1984): Immunocytochemical studies of GABAergic neurons in rat basal ganglia and their relations to other neuronal systems. Neurosci. Lett., 47, 233-238. Olson L, Seiger A, Fuxe K (1972): Heterogeneity of striatal and limbic dopamine innervation: highly fluorescent islands in developing and adult rats. Brain Res., 44, 283-288. Parent A, Hazrati L-N (1993): Anatomical aspects of information processing in primate basal ganglia. Trends Neurosci., 16, 111-116. Parent A, Hazrati L-N (1994): Multiple striatal representation in primate substantia nigra. J. Comp. Neurol., 344, 305-320. Park MR, Falls WM, Kitai ST (1982): An intracellular HRP study of the rat globus pallidus. I. Responses and light microscopic analysis. J. Comp. Neurol., 211,284-294. Parthasarathy HB, Schall JD, Graybiel AM (1992): Distributed but convergent ordering of corticostriatal projections: analysis of the frontal eye field and the supplementary eye field in the macaque monkey. J. Neurosci., 12, 4468-4488. Pasik P, Pasik T, Holstein GR, H/tmori J (1988): GABAergic elements in the neuronal circuits of the monkey neostriatum: a light and electron microscopic immunocytochemical study. J. Comp. Neurol., 270, 157-170. Penney GR, Wilson CJ, Kitai ST (1988): Relationship of the axonal and dendritic geometry of spiny projection neurons to the compartmental organization of the neostriatum. J. Comp. Neurol., 269, 275-289. Percheron G, Yelnik J, Francois C (1984): A Golgi analysis of the primate globus pallidus. III. Spatial organization of the striato-pallidal complex. J. Comp. Neurol., 227, 214-227. Pert CB, Kuhar MJ, Snyder SH (1976): Opiate receptor: autoradiographic demonstration of localization in rat brain. Proc. Nat. Acad. Sci. USA, 73, 3729-3733. Petralia RS, Yokotani N, Wenthold RJ (1994): Light and electron microscope distribution of the NMDA receptor subunit NMDAR 1 in the rat nervous system using a selective anti-peptide antibody. J. Neurosci., 14, 667-696. Pickel VM, Sumal KK, Beckley SC, Miller RJ, Reis DJ (1980): Immunocytochemical localization of enkephalin in the neostriatum of rat brain: a light and electron microscopic study. J. Comp. Neurol., 189, 721-740. Powell TPS, Cowan WM (1956): A study of thalamo-striate relations in the monkey. Brain, 79, 364-395. Rajakumar N, Elisevich K, Flumerfelt BA (1993): Compartmental origin of the striato-entopeduncular projection in the rat. J. Comp. Neurol., 331,286-296. Ram6n y Cajal S (1911). Histologie du SystOme Nerveux de l'Homme et des VertdbrOs. 2: 504-518. Rausell E, Jones EG (199 la): Chemically distinct compartments of the thalamic VPM nucleus in monkeys relay principal and spinal trigeminal pathways to different layers of the somatosensory cortex. J. Neurosci., 11, 226-237. Rausell E, Jones EG (199 lb): Histochemical and immunocytochemical compartments of the thalamic VPM nucleus in monkeys and their relationship to the representational map. J. Neurosci., 11,210-225. Rausell E, Bae CS, Vinuela A, Huntley GW, Jones EG (1992): Calbindin and parvalbumin cells in monkey VPL thalamic nucleus: distribution, laminar cortical projections, and relations to spinothalamic terminations. J. Neurosci., 12, 4088-4 111. Redgrave P, Marrow L, Dean P (1992): Topographical organization of the nigrotectal projection in rat: evidence for segregated channels. Neuroscience, 50, 571-595. Ribak CE, Vaughn JE, Roberts E (1979): The GABA neurons and their axon terminals in rat corpus striatum as demonstrated by GAD immunocytochemistry. J. Comp. Neurol., 187, 261-284. Richfield EK, Penney JB, Young AB (1989): Anatomical and affinity state comparisons between dopamine D1 and D2 receptors in the rat central nervous system. Neuroscience, 30, 767-777. Robeldo P, F6ger J (1990): Excitatory influence of rat subthalamic nucleus to substantia nigra pars reticulata and the pallidal complex: electrophysiological data. Brain Res., 518, 47-54.

465

Ch. H

C R. G e r f en a n d C J. Wilson

Robertson GS, Fibiger HC (1992): Neuroleptics increase c-fos expression in the forebrain: contrasting effects of haloperidol and clozapine. Neuroscience, 46, 315-328. Robertson HA, Peterson MR, Murphy K, Robertson GS (1989): D l-dopamine receptor agonists selectively activate striatal c-fos independent of rotational behaviour. Brain Res., 503, 346-349. Robertson GS, Vincent SR, Fibiger HC (1990): Striatonigral projection neurons contain D1 dopamine receptor-activated c-fos. Brain Res., 523, 288-290. Royce GJ (1983): Cortical neurons with collateral projections to both caudate nucleus and the centromedianparafascicular thalamic complex: a fluorescent retrograde double labeling study in the cat. Exp. Brain Res., 50, 157-165. Saper CB (1984): Organization of cerebral cortical afferent systems in the rat. II. Magnocellular basal nucleus. J. Comp. Neurol., 222, 313-342. Schell GR, Strick PL (1984): The origin of thalamic inputs to the arcuate premotor and supplementary motor areas. J. Neurosci., 4, 539-560. Schiffmann SN, Vanderhaeghen JJ (1993): Adenosine A2 receptors regulate the gene expression of striatopallidal and striatonigral neurons. J. Neurosei., 13, 1080-1087. Seeburg PH, Wisden W, Verdoorn TA, Pritchett DB, Werner P, Herb A, Luddens H, Sprengel R, Sakmann B (1990): The GABAA receptor family: molecular and functional diversity. Cold Spring Harbor Symp. Quant. Biol., 55, 29-40. Selemon LD, Goldman-Rakic PS (1985): Longitudinal topography and interdigitation of corticostriatal projections in the rhesus monkey. J. Neurosci., 5, 776-794. Shivers BD, Killisch I, Sprengel R, Sontheimer H, Kohler M, Schofield PR, Seeburg PH (1989): Two novel GABAA receptor subunits exist in distinct neuronal subpopulations. Neuron, 3, 327-337. Smith Y, Bolam JP (1989): Neurons of the substantia nigra reticulata receive a dense GABA-containing input from the globus pallidus in the rat. Brain Res., 493, 160-167. Smith Y, Bolam JP (1990): The output neurones and the dopaminergic neurones of the substantia nigra receive a GABA-containing input from the globus pallidus in the rat. J. Comp. Neurol., 296, 47-64. Smith Y, Bolam JP (1991): Convergence of synaptic inputs from the striatum and the globus pallidus onto identified nigrocollicular cells in the rat: a double anterograde labelling study. Neuroscience, 44, 45-73. Smith Y, Parent A (1986): Neuropeptide Y-immunoreactive neurons in the striatum of the cat and monkey: morphological characteristics, intrinsic organization and co-localization with somatostatin. Brain Res., 372, 241-252. Smith Y, Parent A, Seguela P, Descarries L (1987): Distribution of GABA-immunoreactive neurons in the basal ganglia of the squirrel monkey (Samiri sciureus). J. Comp. Neurol., 259, 50-61. Smith Y, Bolam JP, Von Krosigk M (1990): Topographical and synaptic organization of the GABA-containing pallidosubthalamic projection in the rat. Eur. J. Neurosci., 2, 500-511. Somogyi P, Bolam JP, Smith AD (1981): Monosynaptic cortical input and local axon collaterals of identified striatonigral neurons. A light and electron microscopic study using the Golgi-peroxidase transport-degeneration procedure. J. Comp. Neurol., 195, 567-584. Spencer HJ (1976): Antagonism of cortical excitation of striatal neurons by glutamic acid diethylester: evidence for glutamic acid as an excitatory transmitter in the rat striatum. Brain Res., 102, 91-101. Staines WA, Fibiger HC (1984): Collateral projections of neurons of the rat globus pallidus to the striatum and substantia nigra. Exp. Brain Res., 56, 217-220. Staines WA, Atmadja S, Fibiger HC (1981): Demonstration of a pallidostriatal pathway by retrograde transport of HRP-labeled lectin. Brain Res., 206, 446-450. Steiner H, Gerfen CR (1993): Cocaine-induced c-fos messenger RNA is inversely related to dynorphin expression in striatum. J. Neurosci., 13, 5066-5081. Strick PL (1985): How do the basal ganglia and cerebellum gain access to the cortical motor areas? Behav. Brain Res., 18, 107-123. Surmeier DJ, Eberwine J, Wilson CJ, Cao Y, Stefani A, Kitai ST (1992): Dopamine receptor subtypes colocalize in rat striatonigral neurons. Proc. Nat. Acad. Sci. USA, 89, 10178-10182. Swanson L, Cowan W (1975): A note on the connections and development of the nucleus accumbens. Brain Res., 92, 324-330. Takagi H, Somogyi P, Somogyi J, Smith AD (1983): Fine structural studies on a type of somatostatinimmunoreactive neuron and its synaptic connections in the rat neostriatum: a correlated light and electron microscopic study. J. Comp. Neurol., 214, 1-16. Tang F, Costa E, Schwartz JP (1983): Increase ofproenkephalin mRNA and enkephalin content of rat striatum after daily injection of haloperidol for 2 to 3 weeks. Proc. Nat. Acad. Sci. USA, 80, 3841-3844. Tempel A, Zukin RS (1987): Neuroanatomical patterns of the mu, delta, and kappa opioid receptors of rat brain as determined by quantitative in vitro autoradiography. Proc. Nat. Acad. Sci. USA, 84, 4308-4312.

466

The basal ganglia

Ch. H

Tennyson VM, Barrett RE, Cohen G, Cote L, Heikkila R, Mytilneou C (1972): The developing neostriatum of the rabbit: correlation of fluorescence histochemistry, electron microscopy, endogenous dopamine levels, and [3H]dopamine uptake. Brain Res., 46, 251-285. Tepper JM, Sawyer SF, Groves PM (1987): Electrophysiologically identified nigral dopaminergic neurons intracellularly labeled with HRP: light-microscopic analysis. J. Neurosci., 7, 2794-2806. Thompson RC, Mansour A, Akil H, Watson SJ (1993): Cloning and pharmacological characterization of a rat mu opioid receptor. Neuron, 11,903-913. Trugman JM, Wooten GF (1987): Selective D1 and D2 dopamine agonists differentially alter basal ganglia glucose utilization in rats with unilateral 6-hydroxydopamine substantia nigra lesions. J. Neurosci., 7, 2927-2935. Van der Kooy D, Carter D (1981): The organization of the efferent projections and striatal afferents of the entopeduncular nucleus and adjacent areas in the rat. Brain Res., 211, 15-36. Vincent SR, H6kfelt T, Christensson I, Terenius L (1982a): Dynorphin-immunoreactive neurons in the central nervous system of the rat. Neurosci. Lett., 33, 185-190. Vincent SR, H6kfelt T, Christensson I, Terenius L (1982b): Immunohistochemical evidence for a dynorphin immunoreactive striatonigral pathway. Eur. J. Pharmacol., 85, 251-252. Vincent SR, Johansson O, H6kfelt T, Skirboll L, Elde RE Terenius L, Kimmel J, Goldstein M (1983a): NADPH-diaphorase: a selective histochemical marker for striatal neurons containing both somatostatinand avian pancreatic polypeptide (APP-) like immunoreactivity. J. Comp. Neurol., 217, 252-263. Vincent SR, Staines WA, Fibiger HC (1983b): Histochemical demonstration of separate populations of somatostatin and cholinergic neurons in the rat striatum. Neurosci. Lett., 35, 111-114. Voorn P, Jorritsma-Byham B, Dijk CV, Buijs RM (1986): The dopaminergic innervation of the ventral striatum in the rat: a light- and electron-microscopical study with antibodies against dopamine. J. Comp. Neurol., 251, 84-99. Voorn P, Gerfen CR, Groenewegen HJ (1989): Compartmental organization of the ventral striatum of the rat: immunohistochemical distribution of enkephalin, substance P, dopamine, and calcium-binding protein. J. Comp. Neurol., 289, 189-201. Webster KE (1961): Cortico-striate interrelations in the albino rat. J. Anat., 95, 532-544. Weiner DM, Levey AI, Brann MR (1990): Expression of muscarinic acetylcholine and dopamine receptor mRNAs in rat basal ganglia. Proc. Nat. Acad. Sci. USA, 87, 7050-7054. Wilson CJ (1986): Postsynaptic potentials evoked in spiny neostriatal projection neurons by stimulation of ipsilateral and contralateral neocortex. Brain Res., 367, 201-13. Wilson CJ (1987): Morphology and synaptic connections of crossed corticostriatal neurons in the rat. J. Comp. Neurol., 263, 567-580. Wilson CJ, Groves PM (1980): Fine structure and synaptic connections of the common spiny neuron of the rat neostriatum: a study employing intracellular inject of horseradish peroxidase. J. Comp. Neurol., 194, 599-615. Wilson CJ, Phelan KD (1982): Dual topographic representation of neostriatum in the globus pallidus of rats. Brain Res., 243, 354-359. Wilson CJ, Chang HT, Kitai ST (1990): Firing patterns and synaptic potentials of identified giant aspiny interneurons in the rat neostriatum. J. Neurosci., 10, 508-519. Wisden W, Laurie DJ, Monyer H, Seeburg PH (1992): The distribution of 13 GABAA receptor subunit mRNAs in the rat brain. I. Telencephalon, diencephalon, mesencephalon. J. Neurosci., 12, 1040-1062. Xu ZC, Wilson CJ, Emson PC (1989): Restoration of the corticostriatal projection in rat neostriatal grafts: electron microscopic analysis. Neuroscience, 29, 539-550. Xu ZC, Wilson CJ, Emson PC (1991): Restoration of thalamostriatal projections in rat neostriatal grafts: an electron microscopic analysis. J. Comp. Neurol., 303, 22-34. Yelnik J, Percheron G (1979): Subthalamic neurons in primates: a quantitative and comparative analysis. Neuroscience, 4, 1717-1743. Yelnik J, Percheron G, Francois C (1984): A Golgi analysis of the primate globus pallidus. II. Quantitative morphology and spatial orientation of dendritic arborizations. J. Comp. Neurol., 227, 200-213. Yelnik J, Francois C, Percheron G, Heyner S (1987): Golgi study of the primate substantia nigra. I. Quantitative morphology and typology of nigral neurons. J. Comp. Neurol., 265, 455-472. Yelnik J, Francois C, Percheron G, Tande D (1991): Morphological taxonomy of the neurons of the primate striatum. J. Comp. Neurol., 313, 273-294. Yeterian EH, Hoesen GWV (1978): Cortico-striate projections in the rhesus monkey: The organization of certain cortico-caudate connections. Brain Res., 139, 43-63. Yoshida M, Precht W (1971): Monosynaptic inhibtion of neurons of the substatia nigra by caudato-nigral fibers. Brain Res., 32, 225-228.

467

Ch. H

C R. G e r f en and C J. Wilson

Young ST, Porrino LJ, Iadarola MJ (1991): Cocaine induces striatal c-Fos-immunoreactive proteins via dopaminergic D~ receptors. Proc. Nat. Acad. Sci. USA, 88, 1291-1295. Young WS III, Bonner TI, Brann MR (1986): Mesencephalic dopaminergic neurons regulate the expression of neuropeptide mRNAs in the rat forebrain. Proc. Natl. Acad. Sci. USA, 83, 9827-9831. Zhang JH, Sato M, Tohyama M (1991): Different postnatal development profiles of neurons containing distinct GABAA receptor beta subunit mRNAs (ill, f12, and f13) in the rat forebrain. J. Comp. Neurol., 3O8, 586-613.

468