Analysis of recurrent inhibitory circuit in rat thalamus: Neurophysiology of the thalamic reticular nucleus

Progress in Neurobiology Vol. 32, pp. 77 to 102, 1989 Printed in Great Britain. All rights reserved

0301-0082/89/$0.00+ 0.50 Copyright © 1988 Pergamon Press plc

ANALYSIS OF RECURRENT INHIBITORY CIRCUIT IN RAT THALAMUS: NEUROPHYSIOLOGY OF THE THALAMIC RETICULAR NUCLEUS A.

SHOSAKU,*Y. KAYAMA,t,¶I. SUMITOMO,$ M. SUGITANI§and K. IWAMAI]

*Department of Neurophysiology, Institute of Higher Nervous Activity, Osaka University Medical School, Kita-ku, Osaka 530, Japan ~fDepartment of Physiology, Akita University School of Medicine, Akita 010, Japan *Laboratory of Biological Science, Osaka Keizai University, Higashiyodogawa-ku, Osaka 533, Japan §Department of Physiology, Kanazawa Medical University, Uchinada, Ishikawa 920-02, Japan IIPhysiological Laboratory, Kinki University Faculty of Pharmacy, Higashi-Osaka 577, Japan

(Received 1 February 1988)

CONTENTS 1. Introduction: development of the study 2. Neural circuits involving the TR 2.1. Connection with relay nuclei of the thalamus 2.2. Corticofugal axons 2.3. Ascending projections from the brainstem 3. Firing properties of TR neurons 3.1. Burst discharges and relation to EEG spindles 3.2. Membrane properties 3.3. Modulation by corticofugal inputs 3.4. Modulation by ascending brainstem inputs 4. TR neurons activated by sensory stimulation 4.1. Subdivisions of the TR 4.2. Somatotopic and retinotopic organization 4.3. Receptive field properties 5. Inhibitory action on relay neurons 5.1. Destruction of the TR 5.2. Stimulation of the TR 5.3. Correlation between relay and reticular neurons 6. Concluding remarks: physiological functions of the TR 6.1. Formation of EEG spindle activity 6.2. Setting excitation level of relay neurons 6.3. Post-excitatory inhibition and surround inhibition References

1. I N T R O D U C T I O N : THE

DEVELOPMENT

77 78 78 79 79 80 80 81 82 83 87 87 89 90 92 92 93 94 98 98 98 98 99

OF

geniculate nucleus (LGNd) of the rat with characteristic responses to single shock stimulation of the optic nerve; one was those which responded initially with one spike which was followed after a lapse of time by a repetition of burst discharges, and the other was those which showed merely a repetition of burst discharges. The former were named P-cells, because they were the principal member of the LGNd (87% of all neurons by Burke and Sefton, 1966a), and were proved to be thalamocortical relay neurons. The latter were named I-ceUs; since they did not respond antidromically to stimulation of the visual cortex, they were thought to be interneurons. With this classification of the cell type Burke and Sefton proposed a model of neuronal circuit that I-cells were innervated by axon collaterals of P-cells and I-cells sent axons back to P-cells to exert an inhibitory influence. Thus, I-cells in this schema were elements

STUDY

The thalamic reticular nucleus (TR) is a sheet-like nucleus partially enclosing the dorsolateral a n d anterior aspects o f the thalamus. In this nucleus, n e u r o n s exerting recurrent inhibition o n thalamocortical relay n e u r o n s are assembled. In this p a p e r we will overview the studies o f o u r g r o u p o n physiology o f the rat TR. O u r studies were initiated to confirm electrophysiological studies of Burke and Sefton (1966a, b, c). These workers reported t h a t two types o f n e u r o n s were distinguished in the dorsal lateral ¶All correspondence should be sent to Y.K. at his present address: Yukihiko Kayama, M.D., Department of Physiology, Fukushima Medical College, l Hikari-ga-oka, Fukushima 960-12, Japan. JP~

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FIG. 1. (Upper part) A schema of the local circuits around the dorsal lateral geniculate nucleus (LGNd) and the visual portion of the thalamic reticular nucleus (TR). Axons and terminals from remote structures are also shown except those from the dorsal raphe nucleus because of lack of space. Other abbreviations: I, 1-cell (internuncial neuron); LC, locus coeruleus; LDT, laterodorsal tegmental nucleus; P, P-cell (principal or relay neuron); PPT, pedunculopontine tegmental nucleus; VC, visual cortex. (Lower part) Identification of the three kinds of neurons with their responses evoked by single- or double-shock stimulation of the optic nerve at the optic chiasm (small arrows).

That the neurons constituting recurrent circuits were located outside of relay nuclei of the thalamus enabled us to examine effects of stimulation or destruction of the TR upon activity of relay neurons in the LGNd, ventrobasal complex (VB) or medial geniculate nucleus (MGN) (Sumitomo et al., 1976a; Shosaku and Sumitomo, 1983; Mushiake et al., 1984; Kayama, 1985). These studies were followed by cross-correlation analyses of activities of relay and TR neurons (Shosaku, 1986). On the other side, we were interested in a peculiar firing pattern of TR neurons in anesthetized condition, that is, repetition of grouped discharges (bursts). Its mechanism was successfully investigated by intracellular recordings from TR neurons (Kayama et al., 1986b; I. Sumitomo, Y• Takahashi, Y. Kayama and T. Ogawa, in preparation). As outlined above, we have investigated physiological characteristics of TR neurons from various aspects in urethane-anesthetized rats; their localization, intra-TR organization, receptive field properties, peculiar firing properties and underlying membrane mechanisms, modification of firing by remote inputs, effects of destruction or stimulation of the TR, and interactions with relay neurons as revealed by cross-correlation analyses of spontaneous discharges. These will be reviewed in detail in following sections• 2. NEURAL CIRCUITS INVOLVING THE TR 2.1.

CONNECTION WITH RELAY THALAMUS

NUCLEI

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Local circuits involving a thalamic relay nucleus and TR are constituted by three cellular elements, which receive axonal projections from several remote structures. A schematic illustration in Fig. 1 shows constituting the recurrent inhibitory circuit in the the circuits around the LGNd as a typical model. A LGNd. Our group followed Burke and Sefton by relay neuron sends out a cortically projecting axon measuring more precisely the latencies of response of which has a collateral branch innervating TR neuP- and I-cells (Noda and Iwama, 1967), and by rons. Synapses formed by terminals of this axon on observing effects of stimulation of the reticular for- dendrites of TR neurons have morphological characmation or thalamic midline nuclei on discharge of teristics of the excitatory synapse (Ohara and LiebBurke and Sefton's I-cells (Fukuda and Iwama, 1970, erman, 1985), but the transmitter has not been identified yet. A TR neuron sends out an axon back 1971; Sumitomo, 1974). However, several years after we noticed that the to the LGNd to make synapses with dendrites or I-ceils of Burke and Sefton were not in the L G N d but somata of relay neurons; these synapses have morin the TR (Sumitomo et al., 1975, 1976a, b), indi- phological characteristics of inhibitory synapses utilizing gamma-aminobutyric acid (GABA) as the cating that the recurrent inhibitory circuits for LGNd P-cells are constituted not by neurons within the transmitter (Houser et al., 1980; Ohara et al., 1980; LGNd but by TR neurons. Later this was confirmed Montero and Scott, 1981; Montero, 1983; Peschanski anatomically (Ohara et al., 1980; Montero and Scott, et al., 1983; Montero and Singer, 1984). Co-existence 1981). Then we extended the studies to systems other of somatostatin with GABA is reported in TR neuthan the visual one; it was found that one group of rons of the cat and monkey, but such is not proved TR neurons were activated by somatosensory inputs in rat TR neurons (Graybiel and Elde, 1983). Anatomical studies have revealed that besides relay and the other by auditory inputs (Sugitani, 1979; Shosaku and Sumitomo, 1983). On the basis of this neurons another type of neuron exists in the LGNd. finding we have proposed the terms v-TR, s-TR and They are intrageniculate interneurons. The term "Ia-TR as referring to the portions of TR containing cells" coined by Burke and Sefton (1966a) may neurons activated by visual, somatosensory and audi- properly be used to refer to these intrinsic neurons• tory inputs, respectively (Shosaku and Sumitomo, The I-cells (intrageniculate interneurons) receive syn1983). Besides, it was clarified recently that v-TR can aptic inputs on their dendrites from optic nerve be divided into two parts, one connecting with the terminals which simultaneously make synaptic conLGNd and the other with the visual part of the lateral tacts with dendrites of relay neurons. On the other hand the I-cell dendrites are presynaptic in the posterior nucleus (Sumitomo et al., 1988).

THALAMIC RETICULAR NUCLEUS

dendro-dendritic synapses with relay neurons. These synapses are thought to be inhibitory from morphological features and utilization of G A B A as the transmitter (Lieberman and Webster, 1974; Ohara et aL, 1983; Hendrickson et al., 1983; Fitzpatrick et aL, 1984; Penny et al., 1984; Gabbott et al., 1985; Montero and Singer, 1985). The complex synaptic arrangements made by optic nerve terminals and dendrites of I-cells and relay neurons are called triplets or serial synapses. Very recently it was revealed that I-cells of the cat L G N d had axons which contacted with dendrites of relay neurons by en passant synapses (Montero, 1987). Targets of I-cell axons or even existence of I-cell axons itself is not clarified yet in the rat. I-cells occupy 20% or more of all neuronal population in the LGNd of rat and cat and in the cat VB, while there are no or only a very few (about 0.4%) I-cells in the rat VB where no serial synapses or vesicle-containing dendrites were observed (McAllister and Wells, 1981; Madarasz et al., 1985; Gabbott et al., 1986; Harris and Hendrickson, 1987; Williams and Faull, 1987). Dubin and Cleland (1977) and Sumitomo and Iwama (1977) tried to record from intrageniculate I-cells. The former used cats and the latter used rats. They encountered a small population of neurons which could not be activated antidromically from the visual cortex. To record extracellular spikes of these neurons in the rat, microelectrodes with finer tip diameter had to be used than those for recording from relay neurons. This corresponds to the morphological finding that I-cells have smaller diameter than relay neurons. In the rat the I-cells so identified electrophysiologically can be easily distinguished from relay neurons in the response pattern to doubleshock stimulation of the optic nerve of 10-100 msec interval; I-cells respond to two shocks separately while relay neurons fail to respond to the second one because of a long-lasting inhibition after the initial excitation (Fig. la, b). This shows that I-cells receive a very weak, if any, input from the TR. Besides, no I-cells have a suppressive or antagonistic surround component of the receptive field (Sumitomo and Iwama, 1977; Kayama et al., 1986a). In this respect, I-cells of the rat had different properties from those of the cat; the cat I-cells seemed to receive an inhibitory input from TR neurons (Ahls6n et al., 1985), and had receptive fields with center-surround organization (Dubin and Cleland, 1977). Thus, relay neurons receive two inhibitory inputs from local neurons; feed-back inhibition from TR neurons and feed-forward inhibition from I-cells (Dubin and Cleland, 1977). Though some suggestions on functional roles of TR neurons have been obtained from various experiments (see the last section), nothing is known as to the real function of the I-ceils except a suggestion that they are concerned with precise, spatially organized inhibition of relay neurons (Dubin and Cleland, 1977). 2.2. CORTICOFUGAL AXONS

Except innervation by the main sensory inputs (optic nerve in Fig. 1) TR and relay neurons receive the same kind projections from remote structures. [Sumitomo et al. (1976b) once reported that some

79

v-TR neurons would be innervated directly by the optic nerve, but this seems to be a mistake due to somewhat crude experimentation of the old age.] The remote projections include those descending from the specific sensory cortex and those ascending from the brainstem nuclei. In the primary visual cortex corticothalamic projection neurons are distributed in layer VI. It has been proved in cats that L G N d neurons innervated by a visual corticothalamic neuron are those with the same receptive field position as the cortical neuron (Tsumoto et al., 1978). Tsumoto and Suda (1980) also have shown that visual corticothalamic neurons of the cat can be classified into three groups. However, no such refined experiments have been done in rats. Corticothalamic axons terminate on distal portions of relay cell dendrites, making synapses with morphological characteristics of the excitatory synapse (Lieberman and Webster, 1974). Their transmitter is suggested to be glutamate or related amino acid (Lurid Karlsen and Fonnum, 1978), but conclusive evidence remains to be obtained in future. It is doubtful whether corticothalamic axons terminate on I-cells (Lieberman and Webster, 1974), though very strong cortical stimulation evokes orthodromic responses in some I-cells (Sumitomo and Iwama, 1977). Corticothalamic axons traverse the TR and there they have collateral branches which innervate TR neurons via the same kind of synapses as in the relay nucleus (Scheibel and Scheibel, 1966; Ohara and Lieberman, 1981, 1985). 2.3. ASCENDING PROJECTIONS FROM THE BRAINSTEM As a part of the diffuse projection to the forebrain, three kinds of ascending axons from the brainstem nuclei reach the thalamus including TR. They are (1) the noradrenergic projection from the locus coeruleus; (2) the serotonergic projection from the dorsal raphe nucleus; and (3) the cholinergic projection from the laterodorsal tegmental nucleus and its rostrolateral extension, the pedunculo-pontine tegmental nucleus. The last one was clarified most recently by immunohistochemicai studies (Sofroniew et al., 1985); neurons of this system have many electrophysiological properties very similar to those of monoaminergic neurons of the first two systems (Kayama and Ogawa, 1987). [Only the TR receives other exceptional cholinergic afferents from the basal forebrain nuclei but other thalamic nuclei do not (Hallanger et aL, 1987).] In rats these brainstem nuclei are well segregated from each other, and they have neurons retrogradely labelled after injection of a marker into the TR or the L G N d (Mackay-Sire et al., 1983). Thalamic projections of noradrenergic, serotonergic and cholinergic neurons are also shown in cats (De Lima and Singer, 1987b), but neurons which are the origin of these projections, especially those of noradrenergic and cholinergic systems, are found to intermingle with each other considerably. In the TR, as well as in the relay nuclei, every axon of noradrenergic, serotonergic and cholinergic neurons, forms many varicosities linked by axons with fine calibers. It has been proved in rats and/or in cats that en passant synapses are made between the varicosities and dendrites of neurons in the TR or relay

80

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FIG. 2. Responses of an a-TR neuron to single shock stimulation of the inferior colliculus (IC) (a, b, e) and of auditory cortex (AC) (c, f), and to tone pip (4 kHz, 5 msec) (d, g). (a) Grouped discharge (burst) was elicited six times by a stimulus applied at the dot. (b~t) Initial discharges recorded with a fast sweep. (e-g) Post-stimulus time histograms. Stimuli were applied at triangles. Each histogram consists of 20 responses. Bin width, 5 msec. Reproduced with permission from Shosaku and Sumitomo (1983), Exp. Brain Res., Vol. 49.

nuclei (De Lima and Singer, 1985, 1987a; L6th et al., 1980; Shimizu et al., 1980). 3. FIRING PROPERTIES OF TR NEURONS 3.1. BURST DISCHARGES AND RELATION TO EEG SPINDLES

In electrophysiological experiments, TR neurons can be identified easily with their peculiar response evoked by stimulation of specific afferent pathways (optic nerve or tract for v-TR, medial lemniscus for s-TR, and inferior colliculus for a-TR) (Sumitomo et al., 1976a; Sugitani, 1979; Shosaku and Sumitomo, 1983). They respond with a burst comprised of several spikes; the burst repeats several times (Fig. Ic). Inter-burst intervals are 60-100 msec. The interval between the first and second bursts is usually longer than the other but it is changeable according to the level of cortical activity and other factors (Section 3.3). Quite similar responses can be evoked by natural stimulation or by stimulation of the cortical area which evokes antidromic responses in relay neurons (Fig. 2). In contrast to the burst response of TR neurons, neurons in the relay nucleus respond initially with a single spike to stimulation of the specific input pathway (Fig. la, b). After the initial response, relay neurons suffer a long-lasting (up to several hundred msec) suppression of discharge. During this period the cells are hyperpolarized by G A B A released from TR axons (Curtis and Teb~cis, 1972; Kayama et al., 1981; Kayama, 1985; see Section 5.2). The suppression terminates in a rebound burst discharge; this latter burst is comprised of a fewer number of spikes than that of TR neurons. The rebound discharge tends to be evoked by weaker stimuli than for the initial response.

As described above, both relay and TR neurons show burst discharges, but such a property is more conspicuous in TR neurons than in relay neurons (Negishi et al., 1962). TR neurons frequently show burst discharges not only in response to sensory stimulation but also spontaneously. The spontaneous burst appears sporadically or sometimes rhythmically with inter-burst intervals of 60-100msec (mean, about 80msec, i.e. about 13Hz). This rhythm is about the same as seen in the response evoked by sensory stimulation. The spontaneously occurring rhythmic repetition of the burst firing of TR neurons is usually seen when the brain is in a condition characterized by spindles in the cortical EEG. To clarify a relation between firings of TR neurons and EEG spindles, Sumitomo and Iwama (in preparation) performed a subtle experiment in which the EEG was recorded with a semi-microelectrode from the vibrissal part of the rat somatosensory cortex (SI area) where neurons are driven from one and the same vibrissa cluster forming a barrel structure. Simultaneously with the EEG, single neuronal activity was recorded from an s-TR neuron, or from a relay neuron in the VB, with the receptive field on a vibrissa. (These neurons are driven from only a single vibrissa, as described in detail in Section 4.) When the receptive field of the s-TR neuron coincided with that of cortical neurons around the EEG electrode, the rhythmic repetition of burst firing of the s-TR neuron occurred with the same timing as the EEG spindle (Fig. 3, A l). A complete synchronization was observed between the burst firing and individual wave of the spindle (Fig. 3, A2). A similar relation was observed between the firing of a VB neuron and the cortical EEG (Fig. 3, BI), but in this case the VB neuron frequently failed to follow individual waves of the spindle (Fig. 3, B2). No synchronism could be found between the firing of

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FIG. 3. Comparison of cortical spindle waves and burst discharges of thalamic neurons. Cortical EEG (upper trace of each record) was recorded from one point of vibrissal portion (barrel field) of the somatosensory area I (SI), and thalamic unit discharges (lower trace, only timings of burst firing were marked) were from an s-TR neuron in A and from a VB relay neuron in B. An alphabetic letter plus a number in parentheses after SI, s-TR or VB, is the name of vibrissa giving exclusive excitatory input to recorded site or neuron (receptive field). A-I and B-1, cases in which the receptive fields of the cortical site and thalamic neuron coincided with each other. A-2 and B-2, records during a single episode of spindle ~tivity in an expanded time scale, obtained following A-I and B-l, respectively. A-3 and B-3, control cases for A- ! and B- I, respectively, in which the receptive fields of the cortical site and thalamic neuron did not coincide. an s-TR neuron or a VB neuron and the EEG of a cortical site driven from different vibrissae (Fig. 3, A3 and B3). These results suggest strongly that a rhythm of EEG spindles is developed by a neuronal circuit involving TR, relay nuclei and cerebral cortex. Among them, the TR may be a main generator of spindle rhythmicity, as Steriade et al. (1987) found that the cat TR, deafferented from the surrounding structures, still showed spindle-related rhythms. A cross talk or a mutual inhibition among TR neurons (Ahls~n and Lindstr6m, 1982) may play a role in synchronizing the oscillatory rhythm. This can be achieved through GABAergic synapses made by intra-TR collateral axons of TR neurons (Houser et al., 1980; Montero and Singer, 1984). In addition to this, in cats dendro-dendritic synapses are supposed to contribute to generation of the oscillation (Montero and Singer, 1984; Desch~nes et al., 1985; Yen et al., 1985). There is no report on behaviors of TR neurons in relation to the vigilance level in unanesthetized rats. In chronically prepared cats, TR neurons fire with the bursting pattern during slow wave sleep, whereas during wakefulness or REM sleep they show tonic discharges comprised of single solitary spikes (Hirsch et al., 1982; Mukhametov et al., 1970; Steriade et al., 1986). In an anesthetized condition TR neurons show tonic discharges temporarily only when they receive strong excitatory inputs (see later Section 3.4). 3.2. MEMBRANE PROPERTIES

Recent studies by Llimis and Jahnsen (Llimis and Jahnsen, 1982; Jahnsen and Llimis, 1984a, b) using in

vitro slice preparations of the guinea-pig thalamus

revealed several important properties of the membrane of thalamic neurons. They found that thalamic neurons had two distinct types of spiking activity: low-threshold, broad spikes of small amplitude were generated by a voltage-dependent change in Ca 2+ conductance, and ordinary fast spikes by a voltagedependent change in Na ÷ conductance. The lowthreshold spike, usually accompanied by a burst of fast spikes superposed on its broad peak, was seen only when the membrane was hyperpolarized below about - 60 mV. The spike complex consisting of the low-threshold broad spike and a burst of fast spikes was triggered in the hyperpolarized condition by a transient depolarization induced synaptically or induced by a direct current injection. It was also initiated upon a break of hyperpolarizing current. When the resting membrane potential decreased to above - 6 0 m V , the Ca2÷-dependent mechanism of the low-threshold spike was inactivated, and only ordinary fast spikes were generated tonically. The more the membrane was depolarized, the higher the rate of the tonic discharge was. [As shown in Fig. 4 in which some "low-threshold spikes" have lower amplitudes, they are not necessarily all-or-none. Therefore, if action potential which should be all-ornone is indicated with the term "spike", the "lowthreshold spike" may not be an appropriate term. Actually, some workers described it only as depolarization (Fourment et al., 1985). Here we use "spike" for convenience' sake, following Jahnsen and Llimis.] Jahnsen and Llimis (1984a) reported briefly that TR neurons are quite similar to other thalamic neurons in general properties of electrical activities.

82

A. SHOSAKUet al.

TR LM

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V8 500ms FIG. 4. Intracellular recordings from an s-TR neuron (A and B) and from VB neurons (C, and D and E). A and 13, and D and E contrast oscillations evoked by lemniscus medialis (LM) stimulation (A, D) and occurred spontaneously (B, E) in the same neuron. Neurons of A and C were recorded in the same animal. McCormick and Prince (1986) confirmed it also in slice preparations from the guinea-pig brain, except that the input resistance was high in TR neurons (75-250 Mfl) as compared with other thalamic neurons (24-60 Mfl, Jahnsen and Llin/ts, 1984a). We have succeeded in intracellular recordings from TR neurons of the rat in vivo (I. Sumitomo, Y. Takahashi, Y. Kayama and T. Ogawa, in preparation; preliminary report in Kayama et al., 1986b), and found that the low-threshold broad spikes with a burst of fast spikes superposed (the spike complex) and the tonic firing of solitary fast spikes are identified as observed in vitro. However, there was a conspicuous difference between in vivo and in vitro preparations; thalamic neurons (TR and also relay neurons) in vitro generated the spike complex only when they were stimulated synaptically or by current injection, whereas the spike complex occurred spontaneously in in vivo preparations. In TR neurons in eivo the spontaneous spike complex frequently appeared repetitively with a rhythm of about 13 Hz, just in the same way as those after stimulation of input pathways (Fig. 4). The same was reported in TR neurons of the cat in vivo (Muile et al., 1986). A rhythmic event with the same frequency as in the TR neurons (about 13 Hz) was observed also in relay neurons. However, as shown in Fig. 4, in relay neurons the rhythmic activity was made of hyperpolarizations occurring spontaneously or after sensory stimulation. Each of the hyperpolarizations would be an IPSP mediated by G A B A released from TR axon terminals by a burst of firing, since the rhythm disappeared after isolation of relay nuclei from the TR (Steriade et al., 1985). Some hyperpolarizations led to a rebound occurrence of the spike complex. The same phenomena were observed in relay neurons of the cat thalamus (Desch~nes et al., 1984; Roy et al., 1984). It is a good contrast that the rhythm is made of hyperpolarizations in relay neurons and of depolarizations in TR neurons. No clear hyperpolarizing potential was observed in TR neurons during an episode of spike complex repetition. Steriade et al. (1987) suggest that the depolarizing rhythm is generated by intrinsic membrane properties of TR neurons, since the TR isolated from the relay nuclei and cortex still has the spindle rhythm. How-

ever, even if TR neurons have such peculiar properties, we think that excitatory inputs to TR neurons are important to generate the spike complex or to modify them, since a detailed observation of the low-threshold broad spike revealed that small notches were always superposed on its rising phase (Fig. 5B). It seems that the notches are EPSP, because the notches are very similar to EPSPs which are evoked by single-shock stimulation of sensory pathways but remain subliminal for generation of spikes (Sumitomo et al., in preparation). The broad spike of relay neurons has a smooth rising phase with no EPSP-like steps (Fig. 5C). Differently from TR neurons, relay neurons possibly generate the broad spike without excitatory inputs but only upon a release from hyperpolarization. Another difference between the TR and relay neurons with regard to the broad spike is in the breadth of the peak; the broad spike of TR neurons has a much wider peak (Fig. 5). TR neurons usually have more numerous spikes in a burst than relay neurons, but the number of spikes changes depending upon amplitudes of the broad spike, which in turn depends upon how strongly the cell has been hyperpolarized (Fig. 5). 3.3. MODULATION BY CORTICOFUGAL INPUTS

Though many workers studied influences of the corticothalamic projection on relay neurons, those on TR neurons were reported only by a few groups (Schmielau, 1979). In rats, Kayama et aL (1984) attempted to reveal influences of the corticothalamic projection upon TR neurons by cooling of the visual cortex (VC) temporarily. The effects of cooling of the VC on photically evoked activity in two v-TR neurons are shown in Fig. 6, A and B. Both neurons fired faster when their receptive fields were illuminated. Their low-rate discharges during periods without receptive field illumination were in the same range as the spontaneous activity. Neuron A was influenced more strongly by VC cooling than neuron B; the response of A was eliminated by the end of about 40 sec of cooling, while in neuron B the spontaneous discharge disappeared soon after the onset of VC cooling, but the discharge evoked by photic stimu-

83

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50ms 50ms FIG. 5. (A) Low-threshold spikes with fast spikes superposed of an s-TR neuron whose resting potential was set at various levels with hyperpolarizing currents. Note that the more hyperpolarized the cell is, the higher the amplitude of the low-threshold spike, and the more the number of fast spikes superposed. (B) Low-threshold spikes of another s-TR neuron in an expanded scale to show EPSP-Iikenotches in the rising phase. Fast spikes were clipped. (C) Low-threshold spikes with fast spikes superposed of 3 different VB neurons.

lation was maintained at a somewhat reduced rate. It was frequently observed that the tonic type of photic response was strongly suppressed, leaving only a phasic response at the change of illumination (e.g. Fig. 6A). While such a change in response type is not seen in Fig. 6B, a similar change was readily induced by decreasing the stimulus intensity, as illustrated in Fig. 6B'. The effects of VC cooling were also examined on discharges of v-TR neurons evoked by electrical pulses applied to the optic chiasm. As shown in Fig. 7A and B, the effects differed depending upon the strength of chiasmal stimulation. In the test shown in Fig. 7A, a v-TR neuron was excited by barely supraliminal stimulation, which evoked only one or two bursts. In such circumstances, cooling the VC eliminated all responses except the single initial spike. On the other hand, when the same neuron was excited with chiasmal stimulation at an intensity of twice threshold, yielding several bursts (Fig. 7B), VC cooling did not affect the number of spikes in each burst, but prolonged the latencies of the second and later bursts, again evidencing a suppressive effect of the cooling. The same effects of VC cooling could be observed in LGNd relay neurons (Fig. 6C, D), but with a lower possibility than in v-TR neurons (Table 1). These results show that the corticofugal influence on thalamic neurons is excitatory, and upon elimination of the influence disfacilitation in many LGNd neurons is counterbalanced by disinhibition due to the disfacilitatory suppression of the inhibitory v-TR neurons. The fact that substantially all v-TR neurons in the rat are highly dependent upon the VC in its activity suggests a possibility that the TR is likely to be primarily a tool of the cortex in the modulation of thalamic events. Differently from the results of acute cryogenic inactivation of VC, chronic ablation of the VC produced effects which were interpreted as disinhibition of v-TR neurons (Sumitomo et al., 1977). Interpretation of this result is difficult, now that all corticofugal projections are thought to be excitatory, arising from pyramidal neurons and having glu-

tamate as a transmitter (see Section 2.2). Chronic decortication induces degeneration of at least some of the relay neurons, which may in turn induce some changes in the input--output organization of TR neurons. 3.4. MODULATIONBY ASCENDING BRAINSTEMINPUTS The thalamus receives three kinds of ascending projection from the brainstem: cholinergic, nor-

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FIG. 6. Effects of cooling the visual cortex on photic responses of v-TR neurons (A, B, B') and LGNd neurons (C, D). Each record consists of output of ratemeter (uppermost trace, bin width, 0.5 sec), horizontal thick bar indicating period of cooling, and output of photodiode placed in receptive field (lowermost trace, light-on is upward). B and B' were recorded from the same neuron, the intensity of photic stimulation in B' being i/16 that in B. Reproduced with permission from Kayama et aL 0984), Exp. Brain Res., Vol. 54.

84

A. SHOSAKUet al.

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FIG. 7. Effects of cooling the visual cortex on responses evoked in a v-TR neuron by single shock stimulation of the optic chiasm (OX). Records of A and B were obtained from the same neuron; in A intensity of OX stimulation was barely supraliminal, while in B this intensity was doubled. For both A and B, examples of responses photographed in control state and during cooling are shown at the left, and at the right are shown the numbers of spikes in the initial and second bursts (A) or latencies of the second burst (B) with horizontal thick bars indicating period of cooling. Reproduced with permission from Kayama et al. (1984), Exp. Brain Res., Vol. 54.

adrenergic and serotonergic. We have studied functions of these projections in the LGNd and TR by stimulating each brainstem nucleus from which they arise. Among them, the function of the serotonergic system was most difficult to determine; it was inhibitory on LGNd relay neurons, but this emerged with a long latency only after prolonged repetitive stimulation of the dorsal raphe nucleus, and it was frequently concealed by spontaneous changes in activity level of the whole brain as evidenced by the cortical EEG (Y. Kayama, S. Shimada, Y. Hishikawa and T. Ogawa, in preparation). Because of this difficulty in experimentation, we could not obtain sufficient data to clarify effects of dorsal raphe stimulation on TR neurons. Therefore, serotonergic influence on TR neurons was studied only by iontophoretic application, and it was inhibitory in most TR neurons but excitatory in some neurons (Fig. 11). Another group reported that raphe stimulation exerts an inhibitory effect on responses of v-TR neurons evoked by electrical stimulation of the optic pathways (Yoshida et al., 1984). So far effects of raphe stimulation on the pattern of spontaneous discharges or on responses to natural sensory stimulation of TR neurons have not been reported. Cholinergic influences on TR neurons were successfully examined in rats by stimulating the laterodorsai tegmental nucleus (LDT) in which cholinergic neurons with ascending projection were packed tightly (Kayama et al., 1986b). As to the discharge rate of v-, s- and a-TR neurons, repetitive LDT stimulation was found to decrease it in some neurons and to increase it in others. Still in other neurons the discharge rate either decreased or increased depending upon the intensity of LDT stimulation; strong LDT stimulation increased the rate, whereas weak stimulation caused only a decrease (Fig. 8). Careful observations of the discharge pattern, and simultaneous recordings of the cortical

EEG with the firing, led to emphasis of the following two points. (1) LDT stimulation, weaker or stronger, always suppressed burst discharges of TR neurons. The decrease in the discharge rate with weaker stimulation was due to a suppression of bursts seen in the control state. Stronger stimulation replaced the burst with the tonic discharge, accelerating the overall rate of discharge. (2) In most TR neurons tested, a threshold of LDT stimulation for inducing tonic discharges was of almost the same intensity as that for desynchronizing the cortical EEG (Fig. 8). These findings were in contrast with the effects of LDT stimulation on LGNd relay neurons; their firing rate was always increased even by weak LDT stimulation which was insufficient to cause EEG desynchronization. It was proved that these effects were mediated by acetylcholine via muscarinic receptors (Kayama et al., 1986a, b). We interpreted that both suppression of the burst firing and induction of the tonic firing by LDT stimulation were due to depolarization of the membrane (Kayama et al., 1986b). As shown in Fig. 9 which was obtained from one and the same TR neuron, discharge patterns of intracellularly impaled TR neurons changed depending on the level of TABLE

I. SUPPRESSIVE EFFECTS OF COOLING V C RESPONSES OF UNITS IN v - T R VERSUS L G N d

Spontaneous activity

UPON

v-TR

LGNd

32,/32* 100%

12/22 55%

Photically evoked 27/33 82% 12/35 34% response Chiasm-induced 8/10 80% 2/7 29% response One or more of 37/38 97% 17/41 41% the above * Number of neurons affected versus number studied.

85

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5V FIG. 8. Effects o f laterodorsal tegmental nucleus stimulation on spontaneous discharges of a v-TR neuron (A) and an LONd relay neuron (B). The stimulus was composed of square pulses o f 0.05 msec in duration repeated at 200 Hz for several seconds. Each record consists of output of ratemeter (upper trace, bin width, 0.5 see), horizontal thick bar indicating period of stimulation, and cortical EEG recorded simultaneously with unit activity (lower trace). Amplitude of EEG was not calibrated exactly, but was about 0.4 inV. Actual records of spike discharge during periods indicated by a-I, a-2 and b under the EEG are shown in the lower part o f the figure. Intensity of stimulation is shown under each record. Reproduced with permission from Kayama et al. (1986b), J. Neurophysiol., Vol. 56.

¢

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i

1sec FIG. 9. Spiking activity recorded intracellularly from one and the same s-TR neuron. Currents shown under A, B, C, and D were injected to hyperpolarize the resting potential. Straight line, level of threshold for fast spikes (about - 50 mV). Broken line, average level of resting potential set by injection of current of each intensity. Note that in a relatively hyperpolarized state the cell discharged low-threshold broad spikes on which a burst o f fast spikes superposed, and slight depolarization from this state abolished the spiking activity (trace A). In a more depolarized state it discharged single fast spikes tonically (traces B and C). Each o f the small arrows in trace D indicates mesencephalic reticular formation stimulation with 6V square pulses o f 0.05 msec in duration. Two records o f D are separated by a period o f 4 sec during which no spiking activity was observed. The reticular formation stimulation depolarized the membrane to induce fast spike discharges. Reproduced with permission from Kayama et al. (1986b), J. NeurophysioL, Vol. 56.

86

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A

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I

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FIG. 10. Effects of locus coeruleus (LC) stimulation on spontaneous discharges of v-TR neurons. In A, LC was stimulated with 5V electrical pulses of 0,05 msec in duration repeated at 200 Hz for several seconds, while in B, LC neurons were activated with an infusion of a glutamate solution into the LC region to avoid stimulation of axons passing through or by LC. Actual spiking activity is shown for A, in which dots indicate grouped discharges (bursts), while in B output of ratemeter (bin width, 0.5 sec) is shown. Two traces of B are continuous at asterisks. Reconstructed with permission from figures in Kayama et al. (1982), Neuroscience, Vol. 7.

membrane potential. When TR neurons were very strongly hyperpolarized by an intraceUularly injected current, no spiking activity was seen (not shown). With a hyperpolarization to a moderate degree, they discharged low-threshold broad spikes on which a burst of fast spikes was superposed (the spike complex, Fig. 9A). A slight depolarization from this state abolished the spiking activity. When the hyperpolarizing current was slightly weaker (Fig. 9B), the frequency of the spike complex increased, but during a period of depolarization which occurred spontaneously the firing pattern changed to a tonic firing with single fast spikes. A much weaker hyperpolarizing current did not induce a bursting of fast spikes anymore (Fig. 9C, D), and only a slight depolarization caused a tonic firing of solitary fast spikes. Furthermore, in these experiments it was observed that mesencephalic reticular formation (MRF) stimulation always depolarized the membrane of TR neurons (Fig. 9D). (The site of stimulation in the M R F was the lateral edge of the pedunculo-pontine tegmental nucleus where cholinergic neurons existed scatteringly. Stimulation of the LDT was not attempted because of a difficulty in experimentation.) Depending on the membrane potential set by intracellular current injection, and on the strength of M R F stimulation, the depolarization resulting from M R F stimulation influenced discharge patterns in various ways: (1) generation of the spike complex in a strongly hyperpolarized silent state; (2) arrest of the on-going spike complex with a transition to a more depolarized silent state; (3) replacing spike complexes with tonic discharges of fast spikes; (4) initiation of a tonic discharge of fast spikes in a silent state as seen in Fig. 9D; or (5) increasing the rate of tonic discharge. These findings support the interpretation that the cholinergic input from the brainstem depolarizes TR neurons. In this sense influences of the cholinergic projection on TR neurons are concluded to be ex-

citatory. This cholinergic excitation is supplemented by an indirect excitatory input from the cortex activated by LDT stimulation strong enough to desynchronize EEG. These conclusions can settle an inconsistency in previous studies as to whether M R F stimulation excites or inhibits TR neurons of the rat and cat (Dingledine and Kelly, 1977; Fourment et al., 1983; Fukuda and Iwama, 1971; Schlag and Waszak, 1971; Steriade and Deschrnes, 1984; Yingling and Skinner, 1975). As to why both thalamic relay neurons and their inhibitory element, TR neurons, are excited by the cholinergic system, we have made some discussion and supposition (Kayama et al., 1986b). However, data were reported by McCormick and Prince (1986) which were inconsistent with our conclusion that the cholinergic system depolarizes TR neurons. These workers studied TR neurons in slice preparations from the guinea-pig brain, and found that these neurons were hyperpolarized by acetylcholine via muscarinic receptors. They maintain that the response to acetylcholine varies from species to species, and from nucleus to nucleus of the thalamus (McCormick and Prince, 1987). For example, in cat, LGNd, acetylcholine induces a nicotinic fast depolarization which is followed in many cases by a muscarinic slow depolarization and in a few cases by a muscarinic hyperpolarization. In cat medial geniculate nucleus (MGN) the nicotinic fast depolarization is invariably followed by a muscarinic hyperpolarization, and in some neurons followed further by a slow depolarization. In guinea-pig LGNd and MGN, the majority of neurons are hyperpolarized by acetylcholine via muscarinic receptors, and in about half of them the hyperpolarization was followed by a slow depolarization. In rat LGNd, however, only the muscarinic depolarization is induced by acetylcholine. Thus, even if it is true that TR neurons of the rat are depolarized by acetylcholine as described above, acetylcholine response of TR neurons may not

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FIG. 11. Effects of iontophoreticallyapplied acetylcholine (ACh), noradrenaline (NA) and serotonin (5HT) on firings of three TR neurons (A, B, and C). For each neuron, output of ratemeter (bin width, 0.5 sec) is shown. The numbers after drug names are intensity of current (hA) flowed to eject drugs. Note that effects of ACh appeared and disappeared very quickly compared with those of others.

necessarily be depolarization in other species of animals. We also examined noradrenergic influences on v-TR neurons by locus coeruleus stimulation (Kayama et al., 1982). Upon stimulation of the locus coeruleus with repetitive electrical pulses or with infusion of a glutamate solution, sporadic burst discharges of v-TR neurons were suppressed and replaced by a tonic firing (Fig. 10). It was proved that this effect was mediated by noradrenaline acting upon alpha-receptors. This shows that, as in the case of the cholinergic projection, the noradrenergic projection exerts excitatory influences on TR neurons. However, a qualitative difference was noticeable between the excitations by cholinergic and noradrenergic inputs; the effect of locus coeruleus stimulation remained long after the cessation of stimulation (up to a minute at maximum) and subsided gradually, while the effect of LDT stimulation disappeared quickly after the stimulation, or even began to fade within a few seconds despite continuing stimulation (Fig. 8). A similar difference is seen in excitation of L G N d relay neurons by cholinergic and noradrenergic inputs (Kayama et al., 1986a). The same is true with excitation by iontophoretic application of acetylcholine and noradrenaline (Fig. 11). Both drugs increased the firing rate of TR neurons, but the effect of acetylcholine appeared and disappeared within a second, while the effect of noradrenaline appeared and disappeared gradually taking more than several tens of seconds. In these experiments effects of serotonin were also examined; they appeared and disappeared gradually as in the case of noradrenaline. In most TR neurons serotonin caused inhibition, but in a few eases it exerted excitatory effects (Fig. 11C). The ascending cholinergic and noradrenergic projections from the brainstem nuclei may be a real substrate for the ascending reticular activating system, which was defined by Moruzzi and Magoun in

1949. The distinctive effects on thalamic neurons of the cholinergic and noradrenergic inputs (Kayama et al., 1982, 1986a, b) suggest that there may be a double activating system; the cholinergic projection from the LDT plays a role as a phasic activating system to produce attention, while the noradrenergic projection from the locus coeruleus acts as a tonic activating system to produce arousal. Observations on behaviors of cholinergic and noradrenergic neurons in response to sensory stimuli (Kayama and Ogawa, 1987) support this hypothesis.

4. TR NEURONS ACTIVATED BY SENSORY STIMULATION 4.1. SUBDIVISIONS OF THE TR

Jones (1975) showed by anatomical methods using horseradish peroxidase and labelled amino acid that the TR of the rat, cat and monkey was divided into several "sectors", each sending axons to a particular thalamic relay nucleus and receiving axon collaterals from the same relay nucleus. He illustrated the whole extent of such sectors for the cat thalamus. Solely by physiological methods we have found that the TR of the rat is divided into small portions according to the connections with different relay nuclei. The series of maps in Fig. 12 are drawn mainly on the basis of our previous data and partly with reasonable assumption. In these maps the TR is divided into several portions marked with different symbols. These maps are taken as a physiological counterpart of Jones' map of sectors. Physiological mappings of the sectors of the TR were made in the following way. First, the cluster of TR neurons receiving visual inputs (v-TR neurons) was identified in the rat thalamus by Sumitomo et al. (1976). This cluster was located immediately rostral and lateral to the LGNd. The cluster of s-TR neurons

88

A. SHOSAKU et al.

,A

B

C

D

FIG. 12. A schematic diagram of the rat thalamus. Illustrations are modified from Paxinos and Watson (1982), arranged from rostral to caudal coronal planes (A to G) with intervals of 0.5 mm, except the last one with 1mm intervals. Areas shadowed at edge are the TR. Connections between sites in relay nuclei and TR are shown with the same symbols. Because no complete anatomical map of the whole TR of the rat has been published, this figure is based upon our studies of physiologicalmapping, an anatomical study of the rostral part of the rat TR by Nguyen-Legros et al. (1982) and some speculations from anatomical studies of the cat TR (Jones, 1975; Steriade et al., 1984). As shown in this figure, each dorsal thalamic nucleus is related to a different sector of the TR, albeit with a good deal of overlap. AD, anterodorsal nucleus; AM, anteromedial nucleus; AV, anteroventral nucleus; CL, central lateral nucleus; CM, central medial nucleus; LD, lateral dorsal nucleus; LGd, dorsal part of lateral geniculate nucleus; LGv, ventral part of lateral geniculate nucleus; LP, lateral posterior nucleus, for which the visually responsive part is distinguished from the rest (Sumitomo et al., 1988); MD, mediodorsal nucleus; MG, medial geniculate nucleus; PC, paracentral nucleus; Pf, parafascicular nucleus; Po, posterior nuclear group; PTA, pretectal area; VB, ventrobasal complex; VL, ventral lateral nucleus; VM, ventral medial nucleus; ZI, zona incerta.

was delineated by Sugitani (1979) in the part of the TR adjoining the VB laterally or anterolaterally. Later, Shosaku and Sumitomo (1983) found a cluster of a-TR neurons in the postero-ventral part of the TR. These workers attempted to delineate a positional relation of v-, s- and a-TR physiologically (Fig. 13). Each TR neuron was categorized as a v-, s- or a-TR neuron according to the response to single shock stimulation of the central sensory pathways. In a relatively anterior part of the TR (rostral to the frontal plane 2.2 mm posterior to the bregma), only s-TR neurons were found (Fig. 13A-D). In the plane where the VB reached its maximal width, the s-TR area became small and its dorsal and ventral parts were occupied by v- and a-TR neurons, respectively (Fig. 13E). More posteriorly than the frontal plane of the rostral tip of LGNd (Fig. 13G), the s-TR disappeared and the TR was divided dorso-ventrally into two portions; the upper v-TR area and the lower a-TR area (Fig. 13G-J). In summary, s-, v- and a-TR neurons were scattered in the anterior, postero-dorsal and postero-ventral portions of the TR, respectively. This distribution pattern is in good agreement with that shown by anatomical studies of Carman et al.

(1964) and Jones (1975); in the former study done on the rat the TR was partitioned according to connections with different parts of the cortex, and in the latter work concerned with the rat, cat and monkey the division of the TR was made according to connections with thalamic relay nuclei. An interesting finding was made by Shosaku and Sumitomo (1983). They noted that some TR neurons were activated by inputs from two different sensory pathways (double-sensory TR neurons). In the experiment of Fig. 13, 12 neurons plotted with stars were found to be double sensory, as labelled AV, AS or SV (A: activated from stimulation of the inferior colliculus; S: activated from the medial lenmiseus; V: activated from the optic tract). The double-sensory TR neurons were located close to the boundary between the dusters of s-, v- and a-TR neurons. It was examined whether the double-sensory neurons could be activated by natural stimuli of different modalities. In most cases only one modality of natural stimulus was effective. The physiological finding of double sensory T R neurons may correspond with the anatomical one of overlapping of the sectors (Jones, 1975), though the anatomical overlapping

THALAMIC

I.

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Lt II.

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FIG. 13. Distribution maps of thalamic units. Each of the three panels (I, A-C; II, D ~ ; III, H-J) mounts the data from one rat. In each panel maps are arranged from left to right with increasing anteroposterior distances (AP) from the bregma. In each map, ordinates are depths from the cortical surface and abscissae, distances from the midline. Six kinds of units are plotted with different symbols. Double-sensory TR neurons are distinguished from each other with letters AV, AS and SV. Reproduced with permission from Shosaku and Sumitomo (1983), Exp. Brain Res., Vol. 49.

seems to be too extensive to explain the ratio of the double-sensory neurons. In addition to the v-, s- and a-TR neurons, TR neurons responding to a vestibular stimulation were found by Magnin and Putkonen (1978) in the cat. Surprisingly, these TR neurons were reported to distribute above the LGNd, i.e. in the perigeniculate area, where v-TR neurons could be observed.

neurons, the representation of each part of the body in it is fairly accurately drawn as a two-dimensional figure of the whole body. The head and face were represented in a ventro-caudal part occupying about two thirds of the whole s-TR. Particularly a large area was devoted to the vibrissae, nose (rhinarium) and lips. The projections of the hind- and forelimbs and the trunk were to the rostro-dorsal part. Thus, the rostral-to-caudal and dorsal-to-ventral axes of the 4.2. SOMATOTOPICAND RETINOTOPIC ORGANIZATION body are transformed into the ventral-to-dorsal and caudal-to-rostral directions in the s-TR, respectively. AS shown in the previous section, TR neurons are This rotation of axes was seen especially precisely for grouped into different clusters according to the mo- neurons representing the vibrissae; the most dorsal dality of sensory input. A question arises whether a row of vibrissae (row A, see Fig. 20) was represented finer topographic organization exists within each most caudally, and the most caudal row (No. 1, see cluster. So far such an organization has been demon- Fig. 20) most dorsally in the s-TR. A map of the body strated in the s- and v-TR. similar to that in the s-TR can be drawn in the VB Shosaku et al. (1984) could demonstrate a clear (Waite, 1973; M. Sugitani, J. Yano, T. Sugai and H. somatotopic organization in the rat s-TR by a phys- Ooyama, in preparation). The map in the VB is iological mapping experiment, as summarized sche- slightly complicated because of its three-dimensional matically in Fig. 14. Since the TR is a thin sheet of structure.

90

A. SHOSAKUet al.

D

/J

c

/

. _

A

R

V FIG. 14. A schematic drawing of somatotopic representation of the s-TR projected onto the sagittal plane. R, rostrat; C, caudal; D, dorsal; V, ventral. Reproduced with permission from Shosaku et al. (1984), Brain Res., Vol. 31 I.

Somatotopic representation in the s-TR of awake cats and monkeys was reported by Pollin and Rokyta (1982). Although their observations were not detailed enough, an arrangement that the limbs and the face are represented in the rostral and caudal parts of the s-TR, respectively, is in good agreement with that of the rat (Shosaku et al., 1984). However, Pollin and Rokyta (1982) also reported that areas of the TR representing different parts of the body overlapped each other considerably. Besides, they found particularly in monkeys that there were many TR neurons which represented ipsilateral body parts. These findings are not consistent with those in the rat (Shosaku, 1984). Visual field representation or retinotopic organization in the v-TR have been demonstrated by some authors. In the cat v-TR (perigeniculate nucleus), Sanderson (1971) described a visual field representation which was organized in the same way as a retinotopic map in the underlying LGNd. Although not such a systematic mapping as in the cat v-TR was carried out in the rat, Hale et al. (1982) suggested the existence of retinotopic organization in the rat v-TR; the naso-temporal axis in the visual field was represented ventro-dorsally, and the upper visual field was represented caudally in the v-TR. A retinotopic organization in the rabbit v-TR was demonstrated by Montero et al. (1977) with a double-label autoradiography after injection of labelled amino acids to the striate cortex. This retinotopic map in the TR was similar to a map established in the LGNd, though the TR map showed an elongation in the dorso--ventral axis. 4.3. RECEPTIVE FIELD PROPERTIES Shosaku (1985) examined receptive field properties of rat s-TR neurons receiving inputs from vibrissae. The majority of these cells responded to a displacement of only one vibrissa. In this point the s-TR neurons resembled the majority of vibrissaresponding VB neurons. However, there was a noticeable difference in direction selectivity between

s-TR and VB neurons. As shown in Fig. 15 (A and C), the VB neurons were generally activated by a deflection of a vibrissa only in one direction, while most of s-TR neurons responded equally well to deflections in all directions. This property of s-TR neurons results probably from a convergence of inputs to one s-TR neuron from many VB neurons with different directional selectivities. As shown in Fig. 15A, activity of most VB neurons was suppressed transiently not only by vibrissal movement in preferred direction (post-excitatory suppression), but also by that in non-preferred direction. A mechanism of the suppressions may be explained as shown in Fig. 16; a deflection of a vibrissa in one direction excites a group of VB neurons, which in turn activate many s-TR neurons (A), and the inhibitory effect recurring from them suppresses all VB neurons (B). (As for more detailed aspects of connectivity between VB and s-TR neurons, see Section 5.3.) The inhibition of initially excited VB neurons would serve to improve temporal discrimination of the stimulus sequence. The inhibition of other neurons would serve to improve discrimination of the direction of vibrissal movements. There are a few VB neurons which can not be excited by deflection of the receptive-field vibrissa in any direction (vibrissa-suppressed neuron, Fig. 15B). It may be possible that some way other than deflection (pushing, pulling, rotation, etc.) is required to excite them, and a deflection to any direction suppressed their activity via s-TR neurons. Receptive field properties of rat v-TR neurons were examined by Hale et al. (1982) and by us (Kayama et al., 1984). The receptive fields of v-TR neurons are circular or elliptical with no surround inhibitory area. Most v-TR neurons responded phasic,ally with a burst of several spikes at both turning-on and -off of visual stimulation. This was in contrast with the fact that the majority of L G N d relay neurons are classified as showing either on- or off-responses (Fukuda et al., 1979). Sometimes, however, v-TR neurons responded to visual stimulation with repetition of burst discharges or even with more sustained

THALAMIC

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FIG. 15. Typical response patterns of vibrissa-excited VB neuron (a), vibrissa-suppressed VB neuron (b) and s-TR neuron (c). In the VB the majority o f neurons responded like A, while only a very few like B. For each unit, peri-stimulus time histograms to the deflection o f a vibrissa in the 4 directions (r, rostral; c, caudal; d, dorsal; v, ventral) are shown as indicated by arrows. The trace under each histogram is wave form o f vibrissa movement at I0 mm from the vibrissa base. The vibrissa was always moved from and returned to its resting position. Each histogram cumulates 20 responses. Bin width, 10 msec. Reproduced with permission from Shosaku (1985), Brain Res., Vol. 347.

92

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FIG. 16. Functional model for the s-TR recurrent inhibitory action. Four s-TR and 8 VB neurons are assumed to have receptive fields on 1 vibrissa. All s-TR neurons are supposed to be insensitiveto direction. Every VB neuron is supposed to be sensitive to only I of 4 directions. Their preferred directions are indicated by arrows. A, excitatory outputs from VB to s-TR neurons when the receptive-fieldvibrissa is deflected in an upward direction. The excited neurons are shaded. One VB neuron excites half of the s-TR neurons as shown in Fig. 23. B, inhibitory outputs from s-TR to VB neurons as a result of the vibrissal deflection. One s-TR neuron inhibits half of the VB neurons as shown in Fig. 23. Reproduced with permission from Shosaku (1986), J. Neurophysiol.. Vol. 55. discharges. This difference in response pattern seems A remaining question concerning the input conto reflect a variability in the excitability of individual vergence onto v-TR neurons of the cat is how it is v-TR neurons rather than differences of neuron types related to the Y/X classification of LGNd neurons. (Hale et al., 1982). The excitability is controlled by Three different possibilities have been proposed. ascending inputs from the brainstem and by deFirst, v-TR neurons may be activated only by Yscending inputs from the visual cortex (see Sections neurons of the LGNd (Dubin and Cleland, 1977). 3.3 and 3.4). Second, they may receive inputs from both Y- and As to the size of receptive field, Hale et al. (1982) X-neurons (So and Shapley, 1981). And last, Y- and reported that the receptive field diameter of v-TR X-neurons may activate separate groups of v-TR neurons was not much bigger than that of LGNd neurons (Ahls6n et al., 1983). A question is also not relay neurons. They suggested that only a small solved as to which types of relay neurons receive inhibitory inputs from v-TR neurons. It seems that number of relay neurons converge on each v-TR the recurrent inhibitory input to the Y-neuron is neuron. Contrary to this, Kayama et al. (1984) and stronger than that to the X-neuron (Y. Fukuda, Sumitomo (unpublished observation) found that vpersonal communication). TR neurons had usually much bigger receptive fields than relay neurons. This discrepancy may be due to difference in the strain of the rat used; hooded rats 5. INHIBITORY ACTION ON RELAY were used by Hale et al. (1982), and albino SpragueNEURONS Dawley rats were by the other group. It is known that albino animals usually have some abnormalities in 5.1. DESTRUCTIONOF THE TR the visual system and their visual performance is Sumitomo et al. (1976a) examined effects of elecinferior to that of pigmented animals. Many investigators examined receptive field prop- trolytic lesion of the v-TR upon excitability of LGNd erties of v-TR (perigeniculate nucleus) neurons of the relay neurons. This was achieved by measuring recat in comparison with those of LGNd neurons sponse probabilities of LGNd relay neurons to the (Ahls6n et al., 1983; Dubin and Cleland, 1977; second one of the double shocks to the optic tract Sanderson, 1971; So and Shapley, 1981). In general, with various intervals (Fig. 17). In the condition of cat v-TR neurons were binocularly driven, and the intact v-TR it was found that LGNd neurons, showed on- and off-responses to spot illumination once excited by the first shock, remained unthroughout their receptive field. These results suggest responsive to the second shock for a period of 100 msec or more. After a large part of the v-TR was that v-TR neurons receive inputs converging from LGNd relay neurons in both layers A and AI (layers destroyed, relay neurons in the same LGNd were receiving retinal afferents from contra- and ipsi- found to recover responsiveness very promptly. The lateral eyes, respectively), and also from both on- and recovery time was reduced nearly to the refractory off-center relay neurons, since every relay neuron of period left after the excitation to the first shock. From the cat LGNd is monocularly driven and has either these data it was concluded that v-TR neurons proan on- or off-center receptive field. The binocularly duced an inhibition on LGNd relay neurons lasting driven v-TR neurons are possibly the source of more than 100 msec. This finding was confirmed by inhibition in LGNd relay neurons caused by stimu- French et al. (1985). In an alert behaving rat we observed a drastic lation of the non-dominant eye (Sanderson et al., 1971; Singer, 1970; Suzuki and Kato, 1966), since the change of the sensory response to occur following a I-cell of the cat LGNd, the other inhibitory element, lesion of the s-TR (S. Mushiake and Y. Kayama, seems to have similar properties to those of relay unpublished observation). A rat, in a deep anesthetized condition, received an injection of a small neurons including the monocular nature.

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FIG. 17. Postexcitatory recovery curves of LGNd relay neurons measured by double-shock stimulation of the optic tract. (A) Recovery curves of four neurons sampled from LGNd of one side with v-TR intact. (B) Recovery curves of seven neurons sampled from the same LGNd as in A after an electrolyticlesion had been placed in v-TR. (C) Recovery curves of four neurons sampled from LGNd of the other side (v-TR intact) after the curves of B were obtained. Ordinates, response probabilities to the second of two optic tract shocks. Abscissae, intervals between two optic tract shocks. Abscissal axis is linear from 0 to 10 and 10 to 50 msec with different scales, and logarithmic from 50 msec and above. Reproduced with permission from Sumitomo et al. (1976), Exp. Neurol., Vol. 51.

amount of kainic acid into the s-TR to degenerate neuronal cell bodies. (Axons passing through it would be kept intact). After the animal recovered from anesthesia, we found that it was in a state of hyperesthesia or hyperalgesia; it jumped up and squealed terrifically at a slight touch to the body. This is probably because the inhibitory mechanism for the somatosensory input ceased to work. Although this observation seemed to support a suggestion that the inhibitory function of the TR does play a role in the JPN

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Sumitomo et al. (1976a) also examined whether stimulation of the v-TR was effective to inhibit activity of LGNd relay neurons. This was proved by an experiment shown in Fig. 18; the response probabilities to testing optic tract shocks decreased after conditioning v-TR stimulation which preceded the testing shock 10 to 100 mscc or longer. The duration of v-TR-induced suppression was very similar to the post-excitatory suppression revealed by double shock stimulation of the optic tract (see Fig. 17). Besides, Sumitomo et al. (1976a) showed through quasiintraceilular recordings that stimulation of the v-TR elicited in relay neurons a slow negative wave which lasted longer than 100 msec during which spontaneous firings were suppressed. A similar slow negative wave could be elicited by optic tract stimulation, irrespective of whether this stimulation caused primary excitation of the relay neurons or not. These results indicate that the major part of the v-TRinduced reduction of responsiveness of LGNd relay neurons (Fig. 18) is due to the membrane hyperpolarization which is supposed to be an IPSP produced by an input from the recurrent inhibitory circuit involving v-TR neurons. It is shown histologically that all TR neurons are GABAergic (Homer et al., 1980). This was tested physiologically by examining whether inhibition of LGNd relay neurons by v-TR stimulation could be blocked by bicuculline, a GABA antagonist (Kayama, 1985) (Fig. 19). After it was confirmed that stimulation of the optic tract evoked a single spike response of an LGNd relay neuron (A), and that a conditioning shock applied to the v-TR 20 msec prior to the optic tract shock could consistently suppress the optic tract-induced response (B), bicuculline methiodide was applied iontophoretically with a weak current. Within 30 sec the conditioning v-TR stimulation became ineffective to suppress the test response

94

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FIG. 19. Effects of conditioning stimulation of v-TR on response of an LGNd relay neuron evoked by optic chiasm (OX) stimulation, and the antagonistic action of bicucuUine methiodide. A whole experiment process is shown in the left. Single shock stimulation was applied to OX (arrow) every 1.5 sec to evoke single spike response. In every two sweeps the OX stimulation was preceded by 20 msec by single shock stimulation of v-TR (arrow head). After it was confirmed that the conditioning v-TR shock was effective to suppress OX-induced response (upper half of left column), bicuculline methiodide was applied iontophoretically with a current of 20 nA for 35 sec. Period of application is shown by vertical bars in the lower half of the left column and the middle column. Three columns are continuous at asterisk(s). Four sweeps indicated by short arrows (A-D) are enlarged in the right as representative records to show control conditions (A, B), effect of bicuculline methiodide (C) and recovery from it (D). Reproduced with permission from Kayama (1985). Vision Res., Vol. 25.

(C), and the effect of bicuculline was reversible (D). Thus, it is strongly suggested that v-TR stimulation inhibited L G N d relay neurons by releasing G A B A as a transmitter. In the same year as the experiment of Fig. 18 was reported, Yingling and Skinner (1976) showed that stimulation of appropriate portions of the T R suppressed visual, somatosensory and auditory inputs reaching the respective primary sensory cortices. In the somatosensory and auditory systems, as in the visual system described above, the origin of suppression was later identified to be in the thalamic relay nuclei. For example, stimulation of the a-TR suppressed not only spontaneous activity of M G N relay neurons but also their activity evoked by click sound or by electrical stimulation of the inferior colliculus (Shosaku and Sumitomo, 1983). In another experiment it was shown that local infusion of a glutamate solution in the s-TR was effective to suppress spontaneous or evoked activity of VB relay neurons (Mushiake et al., 1984) (Fig. 20). With the latter experiment it was confirmed that the inhibitory effects of T R stimulation on relay neurons were not due to excitation of axons passing through the TR, but due to excitation of T R neurons themselves. In the experiment of Fig. 20, it was also noticed that glutamate infusion at one site of the s-TR was not effective in suppressing all neurons of the VB; activation of a given group of s-TR neurons seems to inhibit only those VB neurons which have receptive fields congruent with those of that group of s-TR neurons. A possible anatomical basis for this may be

that a group of s-TR neurons project only to that group of VB neurons which return axon collaterals to them. The possibility of such reciprocal connection was examined by cross-correlation analyses of spontaneous discharges in pairs of s-TR and VB neurons (Shosaku, 1986). This will be discussed in detail in the next section. 5.3. CORRELATION BETWEEN RELAY AND RETICULAR NEURONS The fact that there is established a somatotopic organization in the s-TR and a retinotopic one in the v-TR (see Section 4.2) suggests that projections from thalamic relay neurons to T R neurons may not be diffuse but may be confined to those T R neurons whose receptive fields were in the same or nearly the same locations as those of relay neurons. Conversely, the feed-back projection from T R neurons to relay neurons may also be restricted, as suggested in the last part of the previous section. Then, how precisely in terms of receptive field position are relay and T R neurons mutually connected? VB and s-TR neurons of the rat responding to stimulation of vibrissae are thought to be good targets of experiment to answer this question; the majority of neurons of both VB and s-TR respond to only one vibrissa, hence the receptive fields are easily and clearly defined. Besides, the fact that no neurons other than relay neurons exist in the rat VB (see Section 2.1) makes it possible to interpret data only in terms of interaction between relay and T R neurons.

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FIG. 20. Relation between position of receptive fields of VB neurons and effectiveness of glutamate infusion into s-TR. Neurons A to F were recorded in the same animal. The vibrissae shown by large, fillccl circles in I (B2, B3, C2 and C3) are those whose movement evoked neuronal responses at the s-TR site of glutamate infusion. Receptive fields of neurons A, B and C were circumscribed areas of the skin which are shown by hatching in II. Neurons D-F responded only to the movement of the vibrissae shown by open circles in III. One of the vibrissae of the receptive field (C1 for neuron D, C3 for neuron E) was stimulated mechanically every 1.5 sec throughout recordings of neurons D and E. Only spontaneous discharge was tested in the other cases. For each neuron, output of ratemeter (bin width, 0.5 sec) is shown. Thick horizontal bar indicates period of infusion of a glutamate solution (50 n'h~) in each case. Speed of infusion was 0.5gl/min, except for 0.25 #l/rain in experiment D. Reproduced with permission from Mushiake et al. (1984), J. Neurosci. Res., Vol. 12.

Shosaku (1986) carried out cross-correlation analyses of spontaneous discharges of s-TR and VB relay neurons responding to movement of vibrissae. Examining a total of 88 pairs of s-TR and VB neurons, he found a significant correlation of spontaneous discharges only in the pairs having receptive fields on the same vibrissa. If the receptive field of one pair member was located differently from that of the other pair member, even if they were closely adjacent to each other, there were no correlations between the activities of the two units (Table 2). Sample correlograms are presented in Fig. 21, where measurements of spontaneous discharges of one VB neuron having the receptive field on vibrissa B4 were made by pairing it with four different s-TR neurons. In D, a significant correlation was found against an s-TR neuron having the receptive field on vibrissa B4; the correlation in this case is such that s-TRexcitation leads VB-inhibition whereas VB-excitation induces s-TR-excitation. While examining a total of 34 pairs of v-TR and VB neurons having the receptive fields on the same vibrissa, it was found that the pattern of interaction varied from one pair to another. It is summarized in Fig. 22; excitation of s-TR from VB in 7 pairs (A), inhibition of VB from s-TR in l0 pairs (B), excitation of s-TR from VB and inhibition of VB from s-TR in

7 pairs (C), inhibition of VB from s-TR with a c o m m o n excitation from other sources in one pair (D), and no interaction in 9 pairs (E). From these data one can calculate the extent of connectivity between s-TR and VB. Within the group of s-TR and VB neurons having the receptive fields on the same vibrissa, one s-TR neuron receives excitation from 41% of VB neurons and sends inhibition to 53%. Such connectivity of the two species of neurons is shown in a model of Fig. 23 which is based on the assumption that the n u m b e r of VB neurons is twice as large as the n u m b e r of s-TR neurons (reflecting the difference in the volume of nucleus), and hence the n u m b e r of VB neurons excited by one vibrissa is also twice as large as the n u m b e r of s-TR neurons excited

TABLE 2. RELATIONSHIP BETWEEN RELATIVE RECEPTIVE-FIELD (RF) PosmoNs OF SINGLE-VIBRISSA NEURONS AND THE PRESENCE OF CORRELATION

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FIG. 24. Responses of a VB neuron to movements of vibrissae. Poststimulus time histograms made with a 2 msec bin width and 30 sweeps are mounted according to the location of vibrissae stimulated. B2 is receptive field of this neuron. Upon stimulation of it the initial response was elicited and followed by a suppression of spontaneous discharges. In k, the initial spike discharge to receptive-fieldstimulation is displayed with a rapid sweep. From other vibrissae surrounding B2 only suppression of spontaneous discharges was observed with no effect from B4. Triangle below each record is a stimulus mark. Reproduced with permission from Sumitomo and Iwama (1987), Brain Res., Vol. 415.

by the same vibrissa. (Also a simplification is made to regard the proportion of neurons in each group of A, B, C and E of Fig. 22 to be 25% and to ignore neurons of D.) One can see that the output from one s-TR neuron to VB neurons is more divergent than that from one VB neuron to s-TR neurons, and conversely the input to one s-TR neuron from VB neurons is more convergent than that to one VB neuron from s-TR neurons. Another aspect of the inhibition originating in s-TR neurons was revealed by Sumitomo and Iwama (1987). They examined effects of movements of vibrissae in s-TR neurons, distinguishing whether or not vibrissae stimulated were receptive fields of the neurons under examination. In the s-TR they found that each s-TR neuron showed a primary excitation followed by an inhibition when its receptive field vibrissa was simply moved and did not show any response when vibrissae outside the receptive field were stimulated. In contrast to this, there was found a spatial distribution of the effects of vibrissal movements for VB relay neurons. For a given VB neuron stimulation of its receptive field vibrissa of course gave rise to a primary excitation whereas stimulation of other vibrissae caused an inhibition (Fig. 24). Since it has been proved that the suppression takes place in the VB through a GABAergic mechanism (Salt, 1987) and that axon terminals of s-TR neurons are the only GABAergic structure in the VB (see Section 2.1), the vibrissa-induced inhibition of VB neurons must originate in the s-TR. These data led

Sumitomo and Iwama (1987) to a supposition that for processing information of vibrissal movements there is provided in the thalamus some modular organization; each module consists of many VB and s-TR neurons and is responsible almost exclusively for one vibrissa. When a particular vibrissa is stimulated, the module for the vibrissa is brought into action; VB neurons are discharged, resulting in activation of s-TR neurons in the same module. Impulses of s-TR neurons so excited may cause inhibition of the initially excited VB neurons and also inhibition of VB neurons belonging to neighboring modules. In terms of the module defined above, Shosaku's finding (1986) is concerned with the "intra-modular" interaction, while those of Sumitomo and Iwama (1987) are with the "inter-modular" interaction. The intra-modular interaction may be very strong so that it could be detected by analyzing the pattern of spontaneous discharges, whereas the intermodular interaction may be so weak that it was detected only when a majority of neurons in a module are activated simultaneously by adequate stimulation from the periphery. That the inter-modular interaction is weak is supported by a fact that during the period of inhibition after stimulation of a neighboring vibrissa the antidromic spike evoked by stimulation of the somatosensory cortex can invade in the VB neuron (Sumitomo and Iwama, 1987). In contrast, the post-excitatory inhibition induced by stimulation of a receptive-field vibrissa is strong enough to block invasion of the antidromic spike.

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Recurrent inhibitory circuits are supposed to operate in various sites of the central nervous system. However, it has remained unknown whether the so-called recurrent inhibition really recurs to neurons in which the excitatory inputs to the inhibitory neurons originate. This is an important question in understanding the functional role of the inhibitory system. If the inhibition recurs only to those neurons that provide excitation to inhibitory neurons, the inhibition is feed-back inhibition (post-excitatory or true recurrent inhibition). But if the inhibition is fed only to other neighboring neurons, the inhibition is lateral (or surround) inhibition. Studies by Shosaku (1986) and by Sumitomo and Iwama (1987) have revealed that TR neurons are concerned with both types of inhibition. The lateral inhibition functions to make some information more conspicuous, not only to improve discrimination of spatial information (surround inhibition, see Sumitomo and Iwama, 1987), but also to improve other kinds of information such as directionality of vibrissal movements (Shosaku, 1986) or ocularity of visual stimulation (see Section 4.3). 6. CONCLUDING REMARKS: PHYSIOLOGICAL FUNCTIONS OF THE TR

In the preceding sections, the TR was characterized from various aspects. From them the following points emerge as possible physiological functions of the TR: (1) Formation of EEG spindle activity; (2) Setting excitation level of relay neurons; (3) Post-excitatory inhibition and surround hibition.

in-

6.1. FORMATION OF EEG SPINDLE ACTIVITY

The rhythm of EEG spindle activity is certainly formed in the thalamus. Steriade and colleagues (1987) maintain that the spindle rhythm is generated solely by intrinsic membrane properties of TR neurons. But there is also evidence that even if TR neurons have an ability to generate the rhythm by themselves, excitatory inputs to TR neurons are important to set and modify the rhythm (Section 3.2). Anyway, during slow wave sleep of intermediate depth, the membrane potential of TR neurons seems to be set at a level suitable to develop the lowthreshold spikes repetitively with fairly regular intervals. During deep slow wave sleep when EEG spindles disappear leaving only slow waves, TR neurons are possibly hyperpolarized more strongly and the low-threshold spikes appear only sporadically. 6.2. SETTING EXCITATION LEVEL OF RELAY NEURONS

The thalamus is not a simple relay station of sensory information to the cortex; receptive field properties are somewhat modified (see below), and transmission of sensory impulses to the cortex is modified by adjusting the level of excitation of relay neurons. Ascending impulses from brainstem nuclei (eholinergic, noradrenergic and serotonergic) act on relay neurons directly, and at the same time indirectly through their actions on TR neurons, to determine

the excitation level (see Sections 2.3 and 3.4). Another regulator of the thalamic activity is the cerebral cortex, which sends out a descending excitatory projection onto both relay and TR neurons. Elimination of cortical activity by cooling inhibits (disfacilitates) "all" TR neurons, and in many TR neurons effects of this procedure is so strong to suppress "all" activity including sensory-evoked discharges; the TR, at least in rats, is highly dependent upon the cortex in its activity (see Section 3.3). Thus, through its potent inhibitory action on relay neurons, the TR is likely to be primarily a tool of the cerebral cortex in the modulation of thalamic events.

6.3. POST-EXCITATORY INHIBITION AND SURROUND INHIBITION

That the post-excitatory inhibition of relay neurons is provided by recurrent inputs from TR neurons with GABA as a transmitter has been well evidenced by the following findings. (1) Single shock stimulation of the TR produces suppression of relay neurons (Sumitomo et al., 1976; Shosaku and Sumitomo, 1983); (2) Destruction of the TR eliminates the post-excitatory inhibition in relay neurons (Sumitomo et al., 1976; French et al., 1985); and (3) Both the post-excitatory inhibition and the suppression induced by TR stimulation of relay neuronal discharge are antagonized by bicuculline (Curtis and Teb~cis, 1972; Kayama, 1985). In view of the fact that GABA-antagonists, such as bicuculline and picrotoxin, are seizure-inducing drugs, it is natural to conclude that a physiological significance of the post-excitatory inhibition is to suppress excessively repetitive firings of thalamic neurons, and to set them in a state ready to respond to next sensory inputs with an appropriate interval. On the other hand, the suggestion that TR neurons participate in formation of the surround inhibition still lacks strong evidence. Sillito and Kemp (1983) examined the role of GABA-mediated inhibition in the receptive field properties of LGNd neurons in the cat by iontophoretic application of bicucuUine, a GABA antagonist. With this procedure, however, it is not easy to distinguish functions of TR neurons from those of intrinsic interneurons (I-cells), because both neurons use GABA as a transmitter. Eysel et al. (1986) suggest that the center-surround antagonism of the receptive field of cat LGNd neurons is supplied by I-cells and the long-range inhibition which acts beyond the range of the classic surround inhibition is mediated by recurrent pathways via TR neurons, but these are based on only indirect evidence. However, the situation is simpler in the rat somatosensory relay nucleus (VB). A temporary inhibition of a VB neuron after stimulation of a vibrissa neighboring to the receptive field vibrissa (Sumitomo and Iwama, 1987) can be ascribed to activation of s-TR neurons, because the suppression is produced in the VB by GABA (Salt, 1987), and because it is known that in this nucleus there are substantially no GABAergic I-cells (Section 2.1). Therefore, it is certain that TR neurons play some role in formation of surround inhibition. In relay nuclei other than the rat VB (for example in LGNd), relation of this function

THALAMICRETICULARNUCLEUS o f T R neurons with that of I-cells should be clarified in future. T R neurons also relate to other types of lateral inhibition seen in relay neurons, which function to improve discrimination of some kinds of sensory information such as the directionality of vibrissal movements or the ocularity of visual stimuli (Section 5.3). These lateral inhibitions are developed by T R neurons via convergence of inputs from and divergence o f output to relay neurons. The organization for the lateral inhibitions (including surround inhibition), however, seems to be less developed than that for the post-excitatory (feed-back or true recurrent) inhibition. The T R is a peculiar nucleus composed of a homogeneous mass of inhibitory interneurons. Its position outside of the relay nuclei gives us a chance to study many physiological aspects of inhibitory circuit, a chance difficult to be obtained in such a structure as the cerebral cortex where various species of neurons intermingle with each other. We have described the fruits of studies of our group on the rat TR, and hope more concrete function of the TR, or more general signifiance of inhibitory processes in the brain, will be revealed in future. REFERENCES AHLSI~N, G. and LINDSTROM,S. (1982) Mutual inhibition between perigeniculate neurones. Brain Res. 236, 482-486. AHLSI~N,G., LINDSTROM,S. and Lo, F.-S. (1983) Excitation of perigeniculate neurones from X and Y principal cells in the lateral geniculate nucleus of the cat. Acta physiol. scand. 118, 445-448. AHLSf/N,G., LINDSTROM,S. and Lo, F.-S. (1985) Interaction between inhibitory pathways to principal cells in the lateral geniculate nucleus of the cat. Exp. Brain Res. 58, 134-143. BURKE, W. and SEFTO~,A. J. (1966a) Discharge patterns of principal cells and interneurones in lateral geniculate nucleus of rat. d. Physiol., LoRd. 187, 201-212. BURKE, W. and SEFTON, A. J. (1966b) Recovery of responsiveness of cells of lateral geniculate nucleus of rat. J. PhysioL, Lond. 187, 213-229. BURKE,W. and SEFTON,A. J. (1966c) Inhibitory mechanisms in lateral geniculate nucleus of rat. J. Physiol., LoRd. 187, 231-246. CARMAN,J. B., COWAN,W. M. and POWELL,T. P. S. (1964) Cortical connexions of the thalamic reticular nucleus. J. Anat., Lond. 98, 587-598. CURTIS, D. R. and TEag:CIS,A. K. (1972) Bicuculline and thalamic inhibition. Exp. Brain Res. 16, 210-218. DE LIMA, A. D. and SINGER, W. (1987a) The serotonergic fibers in the dorsal lateral geniculate nucleus of the cat: distribution and synaptic connections demonstrated with immunocytochemistry. J. comp. Neurol. 258, 339-351. DE LIMA, A. D. and SINGER, W. (1987b) The brainstem projection to the lateral geniculate nucleus in the cat: identification of cholinergic and monoaminergic elements. J. comp. Neurol. 259, 92-121. DE LIMA, A. D., MONTERO,V. M. and SINGER,W. (1985) The cholinergic innervation of the visual thalamus: an EM immunocytochemical study. Exp. Brain Res. 59, 206-212. DESC~W_.S, M., PARADIS,M., ROY, J. P. and STERIAOE,M. (1984) Electrophysiology of neurons of lateral thalamic nuclei in cat: resting properties and burst discharges. J. NeurophysioL 51, 1196--1219. DESCH~NES,i . , MAOARiAGA-DOMICH,A. and'STERIADE,M.

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