Electrophysiological properties of basal ganglia synaptic relations

Pharmac. Therap. B, 1975, Vol. 1, No. I, pp. 17-38.

Pergamon Press.

Printed in Great Britain

Specialist Subject Editor: O. HORNYKIEWICZ

ELECTROPHYSIOLOGICAL PROPERTIES OF BASAL GANGLIA SYNAPTIC RELATIONS* DOMINICK P. PURPURA Department of Anatomy and the Rose F. Kennedy Center[or Research in Mental Retardation and Human Development, Albert Einstein College of Medicine, Yeshiva University, Bronx, N. Y.

1. INTRODUCTION The earliest electrophysiological studies of the basal ganglia established (a) that the striatum participates in the generalized electrographic effects elicited by stimulation of medial and intralaminar thalamic nuclei (Jasper, 1949; Shimamoto and Verzeano, 1954; Starzl and Magoun, 1951; Stoupel and Terzuolo, 1954); (b) that gross evoked potentials and extracellular unit discharges are recorded from various components of the corpus striatum following appropriate peripheral stimulation (Albe-Fessard et al., 1960a, b; Segundo and Machne, 1956); and (c) that electrical stimulation of the caudate activates a variety of diencephalic neuronal organizations (Buchwald et al., 1961; Laursen, 1963; Purpura et ai., 1958). Following these initial investigations, electrophysiological studies involving largely extracellular recording from basal ganglia and related neuronal systems demonstrated relatively long-latency unit discharges of caudate neurons following stimulation of widespread areas of neocortex (Rocha-Miranda, 1965), peripheral pathways (Sedgwick and Williams, 1967) and the dentate nucleus (Ratcheson and Li, 1969). Similar types of unit responses were observed in pallidal neurons following cortical and peripheral stimulation (Noda et al., 1968). Electrical stimulation of the striopallidum was shown to have prominent inhibitory effects on peripherally evoked nonspecific responses recorded from medial diencephalic structures (Feltz et al., 1967; Krauthamer and Albe-Fessard, 1965) and stimulation of the putamen and pallidum was shown to reproduce the pattern of recruiting responses in cortex (Dieckman and Sasaki, 1970) that was originally described following low-frequency stimulation of medial and intralaminar thalamic regions (Dempsey and Morison, 1942; Morison and Dempsey, 1942). The foregoing electrophysiological studies permit little doubt that the corpus striatum receives a variety of cortical and subcortical inputs, the latter arising predominantly from medial and intralaminar thalamic nuclei. They also indicate a prominent action of striopallidal outflow systems on mesodiencephalic and other basal telencephalic structures (Santini and Purpura, 1969; Spiegel et al., 1965). While these conclusions may satisfy the casual reader, they obviously fail to do justice to the extraordinary complexity of the synaptic mechanisms and interactions which must surely underlie the functional organization of the basal ganglia and related structures. Definition of these complexities requires application of the most rigorous electrophysiological techniques. Since the method of intracellular recording provides the most satisfactory available analytical tool for assessing the intimate synaptic relations of different neuronal organizations it can be expected that data forthcoming from such studies should lead to a more precise understanding of the electrophysiology of extrapyramidal connections. An attempt is made in the following sections to illustrate the types of data that may be derived from the judicious employ of the intracellular recording technique in studies of the basal ganglia and related structures. The author's primary objective in initiating * Work from the author's laboratories summarizedin this review was supported in part by the National Institute of Neurological Diseases and Stroke (NS-07512). JPTB Vol. 1, No. 1--B

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the investigations summarized here was to provide information on the nature of the reciprocal synaptic relations b e t w e e n the corpus striatum and thalamus and to elucidate the intrinsic organization and i n p u t - o u t p u t relations of striopallidum and substantia nigra. Suffice it to say these objectives have been only partially fulfilled. The justification for emphasizing data f r o m the author's laboratories derives solely f r o m the desire to capsulize a particular operational a p p r o a c h as a continuum of closely related studies. While the plan here is to discuss the w o r k of others in the context of these data areas of c o n t r o v e r s y will be underscored m o r e with the intention of focusing on the task ahead rather than the inadequacy of the information at hand. The reader is encouraged to consult reports elsewhere that are primarily concerned with neuroanatomical and neuropharmacological aspects of the electrophysiological problems discussed in this review. 2. I N T R A C E L L U L A R

SYNAPTIC ACTIVITIES OF CAUDATE NEURONS

It has been our experience that caudate neurons (Purpura and Malliani, 1967) do not c o m m o n l y exhibit the range of spontaneous discharges ordinarily encountered in intracellular studies of thalamic neurons (Purpura and Cohen, 1962; P u r p u r a and Shofer, 1963; P u r p u r a et al., 1965a, b; M a e k a w a and Purpura, 1967a, b) and cortical neurons (Purpura and McMurtry, 1965; P u r p u r a and Shofer, 1964; P u r p u r a et al., 1964). This factor should be a m a j o r consideration in attempts to disclose inhibitory effects of striatopetal inputs or applied putative inhibitory substances on caudate neurons examined solely b y extracellular recording methods. The low level of spontaneous activity of caudate neurons has been repeatedly emphasized b y others (Buchwald et al., 1969; H e r z and Zieglg~tnsberger, 1968; Kaji et al., 1971; Rocha-Miranda, 1965). Thalamic stimulation has revealed two m a j o r patterns of synaptic activities in caudate neurons studied in locally anesthetized enc~phale isol~ cats. A c o m m o n l y encountered synaptic event o b s e r v e d in association with cortical recruiting responses elicited b y low-frequency stimulation of the centrum m e d i a n u m - p a r a f a s c i c u l a r complex of the medial thalamus (MTh) is illustrated in Fig. 1. In this experiment the first stimulus of the repetitive train of M T h stimuli elicited a small r e s p o n s e at the level of the m o t o r cortex whereas a long-latency excitatory postsynaptic potential (EPSP) of long duration was recorded in the caudate neuron. The second and subsequent stimuli resulted in facilitation of the E P S P which occasionally triggered a single spike potential. It should be noted that whereas the E P S P in the caudate neuron attained m a x i m u m amplitude following the second stimulus, the cortical recruiting responses attained m a x i m u m amplitude several hundred msec later during the repetitive stimulation. In the study of P u r p u r a and Malliani (1967), latencies of long-duration E P S P s such as those shown in Fig. 1 ranged f r o m 15 to 20 msec. The relationship b e t w e e n cortical recruiting responses and synaptic events in caudate

FIG. 1. Characteristics of EPSPs evoked in a caudate neuron by low-frequency stimulation of medial thalamus (MTh). In this and subsequent figures with dual channel records cortical surface activity is shown in the upper channel (negativity upwards). A and B, Continuous recordings. In this experiment recruiting responses in motor cortex exhibited a 40-msec latency negativity with a prior positivity due to strong thalamic stimulation. Note that the first stimulus of the repetitive train elicits a prominent 15-msec latency subthreshold EPSP of long duration. The caudate neuron EPSP attains maximum amplitude following the second stimulus and a spike potential is initiated. Maximum amplitude of the recruiting response is attained by the fifth stimulus. As illustrated further in Fig. 2, EPSPs of long duration rarely elicit more than a single discharge in caudate neurons. (From Purpura and Malliani, 1%7.)

Electrophysiological properties of basal ganglia synaptic relations

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IOOmsec

FIG.2. Simultaneous recordings from motor cortex (upper channel) and a caudate neuron (lower channel) during low frequency (6/see) stimulation of medial thalamic (MTh) and ventrolateral (VL) thalamic sites. A, Threshold stimulation in MTh elicits prominent long latency surface negative recruiting responses in motor cortex. These are associated with 20-msec latency EPSPs in the caudate neuron. EPSPs show progressive enhancement with repetitive stimulation but fail to evoke spike discharges. B, Supramaximal MTh stimulation. Recruiting responses are of greater amplitude as are EPSPs, which occasionally secure single spike discharges. C, Supramaximal VL thalamic stimulation evokes a typical augmenting response in motor cortex. The same caudate neuron exhibits small EPSPs with slower rise time than the EPSPs evoked by MTh stimulation. VL-evoked EPSPs in the cell fail to trigger spike discharges. (From Purpura and Malliani, 1967.)

neurons is further illustrated by the results of Fig. 2. W e a k M T h stimulation which elicited prominent recruiting responses f r o m m o t o r cortex frequently resulted in the production of subthreshold E P S P s in caudate neurons (Fig. 2A). Increasing stimulus strength, which yielded maximal recruiting responses, occasionally facilitated spike discharge. In contrast to the effects of MTh stimulation, which synaptically activates a large proportion of caudate neurons, stimulation of the ventrolateral (VL) nucleus of the thalamus yielded long-latency low-amplitude E P S P s which were less effective than MTh stimulation in triggering spike discharges (Fig. 2C). Before considering additional patterns of synaptic activity initiated by thalmic stimulation it is necessary to inquire into the role of thalamo-cortical and corticocaudate projections in the production of thalamically evoked P S P s in caudate neurons. Evidence against a thalamo-cortico-caudate loop involving rostral cortico-caudate projections has been obtained in studies in which extensive areas of cortex rostral to the ansate sulcus were ablated several hours prior to caudate recording. In such studies MTh stimulation continued to yield long-latency recruiting responses f r o m midsuprasylvian gyrus and E P S P s and associated spike discharges in neurons of the head of the caudate nucleus. Whether posterior cortical areas might contribute via thalamocortico-caudate relays to production of P S P s in caudate neutrons is not known. H o w e v e r , it is pertinent to note that latencies of caudate discharges to cortical stimulation (Buchwald et al., 1969; Rocha-Miranda, 1965) appear to be as long, if not longer, than latencies of E P S P s and spike potentials o b s e r v e d in caudate neurons. It is also k n o w n that latencies of pyramidal neuron discharges evoked by MTh stimulation are c o m p a r a b l e to latencies of caudate neuron discharges evoked by the same type of thalamic stimulation (Purpura et al., 1964). In any case the latency for a nonspecific thalamo-cortico-caudate relay is likely to be greater than the latencies observed in Figs. 1-3. Additional difficulties arise in attempts to implicate cortical relays in the thalamostriatal activies described here. In view of the relatively weak corticofugal discharges initiated during recruiting responses (Purpura and Housepian, 1961; Purpura et al., 1964) it is difficult to envision that the occasional discharges of corticofugal elements produced b y M T h stimulation could provide the excitatory synaptic drive required to activate caudate neurons. This is all the more evident in the fact that V L stimulation which is k n o w n to induce powerful excitation of corticofugal neurons (Purpura and Housepian, 1961; Purpura et al., 1964) is relatively ineffective in activating caudate neurons. What little excitatory action on caudate neurons is initiated b y V L stimulation may be attributed largely to involvement of intrathalamic internuclear synaptic

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IOOmsec

FIG. 3. Lack of effect of acute rostral cortex ablation on intracellularly recorded synaptic events in caudate neurons during MTh stimulation. A and B, Continuous records, from one experiment. C, From another preparation. In these experiments cortical surface recordings were obtained from midsuprasylvian gyrus. Intracellular records were obtained 1-2hr after suction-ablation of all cortex rostral to the head of the caudate nucleus. EPSP patterns observed in caudate neurons after rostral cortical removals are similar to those elicited in cortically intact preparations. (From Purpura and Malliani, 1967.)

p a t h w a y s linking specific and nonspecific neuronal elements (Desiraju and Purpura, 1971). The foregoing observations and interpretations do not rule out a possible facilitatory effect of thalamo-cortico-caudate relays on thalamo-caudate e v o k e d responses since subthreshold E P S P s have been recorded in caudate neurons in response to cortical stimulation (Buchwald et al., 1969; Hull et al., 1969). H o w e v e r , the intracellular data of Figs. 1-3 falsify the hypothesis of Kaji et al. (1971) who have postulated the operation of direct thalamo-caudate and indirect thalamo-cortico-caudate projections in the effects o b s e r v e d b y single and repetitive stimulation, respectively, of medial thalamic nonspecific nuclei. Kaji et al. (1971) o b s e r v e d that extracellularly recorded caudate neurons exhibited a greater degree of responsiveness to low-frequency nonspecific thalamic stimulation when recruiting responses were elicited by such stimulation than w h e n stimulation failed to e v o k e recruitment or w h e n single stimuli were employed. Since these investigators based their findings on extracellular data f r o m spontaneously active units (which were relatively infrequently found) it follows that they could not o b s e r v e the subthreshold E P S P s which are c o m m o n l y evoked in caudate neurons b y single shock and repetitive stimulation of m a n y rostral and medial thalamic sites. The studies of Kaji et al. (1971) thus illustrate the hazards of interpreting the organization of synaptic p a t h w a y s f r o m data obtained in extracellular recordings. Failure to detect discharges of caudate neurons in such recordings by no means excludes synaptic activation of the 'silent' caudate neuron b y subthreshold E P S P s , which is a c o m m o n observation in intracellular studies of caudate neurons (Purpura and Malliani, 1967). H o w e v e r , it also follows that the failure of even relatively prominent E P S P s to discharge caudate neurons can not be interpreted as reflecting the relatively 'hyperpolarized or inhibited' state of caudate neurons under resting conditions (Buchwald et al., 1969; Hull et al., 1969). F o r this implies either that caudate neurons are subjected to v e r y little tonic excitatory b o m b a r d m e n t b y extrinsic and intrinsic elements or that caudate neurons are tonically inhibited. If these two factors are excluded then it must be inferred that either spike initiation sites in caudate neurons are r e m o t e f r o m the site of generation of E P S P s or that caudate neurons h a v e ' n o r m a l ' m e m b r a n e resting potentials that are in excess of those c o m m o n l y encountered in neurons in other structures. Clearly there is insufficient data to implicate any of these factors in the low-level spontaneous activity and limited responsiveness of caudate neurons. It m a y be noted that caudate neurons are r e m a r k a b l y similar to neocortical and hippocampal neurons of the immature brain in respect to their low-level spontaneous activity and responsiveness to prominent excitatory synaptic activities (Purpura et al., 1965, 1968).

Electrophysiological properties of basal ganglia synaptic relations

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A second pattern of PSPs has been observed in caudate neurons (Purpura and Malliani, 1967) which more closely resembles the typical pattern of synaptic activity observed in thalamic neurons during low-frequency MTh stimulation (Purpura and Cohen, 1962; Purpura and Shofer, 1963). In caudate cells which exhibited a higher rate of spontaneous activity than cells showing 'pure' EPSPs, MTh stimulation elicited EPSP-IPSP sequences such as those illustrated in Fig. 4. This pattern of synaptic excitation succeeded by prolonged inhibition has also been observed in caudate neurons receiving input from cortical, peripheral and brain stem stimulation (Buchwald et al., 1971; Hull et al., 1970). It is of interest that the latter workers have suggested a prepotency of cortical stimulation for regulation of caudate neuron activity influenced by combined cortical and subcortical stimulation. The inference is that cortical stimulation is capable of modulating afferent information reaching the striatum by way of intralaminar and medial thalamic nuclei (Buchwald et al., 1971). However, cortical stimulation is also powerfully effective in inhibiting caudate neuron responses to nigral stimulation (Hull et al., 1970). A

LL LLL.LL_t_L_LL L L L_L 50msec

FIG. 4. Examples of EPSP-IPSP sequences that were recorded from a small proportion of ventrally located caudate neurons in response to repetitive MTh stimulation. A-C, Continuous recording. A, Caudate neuron exhibits relatively high frequency spontaneous discharges which are interrupted by small IPSPs. The first MTh stimulus evokes an EPSP and spike discharge and a succeeding IPSP of about I00 msec duration. C, Spontaneous activity resumes following cessation of MTh stimulation. This pattern of PSPs evoked in caudate neurons by low frequency MTh stimulation is similar to that observed in most thalamic neurons during recruiting responses. (From Purpura and Malliani, 1967.)

The EPSP-IPSP sequences observed in caudate neurons during low-frequency MTh stimulation (Fig. 4) reflect a process of caudate neuronal synchronization which undoubtedly underlies the recruiting-like and spindle burst EEG activities demonstrable in the structure during thalamic stimulation. The thalamic synaptic mechanism underlying such EEG synchronization has been discussed elsewhere (Feldman and Purpura, 1970; Purpura, 1969, 1970). Caudate neurons exhibiting EPSP-IPSP sequences during evoked EEG synchronization induced by low-frequency MTh stimulation also show a pattern of IPSP attenuation and increase in excitatory synaptic activity during high-frequency MTh stimulation (Fig. 5). Thus in respect to the effects of lowand high-frequency stimulation of thalamic regions yielding evoked EEG synchronization and EEG desynchronization, respectively, some caudate neurons exhibit synaptic events which are typically encountered in a variety of thalamic neuronal organizations (Purpura and Cohen, 1962; Purpura and Shofer, 1963). This suggests involvement of caudate neuronal organizations in many of the transactional processes usually assigned to components of the thalamic nonspecific projection system (Purpura, 1970). The site of origin, polarity and projection of brain stem pathways whose stimulation is capable of eliciting synaptic activation or inhibition of caudate neurons is a problem of no little importance. This problem is central to the issue of the electrophysiological demonstration of direct nigro-caudate projections such as those involved in the dopaminergic pathways demonstrable by histochemical and other techniques considered in detail elsewhere in this volume. The difficulties of insuring placement and electrical stimulation of substantia nigra n e u r o n s and not axons or neurons of

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DOMINICK P. PURPURA A

g

C

50m~e FIG. 5. Changes in pattern of PSPs in the same caudate neuron as that shown in Fig. 4 during high-frequency MTh stimulation. Records were obtained shortly after the period of lowfrequency stimulation shown in Fig. 4. Portions of the continuous record were removed between A and B. A, First stimulus as in Fig. 4 initiates a long latency IPSP. During its peak a second MTh stimulus evokes another EPSP which attenuates the membrane hyperpolarization. IPSPs are not observed with successive stimulation. EPSPs become more prominent and initiate double discharges. Note inflection (at arrow) developing on spike in double discharge. Resumption of low-frequency 6/sec stimulation in B and C. Note persistence of prolonged EPSPs and absence of IPSPs in the immediate post-activation period. (From Purpura and Malliani, 1967.)

perinigral elements has been discussed by Frigyesi and Purpura (1967) and Frigyesi and Machek (1970, 1971). In view of the fact that electrical stimulation of the substantia nigra is likely to involve stimulation of peduncular fibers, overlying projections to the diencephalon in the ventral tegmentum or striato-nigral pathways, attempts were made to utilize animals in which destruction of peduncular, lemniscal and cerebello-thalamic projections was effected in chronic animals. Satisfactory intracellular records capable of permitting distinctions between antidromic and monosynaptically evoked orthodromic activation of caudate neurons were not obtained in the study of Frigyesi and Purpura (1967). However, the data from extracellular single unit recordings in animals with chronic destruction of perinigral pathways is strongly suggestive of the existence of monosynaptic excitatory pathways reciprocally linking the caudate and substantia nigra. One feature of this study was particularly noteworthy, i.e., the finding that presumed nigro-caudate evoked responses exhibited long-latency (15-20 msec). To the extent that the data obtained in these electrophysiological investigations are indicative of the operation of a direct monosynaptic connection between the substantia nigra and caudate neurons it follows that the conductile pathway must consist of small-diameter axons with conduction velocities in the range of 1-1.5 m/sec (Frigyesi and Purpura, 1967). The foregoing problem of defining the properties of nigro-striatal projections has not been satisfactorily resolved despite studies of others which have provided additional electrophysiological evidence for a direct orthodromic projection from the nigra to the caudate (Albe-Fessard et al., 1967; Connor, 1968; Feltz and MacKenzie, 1969; McLennan and York, 1967). Attempts to further elucidate the problem have been made in experiments involving stimulation of a large number of brain stem sites while recording intracellularly from caudate neurons in animals with intact perinigral conductile pathways (Hull et al., 1970). Caudate cells responding to brain stem nigral stimulation generally exhibited 4-5 msec latency EPSPs which were frequently succeeded by IPSPs. The finding that only rarely did caudate neurons respond at shorter latencies than 3 msec is consistent with the conclusions of Frigyesi and Purpura (1967) concerning the conductile properties of the projection pathway. However, a disquieting finding of the study of Hull et al. (1970) was the failure to obtain evidence of antidromic activation of caudate neurons following entopeduncular nucleus, globus pallidus and brain stem nigral stimulation. This bears out the long-held impression of the author that evidence for antidromicity in neuronal systems composed of relatively small elements is frequently difficult to obtain under most conditions. This may also apply to the failure of Goswell and Sedgwick (1969) to detect antidromic responses of substantia nigra

Electrophysiological properties of basal ganglia synaptic relations

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Feltz and M a c K e n z i e (1969) made no mention of antidromic activation of caudate neurons b y substantia nigra stimulation in their study involving both extracellular and intracellular recording techniques. On the other hand, orthodromic excitation of caudate neurons was shown by failure of collision b e t w e e n spontaneous and e v o k e d discharges. R e s p o n s e latencies ranged f r o m 8 to 34 msec in their series of caudate neurons and marked irregular increases in latencies were o b s e r v e d following repetitive nigral stimulation. Feltz and M a c K e n z i e (1969) consider it likely that the slow time course of the latency period and its long r e c o v e r y phase following repetitive nigral stimulation 'are compatible with slow changes in synaptic efficiency associated with slow and long E P S P s , and also with the " m e t a b o l i c " influences of the nigrofugal input' (p. 616). The meaning of the latter statement remains unclarified in view of a contrasting conclusion of Goswell and Sedgwick (1969) that 'there is no electrophysiological evidence for the existence of the dopamine containing nigro-striatal p a t h w a y ' (43 P). It is perhaps a sad c o m m e n t a r y on available electrophysiological techniques when the electrophysiological problem of identifying nigro-striatal projections can remain so elusive at a time when such projections have been clearly demonstrated by refined morphological and histochemical methods. 3. S Y N A P T I C A C T I V I T I E S OF L E N T I C U L A R ENTOPEDUNCULAR NEURONS

AND

Intracellular recordings f r o m putamen neurons have disclosed long-latency E P S P s to low-frequency MTh stimulation as in the case of caudate neurons (Malliani and Purpura, 1967). A distinguishing feature of these E P S P s has been their greater t e n d e n c y to elicit repetitive spikes in putamen neurons (Fig. 6A-C). In contrast to this, caudate stimulation initiates long-latency spike discharges which arise f r o m Small E P S P s (Fig. 6D-F). Since the latencies of M T h - e v o k e d E P S P s in p u t a m e n neurons generally exceed the latencies of caudate-evoked E P S P s it is difficult to envision an oligosynaptic connection between the caudate and putamen. Malliani and P u r p u r a (1967) found cells in the lenticular nucleus (medial p u t a m e n and/or lateral pallidus) which were activated b y caudate stimulation and uninfluenced by MTh stimulation as shown in Fig. 7A and B. P u t a m e n cells in ventral locations as well as pallidalentopeduncular neurons also exhibited rhythmical E P S P - I P S P sequences following repetitive caudate stimulation as illustrated in Fig. 7C. The latency of the initial E P S P of these sequences was constant and evoked spikes were securely driven during

w

150reset' FIG. 6. PSPs and discharge characteristics of a dorsally located putamen neuron activated by low-frequency medial thalamic (A-C) and caudate stimulation (D--F). A, B, C, Third, fourth and fifth response, respectively, during recruiting response in motor cortex. Short latency, prolonged EPSPs evoked by MTh stimulation elicit repetitive spike discharges in contrast to findings in caudate elements. D, E, F, First, second and third responses, respectively, during caudate stimulation. The first caudate stimulus evokes a long latency EPSP in the putamen neuron. Latency is curtailed with successive stimuli (E and F) but the evoked EPSPs are small and of short duration compared with the EPSPs evoked by MTh stimulation. Note that caudate stimulation does not elicit a significant cortical response. (From Malliani and Purpura, 1967.)

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PURPURA

la

i

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FIG. 7. Comparison of different synaptic effects of MTh and caudate stimulation on lenticular neurons. A and B, Recordings from the same pallidal cell during low frequency MTh and caudate stimulation, respectively. Caudate stimulation evokes a 15-msec latency EPSP and occasional spike discharges. No effect is observed during MTh stimulation which elicits a long latency surface negative recruiting response in motor cortex. C, Complex EPSP-IPSP sequence in a ventral putamen neuron during repetitive caudate stimulation at 6/sec. (From Malliani and Purpura, 1967.) low-frequency (6/sec) caudate stimulation. I P S P s were well developed in intervals between successive spikes. Such I P S P s were readily inverted to depolarizing potentials following induced membrane hyperpolarization potentials following induced membrane hyperpolarization of lenticular neurons by inward current injection (Fig. 8). A

2

B u

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mV ,

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FIG. 8. Inversion of I P S P s evoked in a lenticular neuron by caudate stimulation during induced membrane hyperpolarization. A and B, Examples from the same neuron. Repetitive caudate stimulation (at arrowheads) elicits a small E P S P and spike potential which is succeeded by a prolonged IPSP (1). During membrane hyperpolarization (indicated by current trace, upper

channel, 0.5 × 10-~/~) caudate stimulation evokes a depolarizing potential (2), which represents summationof early EPSP and inverted IPSP. (FromMalliani and Purpura, 1967.) The most consistent synaptic event observed in pallidal-entopeduncular neurons following caudate stimulation is a 10-20 msec latency prolonged I P S P (Fig. 9) which is occasionally preceded by a subthreshold E P S P . In many pallidal-entopeduncular neurons only 'pure' I P S P s are observed which exhibit summation following repetitive caudate stimulation (Fig. 10). These observations have been confirmed recently by Frigyesi (1972). Although pallidal-entopeduncular cells may fail to respond to MTh stimulation (Fig. 10B) those elements which show I P S P s to the latter stimulation generally have I P S P latencies greater than the I P S P s elicited by caudate stimulation. Unlike the fixed latency, constant amplitude of caudate-evoked I P S P s MTh-evoked I P S P s show marked shifts in latency and amplitude during repetitive MTh stimulation (Fig. 11). It should be emphasized at this juncture that identification of the precise location of a neuron studied in the lenticular and entopeduncular nuclei is by no means readily

Electrophysiological properties of basal ganglia synaptic relations

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A

B

D

FIG. 9. Characteristics of IPSPs evoked in pallidal entopeduncular neurons during lowfrequency (6/sec) caudate stimulation. Findings from three different experiments are illustrated. B and D, From the same preparation. Examples illustrate the small variability in latency of caudate-evoked IPSPs in neurons in different parts of the pallidal-entopeduncular complex. All cells shown were partially depolarized as a consequence of traumatic impalements. Such depolarization accounts for the relatively large amplitude of the IPSPs. Depolarization also explains the appearance of spike potentials during late phases of the IPSP in A. Calibration in D applies to all intracellular records. (From Malliani and Purpura, 1967.)

A ,,k

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mv

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FIG. 10. A, Caudate stimulation (6/sec) evokes 12-14 msec IPSPs in a pallidal neuron. B, MTh stimulation (6/see) does not influence the same element. C, Same neuron as in A. IPSP summation during 25/sec caudate stimulation. D, After movement of the microelectrode to the extracellular position. The upper channel trace is the focal potential recorded in the immediate extracellular location. Calibration in D applies to all intracellular records. (From Malliani and Purpura, 1967.)

B

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~20 mV r I0 msec

FIG. I 1. Comparison of the mode of development of IPSPs in a medial pallidal neuron during caudate (A) and MTh (B) stimulation at 6/sec. The IPSP is of full size and constant latency with the first and subsequent caudate stimuli whereas IPSPs increase progressively in amplitude and shorten in latency with repetitive MTh stimulation. C, Extracellular location of the microelectrode during caudate stimulation as in A. Calibration in C applies to intracellular records in A and B. (From Malliani and Purpura, 1967.) a c c o m p l i s h e d . F o r this r e a s o n l o c a t i o n s c a n b e specified o n l y w h e n care is t a k e n to sacrifice a n d p e r f u s e a n i m a l s with m i c r o p i p e t t e s in situ i m m e d i a t e l y after o b s e r v a t i o n s are r e c o r d e d . F r o m e x a m i n a t i o n s of serial f r o z e n s e c t i o n s it has b e e n p o s s i b l e to p u t t o g e t h e r a t e n t a t i v e d i s t r i b u t i o n of the v a r i o u s P S P p a t t e r n s o b s e r v e d in l e n t i c u l a r e n t o p e d u n c u l a r n e u r o n s f o l l o w i n g c a u d a t e s t i m u l a t i o n (Fig. 12). T h e d i a g r a m i n d i c a t i n g g e n e r a l l o c a t i o n s of cells s h o w i n g different c a u d a t e - e v o k e d P S P s s u m m a r i z e s the o b s e r v a t i o n s that a l t h o u g h p a l l i d a l - e n t o p e d u n c u l a r n e u r o n s f r e q u e n t l y e x h i b i t p u r e I P S P s f o l l o w i n g c a u d a t e s t i m u l a t i o n o t h e r cells m a y s h o w short l a t e n c y E P S P s as well

DOMINICK P. PURPURA

26 CAUDATE

- LENTICULAR

RELATIONS

SYMBOLS • - 10- 2 0 msec IPSP.s

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FIG. 12. Distribution of PSP patterns evoked by caudate stimulation and intracellularly recorded from neurons in different basal telencephalic structures. Each symbol represents the location of two or more elements whose positions were established from estimates of micromanipulator micrometer readings and identification of microelectrode tracts when possible. AMG, amygdaloid complex; CL, claustrum; EP, entopeduncular nucleus; GP, globus pallidus; OT, optic tract; PUT, putamen.

as rhythmical E P S P - I P S P sequences. The finding of E P S P - I P S P sequences in pallidal and entopeduncular neurons following caudate stimulation has been confirmed in a recent preliminary report by Levine et al. (1971). In rare instances it has also been possible to record from cells in the entopeduncular nucleus that showed prolonged bursts of spikes and partial spikes superimposed on long duration EPSPs (Fig. 13). While the temptation is great to identify these elements as likely candidates for inhibitory interneurons the shifts in latency noted in successively evoked discharge bursts is inconsistent with the fixed latency characteristics of the IPSPs elicited in entopeduncular neurons by caudate stimulation. In sum, the fixed latency IPSPs of entopeduncular neurons have been interpreted as a consequence of activation by caudate stimulation of an oligosynaptic, perhaps monosynaptic, inhibitory connection linking the caudate with neurons of the lenticular outflow projection system of the corpus striatum (Malliani and Purpura, 1967). The finding of fixed latency IPSPs in entopeduncular neurons in response to caudate stimulation has been confirmed by Yoshida et ai. (1971). Additional evidence derived from interactions of IPSPs evoked in entopeduncular cells by caudate and substantia nigra stimulation suggests that entopeduncular neuron IPSPs are generated by axoncollaterals of caudatonigral fibers which are inhibitory to elements in both the

A

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A

A

Jk...k..L....k.~k...k...._~L t

50

i

msec

FIG. 13. Discharge characteristics of a neuron encountered in rare instances in the entopeduncular nucleus. Low-frequency caudate stimutation'evokes a variable latency repetitive burst of discharges superimposed on a prominent and prolonged EPSP. Note the partial responses during the peak of the depolarizing potential. It is not known whether such intrasomatically recorded partial responses are associated with impulses in the axon. (From Malliani and Purpura, unpublished observations.)

Electrophysiological properties of basal ganglia synaptic relations

27

entopeduncular nucleus and the substantia nigra (Yoshida and Precht, 1971). It would a p p e a r f r o m recent further studies of Precht and Yoshida (1971) that picrotoxin blocks the positive field potential in the substantia nigra that is associated with I P S P s in nigral cells following caudate stimulation. It has been inferred f r o m these observations that the m o n o s y n a p t i c caudatonigral p a t h w a y responsible, for the inhibition of nigral cells m a y utilize G A B A as the inhibitory transmitter. U p to this point in the present survey the reader has been asked to accept without reservation statements to the effect that 'caudate stimulation' really means electrical stimulation of caudate neurons or their axons and not this plus inadvertent stimulation of extrastriatal capsular fibers which are in close relationship to the corpus striatum. This problem of spurious activation of nonstriatofugal internal capsule fibers is by no means novel in studies of defining the physiological effects of corpus striatum stimulation. Suffice it to say it has plagued all investigators since the earliest studies involving the application of stimulating currents to subcortical telencephalic structures (Wilson, 1914). The problem is complicated by the very different relations of the internal capsule and corpus striatum in primates and carnivores as emphasized by Goldring et al. (1963). Several approaches to the problem of ensuring that electrical stimulation of the caudate is confined to the caudate nucleus have been described. The studies of Frigyesi and Purpura (1964), and Malliani and Purpura (1967) employed a combination of direct visualization of the head of the caudate for placement of stimulating electrodes and e v o k e d potential registration f r o m pericruciate cortex. The production of very short latency spike-like potentials which m a y be superimposed on cortical surface positive responses has been considered indicative of spread of current to fibers of the internal capsule. Such responses are absent in Figs. 6-11 in those records concerned with the effects of caudate stimulation on putamen and pallido-entopeduncular neurons. Studies of the effects of caudate stimulation on substantia nigra neurons employed similar procedures (Frigyesi and Purpura, 1967). It is evident f r o m Fig. 14A that caudate stimulation m a y elicit 3--4 msec E P S P s and spike discharges which are followed b y I P S P s in rostral substantia nigra neurons. Recordings f r o m caudal nigral neurons m a y

A L

3oj mV

20 ms~:

B

(2

30 mV

20 ms~:

FIG. 14. A, Intracellular recording from a nigral neuron during 8/sec caudate stimulation (A). Superimposed records illustrate the constant latency of early evoked discharges which are succeeded by IPSPs and a variable phase of repetitive responses. B and C, From another experiment. Comparison of effects of caudate (A) and medial globus pallidus (n. entopeduncularis) (©) stimulation on a neuron in a caudal region of the substantia nigra. B, Caudate stimulation (8/sec) fails to influence nigral cell activity: C, Entopeduncular nucleus stimulation (8/sec) evokes 8.-10msec EPSPs of long duration with superimposed spike potentials. Note absence of spontaneous discharges following the evoked responses. CX: recordings from motor cortex; SN: intracellular recordings from substantia nigra neurons. (From Frigyesi and Purpura, 1967.)

28

DOMINICK P. PURPURA

show no effects of caudate stimulation but long latency EPSP-IPSP sequences in response to entopeduncular nucleus stimulation (Fig. 14B and C). The fact that in many instances caudate stimulation evokes subthreshold EPSPs followed by prominent IPSPs which may suppress spontaneous discharges of substantia nigra neurons is again indicative of the value of intracellular recording in demonstrating the complex synaptic effects of caudate stimulation on nigral cells. Attention has already been drawn above to the observations of Yoshida and Precht (1971) which have suggested a prominent inhibitory action of caudate stimulation on substantia nigra neurons. In contrast to the observations of Frigyesi and Purpura (1967), Yoshida and Precht (1971) have argued for a direct monosynaptic inhibition of nigral neurons by caudato-nigral axons. The predominant suppressive effects of caudate stimulation on nigral neurons has also been reported by Sutin and McNair (i971). In a further attempt to dissociate the effects of caudate vs. corticofugal fiber stimulation on substantia nigra neurons Goswell and Sedgwick (1971) examined the patterns of extraceUular unit discharges evoked by stimulation of the cortex, caudate and internal capsule. They reported in a preliminary communication that whereas cortex and internal capsule stimulations yielded excitatory-inhibitory responses only caudate stimulation resulted in inhibition of substantia nigra neurons. The conclusion of GosweU and Sedgwick (1971) that caudato-nigral fibers are inhibitory would appear to indicate that their earlier findings (Goswell and Sedgwick, 1969) and the observations of Frigyesi and Purpura (1967) were due to inadvertent stimulation of corticofugal axons. The findings of Goswell and Sedgwick (1971), Sutin and McNair (1971), and Yoshida and Precht (1971) have appeared only in preliminary reports which do not permit examination of the details of their observations or their evaluation of the precautions of Frigyesi and Purpura (1967) to avoid stimulation of capsular elements. This indicates the extraordinary difficulty of providing generally consistent observations in electrophysiological studies which are made all the more complex by the necessity to stimulate and record from elements whose identity cannot be satisfactorily specified. This problem will be discussed further below in respect to studies of the thalamic synaptic effects produced by stimulation of the internal capsule, corpus striatum and related structures.

4. INTRACELLULAR STUDIES OF STRIATO-THALAMIC RELATIONS Studies of extracellular potentials in n. ventralis lateralis (VL) of the thalamus early established that low-frequency stimulation of the caudate nucleus was capable of reproducing the pattern of negative-positive focal potentials associated with excitation and inhibition respectively of VL cells (Frigyesi and Purpura, 1964). The fact that monosynaptically evoked VL focal responses to brachium conjunctivum stimulation were influenced in a manner similar to that observed following stimulation of medial and intralaminar thalamic nuclei (Cohen et al., 1962) permitted the conclusion that caudate stimulation activated thalamic excitatory and inhibitory synaptic pathways that were also influenced by nonspecific-specific internuclear projections (Purpura et al., 1965, 1966). In view of the fact that the internal pallidal segment, or entopeduncular nucleus in the cat (Fox et al., 1966; Fox and Schmitz, 1944; Grofova, 1970; Mettler, 1968) is the major source of the outflow pathway from the corpus striatum to the thalamus (Nauta and Mehler, 1966, 1969) it has been of importance to define the extent to which pallido-thalamic projections engage thalamic elements which are also influenced by stimulation of cerebellofugal projections and nonspecific-specific internuclear pathways. Intracellular recordings from thalamic VL cells have now established that a significant proportion of VL relay elements monosynaptically activated by cerebellofugal projections also receive monosynaptic excitation from pallido-thalamic fibers (Desiraju and Purpura, 1969). Typical examples of this convergent input are illustrated in Fig. 15A-D. One feature of the comparative effect of lenticulofugal and cerebellofugal inputs on VL cells is particularly noteworthy. In most instances cells monosynaptically

Electrophysiological properties of basal ganglia synaptic relations

E

5 sec I Oms-'e~ ~ _ . ~

29

mV

20msec

'

50mY I

' 50msec

FIG. |5. Intracellular recording of convergent monosynaptic excitation of a VL neuron by ansa

lenticularis (A, C and D) and brachium conjunctivum (B) stimulation. Spikes in B and C truncated for display purposes. Note minimal latency differences of EPSPs in B and C. Ansa lenticularis-evoked EPSP is shown in isolation in D. E and F, Records obtained from a different VL neuron following ansa lenticularis (E) and brachium conjunctivum (F) stimulation. Only the brachium-evoked EPSP is succeeded by a prolonged IPSP, the early phase of which exhibits low amplitude oscillations. G and H, Example of convergent but reciprocal synaptic effects observed in a VL neuron following ansa lenticularis (G), and brachium conjunctivum (H) stimulation. Responses in each case were elicited at two levels of membrane polarization. G, Upper record obtained during spontaneous discharges, lower record during a phase of increased membrane polarization in which spontaneous discharges were eliminated. In each instance ansa lenticularis stimulation evokes a 4-6 msec IPSP. H, Lower record of the pair obtained during a spontaneous long duration IPSP. Brachium conjunctivum stimulation elicits a 4-6 msec latency EPSP and spike discharge. The EPSP is revealed in isolation during the spontaneous IPSP. I-L, Example of similar long latency EPSP-IPSP sequences elicited in a VL neuron by repetitive stimulation in the region of n. entopeduncularis (I and J, continuous recording) and stimulation of medial thalamus (K and L, continuous recording). Upper channel records obtained from motor cortex. Note prominent long latency surface negative recruiting response evoked by medial thalamic stimulation. (From Desiraju and Purpura, 1969.) a c t i v a t e d b y a n s a l e n t i c u l a r i s s t i m u l a t i o n e x h i b i t E P S P s w h i c h are n o t s u c c e e d e d b y I P S P s (Fig. 15E). H o w e v e r , the s a m e cells r e c e i v i n g m o n o s y n a p t i c e x c i t a t o r y i n p u t f r o m t h e c e r e b e l l u m m a y e x h i b i t a b r i e f E P S P w h i c h is f r e q u e n t l y s u c c e e d e d b y an I P S P (Fig. 15F) ( P u r p u r a et al., 1965). S u c h findings a r e difficult to r e c o n c i l e w i t h the n o t i o n t h a t t h e I P S P s o b s e r v e d in V L cells f o l l o w i n g b r a c h i u m c o n j u n c t i v u m s t i m u l a t i o n r e f l e c t t h e o p e r a t i o n o f a r e c u r r e n t p a t h w a y . F o r if this w e r e t h e c a s e it w o u l d b e e x p e c t e d t h a t m o n o s y n a p t i c a c t i v a t i o n o f V L cells b y t h e c o n v e r g e n t i n p u t s s h o u l d a c t i v a t e t h e s a m e r e c u r r e n t m e c h a n i s m . A n a l t e r n a t i v e e x p l a n a t i o n is t h a t t h e c e r e b e l l o f u g a l p r o j e c t i o n s e n g a g e a p a r a l l e l i n h i b i t o r y p a t h w a y w h i c h is n o t a v a i l a b l e to t h e d i r e c t p a l l i d a l - t h a l a m i c p r o j e c t i o n s to V L r e l a y cells ( D e s i r a j u a n d P u r p u r a , 1969). The monosynaptic excitatory convergence of pallidothalamic and cerebellofugal a f f e r e n t s o n t o V L cells w a s o b s e r v e d in less t h a n 20 p e r c e n t of V L n e u r o n s s t u d i e d with intracellular recording. A somewhat larger proportion of VL neurons exhibited medium latency (2-6msec) PSPs following both ansa lenticularis and brachium c o n j u n c t i v u m s t i m u l a t i o n . H o w e v e r , u n l i k e the s h o r t e s t l a t e n c y effects o b s e r v e d , w h i c h w e r e e x c l u s i v e l y e x c i t a t o r y , m e d i u m l a t e n c y P S P s w e r e g e n e r a l l y r e c i p r o c a l in nature. Typical examples of these convergent, reciprocal, synaptic actions of ansa l e n t i c u l a r i s a n d b r a c h i u m c o n j u n c t i v u m s t i m u l a t i o n a r e s h o w n in Fig. 15G a n d H . L o n g - l a t e n c y ( 1 0 - 3 0 m s e c ) E P S P - I P S P s e q u e n c e s w e r e also o b s e r v e d in V L n e u r o n s following ansa lenticularis stimulation but these were rarely observed following

DOMINICK P.

30

P U R P U R A

A

B

C

LLL J D

50mY

~

1 ~/t-T--

!~

i i 1

,

50msec FIG. 16. A-D, Examples of PSP patterns recorded from four different V A - V L neurons during low-frequency stimulation of lenticulofugal projections to thalamus. Prolonged long-latency IPSPs are usually preceded by EPSPs. Such EPSP-IPSP sequences are similar to those generally elicited by stimulation of medial thalamic locations. Note absence of evoked responses in motor cortex recordings (upper channel records). (From Desiraju and Purpura, unpublished observations.)

brachium conjunctivum stimulation. The long-latency PSPs evoked in VL neurons by ansa lenticularis stimulation were similar in many respects to the E P S P - I P S P patterns observed in the same neurons during stimulation of medial nonspecific thalamic nuclei (Fig. 15I-L) (Desiraju and Purpura, 1969; Frigyesi and Machek, 1970). Several additional examples of the PSP patterns observed in non-relay cells of the V A - V L complex during repetitive ansa lenticularis stimulation are illustrated in Fig. 16. These E P S P - I P S P sequences resemble the various types of PSP pattern that were originally described for rostral thalamic neurons during evoked recruiting responses to medial thalamic stimulation (Purpura and Cohen, 1962). Attention is directed to the lack of evoked cortical potentials in Fig. 16, which again emphasizes the relatively restricted nature of the stimulating currents utilized in activating the lenticulofugal projection pathway. Suffice it to say that PSP patterns similar to those observed in VA-VL following ansa lenticularis stimulation (Fig. 16) were also observed in neurons of the medial and intralaminar thalamus following entopeduncular nucleus or ansa lenticularis stimulation. Similar observations have been reported by Frigyesi and Rabin (1971). In rare instances, neurons exhibiting median latency E P S P - I P S P sequences in response to ansa lenticularis stimulation failed to show these PSP patterns in response to medial thalamic stimulation (Fig. 17). _A t

t

,~L___

~jL....

B I

___r~._

•

,.

.-..,

50mYi FIG. 17. Intracellular recordings from a VL neuron during entopeduncular nucleus stimulation (A and B) and medial thalamic stimulation (C and D). This element exhibited EPSP-IPSP sequences following entopeduncular stimulation (0) but was unresponsive to medial thalamic stimulation (&) which elicited prominent long-latency recruiting responses in motor cortex (upper channel recordings). Note absence of cortical evoked potentials during entopeduncular stimulation. (From Desiraju and Purpura, unpublished observations.)

Electroph~,'siologicai properties of basal gangiia synaptic relations

31

The conclusions to be drawn from this brief survey of the distribution of evoked synaptic activities in VA-VL and medial thalamic nuclei following stimulation of the lenticulofugal, cerebellofugal and nonspecific-specific thalamic internuclear projections are as follows: (a) A small proportion of VL-relay neurons receives monosynaptic excitatory convergent inputs from the corpus striatum (via the ansa lenticularis) and the cerebellum (via the brachium conjunctivum). This conclusion derived from intracellular studies of Desiraju and Purpura (1969) has been confirmed recently in extracellular studies of Dormont and Ohye (1971). (b) A population of interneurons in VL is engaged by other interneurons activated by lenticulofugal and cerebellofugal projections. These may Show reciprocal synaptic actions following stimulation of the two projection systems (cf. also Frigyesi and Machek, 1970, 1971; and Frigyesi and Rabin, 1971). (c) Finally, a much larger and more dispersed population of interneurons in the thalamus (VA-VL and medial nuclei) exhibits similar patterns of PSPs following repetitive entopeduncular-ansa lenticularis stimulation and repetitive medial thalamic stimulation. The foregoing conclusions leave little doubt that the outflow pathways directed to the thalamus (Nauta and Mehler, 1966; 1969) engage neuronal domains in which territories of pallidal-thalamic and cerebello-thalamic afferents exhibit variable overlap depending upon the degree of convergence onto VL-relay cells and non-relay cells in VA-VL. These interneuronal domains may also be engaged by internuclear, interneuronal synaptic pathways linking nonspecific and specific nuclei. Convergence of pallidofugal and cerebellofugal monosynaptic excitatory projections onto VL-relay cells insures mutual facilitation of VL-relay cell discharge as the immediate consequence of this convergent projection activity. But disynaptic and multisynaptic engagement of more dispersed VA-VL interneuronal elements offers the possibility for reciprocal as well as similar synaptic actions. This suggests a role of these inputs together with nonspecific-specific internuclear pathways in the general control of transactions in A ,

i L

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/

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.__J.

,

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&

•

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'

,__ °

O

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,_

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FzG. 18. Example of step-down transformation of striopallidothalamic input to VL neuronal organizations. Upper channel records obtained from motor cortex to illustrate absence of evoked response during continued 6/sec stimulation in region of nucleus entopeduncularis-ansa lenticularis. A-F, Continuous recording. Stimuli marked by dots. A, B, Initial period of stimulation elicits a slowly incrementing EPSP in a VL neuron. C, With continued stimulation, a delayed EPSP of considerable magnitude makes its appearance with alternate stimuli of the 6/sec train. When the alternation pattern is well established, as in D-F, discharges are superimposed on the long-latency EPSP. These occur in bursts at half the input frequency as a consequence of the alternating EPSP. (From Purpura, 1970.)

32

DOMINICK P. PURPURA

interneuronal pools of the thalamus (Purpura, 1970). Viewed in this fashion it is perhaps not surprising that the widely dispersed effects of pallidofugal inputs to different thalamic interneuronal organizations may set into operation rhythmical processes which may bear little immediate relationship to the paUidofugal input pattern. This point is illustrated in Fig. 18 in an experiment in which continued 6/sec stimulation in the region of the entopeduncular nucleus elicits first an augmentation of EPSP-IPSP sequences in a thalamic VL neuron then a remarkable alternation of the EPSPs and burst-discharges from the impaled neuron. The synaptic events illustrated in Fig. 18 may reflect the activity of an interneuronal 'interface' between pallidofugal, cerebellofugal and nonspecific-specific projections on the one hand, and thalamocortical projection elements, on the other. The proportion and timing of excitatory and inhibitory synaptic activities generated in this interneuronal 'interface' by different input systems may be considered critical factors in modulating the input-output characteristics of thalamic neurons with access to corticofugal elements (Purpura, 1970; Purpura et al., 1966). This formulation of the control of thalamocortical projection activity with parallel loops through the corpus striatum would be incomplete without mention of the operation of specific-nonspecific thalamic reciprocal synaptic pathways (Desiraju and Purpura, 1970) which may provide additional effective control of thalamostriate input. The fact that corticothalamic projections to nonspecific (Purpura, 1972) and other thalamic nuclei (Frigyesi and Machek, 1970) may reproduce PSP patterns which mimic the effects of medial thalamic or caudate stimulation must also be considered in the control of thalamocortical projection activity.

5. PROBLEMS IN ELECTROPHYSIOLOGICAL ANALYSES OF HODOLOGICAL RELATIONS Attention may now be drawn to several problems discussed briefly above in relation to electrical stimulation of different components of the corpus striatum and the nature of the caudate-thalamic projection pathway. It was argued that when precautions are taken to monitor motor cortex evoked potentials following caudate or pallidoentopeduncular stimulation absence of typical short-latency responses could be considered evidence for lack of spread of stimulating currents to fibers of the internal capsule. (Purpura and Malliani, 1967; Frigyesi and Purpura, 1967). In pursuit of this problem in work from our laboratories Frigyesi and Machek (1970, 1971) have provided intracellular data on the comparative effects of caudate and capsular stimulation on a variety of thalamic neuronal organizations. From a large number of intracellular recordings, several of which are illustrated in Fig. 19, it has been shown that the pattern of synaptic effects observed in VL, medial or dorsolateral thalamic neurons following caudate stimulation are not reproduced by stimulation of extensive areas of the internal capsule. This is not to say that capsule stimulation is ineffective in many instances (cf. Fig. 19D). What is to be emphasized is that in intracellular recording from a particular thalamic neuron the identical latency and PSP pattern to caudate and capsule stimulation is never observed. The same conclusion may be drawn in respect to the comparative synaptic effects observed in some thalamic neurons following stimulation of the internal capsule, caudate, substantia nigra and midline thalamus (Fig. 20). The data illustrated in Fig. 20 and in the reports of Frigyesi and Machek (1970; 1971) and Frigyesi and Rabin (1971) raise additional problems concerning the trajectory of the influences exerted by the caudate on thalamic neurons. The fact that direct caudate thalamic projections have not been described in morphological studies (Szabo, 1962; Voneida, 1960) limits the possibilities of mediating caudate-thalamic effects to utilization of relays in the pallidoentopeduncular complex and/or the substantia nigra. Direct connections of the globus pallidus and the nigra with the thalamus are well established (Carpenter and McMasters, 1964; Carpenter and Strominger, 1967; Nauta and Mehler, 1966). However conflicting electrophysiological data and interpretations may be noted in this respect. Thus findings of excitatory and inhibitory effects of caudate stimulation on substantia nigra neurons (Frigyesi and Purpura, 1967) are clearly at variance with the

Electrophysiological properties of basal ganglia synaptic relations

Cx

v

ACd

~ l " ~ - - , , , , , , ~ Ib "20

B

s• c

50

mV

L~ I.C.

C

20

mse¢

FIG. 19. Different effects observed in thalamic VL neurons during stimulation of the caudate (A) and internal capsule (A). A, Example of an EPSP-IPSP sequence elicited in a VL neuron during 8/see caudate stimulation. Response at the cortex consists of a 'double-negativity'. B, Stimulation of the internal capsule, in paracaudate position, elicits prominent anti- and orthodromic responses in motor cortex and no detectable effects in the VL neuron. (Modified from Frigyesi and Machek, 1971.) C and D, Comparison between internal capsule (A) and caudate (A) evoked synaptic activities in a medial thalamic neuron. Examples of effects observed during low-frequency stimulation show an alternating IPSP following internal capsule stimulation and a regular EPSP-IPSP sequence following caudate stimulation. (From Frigyesi and Machek, 1970.)

A

_

B

C

."r-,.,_,..---

FIG. 20. Responses of neurons in VL-VM complex to (8/see) stimulation of (1) contralateral brachium conjunctivum, (2) ipsilateral internal capsule, (3) head of caudate nucleus, (4) substantia nigra, and (5) midline thalamus. Three cells (A, B and C) from different experiments are shown which fall to exhibit monosynaptic responsiveness to brachial stimulation (A,, B,, CO. 2, Capsular stimulation elicits prolonged IPSPs in all three neurons. C2, Capsular evoked IPSP is preceded by short latency brief depolarizing potential. A3, B3, C~, Caudate stimulation elicits long latency IPSPs and preceding polysynaptic EPSPs. Nigral stimulation elicits antidromic corticospinal potentials and long latency negative waves in A, and no detectable alterations in surface recordings in B, and C,. Nigra evoked long latency IPSP preceded by an EPSP is shown in C4. A,, B4, Nigra evoked synaptic effects are not demonstrable. As, Be C~, Midline thalamus evoked EPSP-IPSP sequences are shown. (From Frigyesi and Machek, 1971.) JPTB Vol. 1, No. I--C

33

34

DOMINICK P.

PURPURA

conclusions of Goswell and Sedgwick (1971), Sutin and M c N a i r (1971) and Yoshida and Precht (1971) which suggest an exclusively inhibitory action of caudate stimulation on nigral cells. If the latter conclusion is valid then a m e c h a n i s m would be provided for turning off the nigro-thalamic p a t h w a y by caudate stimulation rather than activating it in a c c o r d a n c e with the observations of Frigyesi and P u r p u r a (1967) and the proposal of Frigyesi and M a c h e k (1971). The second p a t h w a y for caudato-thalamic activation through pallidal-entopeduncular relays m a y provide similar difficulties of interpretation in view of the powerful inhibitory actions of caudate stimulation on pallidoentopeduncular neurons (Malliani and Purpura, 1967; Frigyesi, 1972; Yoshida et al., 1971). H o w e v e r it must be borne in mind that inhibitory effects of caudate stimulation on pallido-entopeduncular neurons are frequently preceded by excitatory actions (Malliani and Purpura, 1967) as described above. Thus it cannot be argued that caudate activation will lead to a ' d e a d - b e a t ' operation of the lenticulofugal projection pathway. All that can be said at the present writing is that considering the difficulties of performing well-controlled electrophysiological experiments on the corpus striatum and its related systems and despite attempts (Frigyesi and Machek, 1970, 1971) to avoid stimulation of the cerebral peduncular-loop (Rinvik, 1968) and other fiber systems in such hodological studies, it is likely that present conflicting views will not be resolved without considerably more hard data on the subject. On the positive side the intracellular studies reported to date have revealed a spectrum of complex synaptic interactions b e t w e e n the corpus striatum, claustrum, substantia nigra and diencephalic neuronal organizations (Desiraju and Purpura, 1970; Frigyesi and Machek, 1970, 1971; Frigyesi and Rabin, 1971; Purpura, 1970). Such complexity is barely evident in the anatomical relations b e t w e e n these structures. In this context electrophysiological observations such as that illustrated in Fig. 21 may be more important for their nuisance value than their contribution to the problem at hand. This figure clearly d e m o n s t r a t e s antidromic activation of a caudate neuron by stimulation in the V A - V L region of the thalamus (Purpura et al., 1967). Could one argue f r o m this rare finding that there is indeed a direct projection p a t h w a y f r o m the caudate to the rostral thalamus? Complexities in electrophysiological studies are introduced b y the fact that whereas morphological studies can effectively trace the extent and distribution of terminal degeneration following lesions of a related structure, morphological analysis stops at the first synapse! The dispersion of polysynaptic events in a population of neurons activated b y a distinct input is clearly not amenable to analysis b y currently available morphological techniques. Thus the demonstration of monosynaptically activated V L

FIG. 21. Comparison of the different effects of stimulation of medial and ventroanterior components of the nonspecific thalamic nuclei on a caudate neuron. A, Low-frequency MTh stimulation evokes a very long-latency (50 msec) recruiting negativity and similar latency EPSP in the caudate neuron. B, Ventroanterior stimulation elicits a 15 msec positive-negative cortical surface potential. An antidromic response of the caudate neuron is succeeded by an orthodromic response; the latter is shorter in latency than that observed following MTh stimulation. (From Purpura et al., 1967.)

Electrophysiologicalproperties of basal ganglia synaptic relations

35

neurons by stimulation of lenticulofugal projections (Desiraju and Purpura, 1969) was predictable from morphological considerations alone. What could not be anticipated was the extraordinary degree of intrathalamic interneuronal dispersion initiated by volleys in such projections and the interaction with activities generated by stimulation of other projection systems, as noted in consideration of striato-thalamic relations. On the other hand witness the difficulties of attempts to define the electrophysiological properties of nigro-striatal projections, which are now generally accepted as morphological realities. Hopefully, further application of electron microscopic techniques to studies of the intrinsic organization of the corpus striatum and its related structures (Kemp and Powell, 1971a, b, c, d) when combined with electrophysiological studies which continue and extend the approaches described here, will resolve many of these vexing problems.

6. G E N E R A L COMMENTS AND CONCLUSIONS Speculations as to the functions of the corpus striatum have repeatedly emphasized interactions between the outflow pathways of the corpus striatum and the cerebellum at different neuraxial sites. Wilson (1914) incorporated Sherrington's concept of the final, common pathway in his scheme of convergent strio-rubro-spinal and cerebello-x-spinal projections to motoneurons. The latter designation is particularly interesting insofar as Wilson considered it likely that the cerebellar projection involved a relay through the thalamus to cortex and thence via the corticospinal tract to the final common path. That Wilson exhibited little patience for details is evident in the following: 'In what way impulses originate in the corpus striatum is immaterial--they may depend on stimuli from the optic thalamus by thalamo-striate fibres; in any case, the evidence for the efferent action of corpus striatum impulses on the final common path is not lightly to be set aside. I have said that this influence is one which steadies pyramidal innervation along the final path' (Wilson, 1914, p. 485). The past half-century of research on the basal ganglia has set many of Wilson's physiological interpretations to rest. Still Wilson cannot be faulted for juxtaposing the operations of the corpus striatum in relation to the cerebellum. General conclusions based on a similar theme have virtually become clich6 as summarizing articles of faith in the final statements of most reports and reviews on the subject, including those of present author. But sincerity of belief is no substitute for facts. And the fact of the matter is that much of the electrophysiological data on the synaptic relations of the corpus striatum currently defies translation into functional operations in the behaving organism. (The same may also be true for much of the recent electrophysiological data on the cerebellum, but this is presently not at issue.) Nor is it likely that speculative arguments concerning the similarities in the structure and patterns of connections of the corpus striatum and cerebellum (Kemp and Powell, 1971e) will remedy this situation, however provocative such speculations may seem at first glance. For the electrophysiological data on the corpus striatum are no more capable of providing an internally consistent hypothesis of the sensorimotor functions of the basal ganglia than the volume of data on the 'reticular formations' have provided concerning the precise role of brain stem organizations in sleep-wakefulness behavior. Nevertheless we remain as confident about assigning a major role to the basal ganglia in sensorimotor activities as we are about assigning a crucial role to brain stem organizations in sleep-wakefulness behavior. Confidence that the basal ganglia are importantly involved in sensorimotor integrative processes derives from the electrophysiological data, summarized in part here: (a) that neurons of the corpus striatum received inputs from cerebral cortex and thalamus; (b) that after suitable data processing this information is fed via intrastriatial, lenticular and probably strionigral projections into a wide variety of diencephalic neuronal organizations; and (c), that the latter organizations give rise to parallel projection systems which activate cortex and striatum. Unfortunately little is known about intrastriatal processing activities and even less concerning the functional significance of the intrathalamic interneuronal distribution of the striatofugal projec-

Electrophysiological properties of basal ganglia synaptic relations

37

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