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Electrophysiological properties of units of the thalamic reticular complex
EXPERIMEKTAL
SEIIROL0C.Y
32, 79-97
Electrophysiological The Thalamic
(1971)
Properties Reticular
of Units Complex
of
Unit activity was recorded in and close to the thalamic reticular complex in of units was characterized by their long high-frecwCphale isol: cats. A group quency burst responses to lO/sec thalamic and cortical stimulations. their sustained high-frequency firing induced by 4&250/sec thalamic and cortical stimulations, the depression of their firing by high-frequency stimulations of the midbrain reticular fortration and caudate nucleus, and their tendency to he more active during EEIG spindles. These units were located along tracks histologically found crossing the thalamic reticular complex. They differed from cells collected along tracks not crossing the reticular complex. on all four electro-physiological properties mentioned above. These properties are shown to be intrinsic for a class of neurons, presumably of the reticular complex. The timing of firing of rcticularis and nonreticularis neurons is compared and it is suggested that reticularis neurons arc at the origin of inhibition of dorsal thalamic cells. It is also postulated that they play a role in the control of thalamic spindle \vaves. Introduction
The thalamic reticular complex is a thin shell of the ventral thalamus surrounding the cellular mass of the dorsal thalamus on its rostra1 and lateral aspects. Electrophysiological recordings from its neurons have been made (12, 14, 16, 19, 20, 22, 2.3. 3.5, 39), 1XIt most often incidentally while exploring a nearby nucleus. From these studies, three features emerge. First, Negishi, Lu, and I’erzeano (22) observed that reticularis neurons in the vicinity of the lateral geniculate body spontaneously discharged in bursts of long duration. This has heen confirmed recently by Rlukhametov, Kizzolatti, and Tradardi (20). Second, Massion (19) noticed that reticular% cells tended to fire when cells of the nucleus ventralis lateralis 1 This work has been supported by U.S. Public Health Service Grants NB-04955 and NB-21633. Dr. Waszak’s present address is: V.% Hospital, Irving -Avenue and University Place, Syracuse, New York 13210. \\:e express our thanks to Mr. D. Kuroda for his technical assistance. and to Miss C. Xucker for the histological preparations. 79
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(\‘L) were silent. Third, Filion, Lamarre, and Cordeau (12) extended this observation on the reciprocity of firing behaviors by showing that rostral reticularis cells were more active and VL cells less active during cortical EEG spindling. These findings deserve attention in view of the particular physical orientation of the reticularis neurons. Their dendritic fields are traversed by most of the thalamocortical and corticothalamic projections. Synaptic contacts are made on this occasion and, as demonstrated by the Scheibels (29) with the Golgi method, most axons project caudally upon the thalamus and the midbrain. The confrontation of these anatomical and electrophysiological data led to the suggestion that reticularis neurons, strategically situated to receive a variety of inputs, may play back on dorsal thalamic cells (31), most probably by inhibiting them directly or indirectly. The present investigation was undertaken to examine this hypothesis. A number of experimental conditions of stimulation were used, under which the behavior of neurons belonging to various dorsal thalamic nuclei has been extensively studied and is now rather well known. This is especially the case for thalamic and cortical stimulations which induce powerful synaptic drives when applied repetitively at low frequencies (6-12/set.) ( 1, 2, 4, 10, 17, 21, 24-26. 33). Unit activity recorded with microelectrodes aimed at the thalamic reticular complex was compared to that of other thalamic units under these conditions. Preliminary results obtained on this problem have been presented in a short paper (34). Materials
and
Methods
The experiments were performed on 22 cats surgically prepared under ether and Brevital anesthesia. The neuraxis was completely transected by suction at the spinomedullary junction and artificial respiration was provided. The cerebral cortex was widely exposed and immediately covered with mineral oil continuously warmed to about 38 C. The body temperature was maintained by a heating pad. All sites of incision and the pressure points of the stereotaxic headholder were infiltrated with 1% lidoCaine. The general anesthesia was interrupted l-2 hr prior to recording and Flaxedil was injected. The cats’ pupils remained fissurated throughout the experiments, including the periods of stimulation. Except in one case, unit recordings were made with glass micropipettes filled with 3 M KCl. The tips of these electrodes were 2 ,u or less in diameter. The potentials were led into a Tektronix 502 oscilloscope (CRO) through a cathode follower without amplification. Photographic records were obtained for all data reported: lo-30 pictures were taken for every test, depending on the stability of the unit behavior observed; and all measurements were made on films. Electrical stimuli (ordinarily 0.5 msec.
TNALAMIC
RETICI.LAR
NEGROSS
Sl
200-450 pa, square pulses) were applied through concentric stainless-steel electrodes. The inner wire was 0.15 mm in diameter ; it was exposed only at the tip and protruded 0.4-0.8 mm from a 22-gauge needle. Stereotaxic placements were made according to the atlas of Jasper and Ajmone-Marsan ( 15,). Micropipette insertions were irregularly distributed in order to permit identification of individual tracks upon examination of the histological material. Confusion could he avoided by varying the number of tracks on successive frontal planes. The sites of stimulation were marked by iron deposits and sul)sequent ferrocyanide reaction. The SO-p histological sections were stained with thionine.’ Results
A+lato/r/ical
Comidrratiocs
On histological sections, a number of electrode tracks were found crossing the thalamic reticular complex on at least parts of their trajectory, as illustrated by different examples in Fig. 1. In A, a track is seen penetrating the lateral sector of the reticular shell. In B. the micropipette was inserted obliquely and the first unit observed differed, in the manner described below, from those encountered subsequently in the dorsal thalamus. In C, five tracks are situated in the rostra1 pole of the reticular complex and all five yielded similar results. D refers to the sole experiment in which a metal microelectrode was used, thereby permitting a marking of the site of unit recording closeto the transition with the zona incerta. In such cases,conditions were satisfied to contact reticularis cells. However, because of the shape of the complex (e.g.. Fig. 1A). possibly neurons from adjacent dorsal thalamic nuclei or from the subthalamic region could also be encountered. Since depth measurements have some imprecision, we could not assert with absolute confidence that given units were reticular. Therefore, we shall objectively refer to them as “found along tracks crossing the thalamic reticular complex.” Other tracks were directed entirely within the confines of the dorsal thalamus (‘namely, in the VL, VPL, T,P, and lateral part of the VZ\) and the results collected there could be used for comparison, since certainly, no reticularis neurons were situated in the electrode path. Still other tracks traversed the internal capsule on their entire course, recording rare and always sharp spikes (of probable asoual origin). During the esperiments, 2 pII1 anatomical locations given in this report refer to actual histological findings. The following anatomical abbreviations will be used in the text: Cd, caudate nucleus; CM, centrum medianum comp!ex; IL, internal medullary lamina of the thalamus ; LP, nucleus lateralis posterior ; RF, mesencephalic reticular formation : VA, nucleus ventralis anterior : VT,. nucleus ventralis lateralis ; \7PI., nucleus ventropcsterolateI-alis.
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such indications of “misses” helped in adjusting the next insertions of microelectrodes toward the thalamic reticular target. Once the target was located, as judged by the electrophysiological results, close by tracks tended to yield the same type of records (as in the case illustrated by Fig. 1C). No explorations of more medial sectors of the thalamus were attempted in this study, since data on more than 200 cells observed in and around the VL nucleus under similar conditions were available for comparison from previous works from this laboratory (21, 33).
FIG.
showing the text.
1. Thionine-stained tracks passing
histological sections of thalamus in four different animals, through the thalamic reticular complex. Other explanations in
THAL.-\MIC
Responsesto Rrprfitive
RETICCLAR
XETROKS
s3
Thalawic Stimulation at TM i)cr Sccoml
Defi&olt of R~spome Paftcrns. Thalamic stimulation at the rate of naturally occurring spindles is known to he particularly effective on thalamic neurons (10, 17, 24, 26, 33 ). Therefore, lO/sec rates were used routinely. Unit responses to stimulation in the region of CM (59 observations j, of IL (75 observations), or in the center of VL (56 observations) yielded similar results: irrespective of the site of recording, the responses were either an immediate cessation of firing or. more often, one of the two patterns illustrated in Fig. 2. As illustrated in records A and B of Fig. 2, the number of discharges after each stimulus tended to increase progressively during the early part of the train. Except for this common feature, the traces differed in the density and duration of the bursts. In Fig. ZA, the unit fired one to three spikes with a constant latency of less than 30 msec. \Vhen units of this type were spontaneously active, lO/sec thalamic stimulation resulted in an over-all depression during and following the train. In particular. discharges were suppressed during the second half of the 100~msec interval between the stimuli. Seventy-seven cells fell in this category: The latencies varied from 3.5 to 10 msec and the number of spikes per response from one to six. Short bursts evoked in the same conditions were obtained from \*I~-identified neurons in our previous study (33 ) . Although recorded only O..; mm away from the first, the unit presented in Fig. 2B differed considerably in the length of its bursts. For cells of this second type, the IO/set stimulation increased the average firing rate up to 350,/set with peaks as high as .SOO/sec. \I’hen the background activity was already intense. the individuality of responses could be lost, and the effect was more adequately described as a frequency modulation at the rate of stimulation (Fig. 6). M’e found 85 cells behaving in this manner. Neasurements were possible in 77: the latencies varied from less than 1 to 36 msec and the nrml)er of spikes per response from seven to 30. The two types of evoked activity illustrated in Fig. 2 could he distinguished with little ambiguity when viewed on the CR0 screen. They were respectively called “short-burst” and “long-burst” for convenience. In order to verify the objectivity of this differentiation, parameters of the firing patterns were analyzed (duration, number of spikes, frequency, and latency). Measurements were made on fully developed responses after stahilization (i.e., the fifth or sixth response in the lO/sec trains) in 151 units. DI4ratiolz of Rlt~.sts. As seen in Fig. 2C. the distribution of all cells according to the duration of the bursts confirmed the impression of two populations. The thick line (between the two white arrows) indicates where the division beetween short-bursts and long-bursts had been subjectively
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placed before resorting to any quantitative analysis. Although this separation was quite arbitrary, it was kept in order to form two groups, because, whatever the criterion adopted, the classification would have been the same except for only three or four units (in the range of 15 to 30-msec bursts). Nzt~!~r of Spikes. The distribution according to the number of spikes per response was also bimodal. It is not presented since it has practically the same shape as the histogram of Fig. 2. In fact, the dividing line in Fig.
20
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80
too
120
FIG. 2. Example of short-burst (A) and long-burst (B) responses to 1Ojsec thalamic stimulation. Calibration marks : 100 msec; 1 mv (upper), 10 mv (other recordings). C. Distribution of cells according to the duration of their thalamically evoked bursts. In A and B, upper traces from anterior sigmoid gyrus, lower traces from thalamic units. Stereotaxic coordinates of unit in B were 0.2 mm more anterior, 0.3 mm more lateral, and 0.1 mm more ventral than for unit in A, in the same animal. In this and all following figures, focal positivity indicated by a downward deflection, cortical surface recordings always monopolar. Stimulation in the IL region. In C, abscissa is duration of bursts in msec, ordinate is number of cells. Hatching: cells found in tracks crossing thalamic reticular complex. Black: cells found in tracks away from reticular complex. White: cells in track of uncertain course. Heavy line (between white arrows) : arbitrary division made for quantitative comparison of two groups of cells.
THALAMIC
RETICrLAR
NEUROKS
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2C was found to separate cells having less and more than six spikes per burst. Comparison of Rcsponsc Patterm and Location. In the histogram of Fig. 2C, it can be noticed that no cells found in tracks entirely situated outside the thalamic reticular complex discharged in long bursts in response to thalamic stimulation. Conversely, only a few cells found in tracks passing through the reticular complex responded by short bursts. This confrontation of electrophysiological with anatomical data indicates that the response modalities were definitely correlated with the sites of recordings. This conclusion is further supported by the fact that units exhibiting different response modes were never interspersed along the same track. They were always clustered: for instance, up to seven units responding by long bursts could be recorded in succession over a 2.5111111 span at the rostra1 pole of the reticular complex, in the region illustrated by Fig. 1C. Sflecijicit~~ of Rcspo~~ Pattems. The production of long high-frequency bursts was an intrinsic property of a class of neurons. Three of these units were tested with thalamic stimulations at two different places (~CM and IL) and responded in the same profuse manner to both. Fourteen units were also tested with cortical stimulations (see below), and 12 responded with long bursts whereas two were progressively silenced. In another unit, lO/sec stimulation of the CM, anterior sigmoid gyrus, and cingulate gyrus evoked SO-msec bursts, whereas lO/sec stimulation in the depth of the presylvian sulcus stopped the spontaneous discharges. Thus, depression of ongoing activity seemed to be the only alternative response modality. No short bursts were ever produced in these cells, under any conditions tested. except when the intensity of stimulation was lowered. It would have been surprising, indeed, if the number of spikes triggered did not depend also on the strength of stimulation. To explore this possibility, in a few instances, the voltage of thalamic stimuli was reduced: this drastically decreased the number of discharges as shown in Fig. 3. But, in comparison with the short bursts described above, such responses were always unstable in latency and duration. It was clear that the long-burst characteristic could be lost when the drive was insufficient, thus preventing a correct identification on the basis of the criterion adopted. admittedly. this may have occurred in our experiments, thereby confusing the distinction or biasing the classification of cells systematically in favor of the short-burst type. Frequency of Fihg. The average frequency of firing could be about the same in short-burst and long-burst responses. But the maximum frequency was always reached immediately in short bursts. whereas it came in the middle of the long bursts [Figs. 2B. 5, 6A. 7, and S). Latelzcy. No obvious difference in latency could he associated with the
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FIG. 5. Effect of reducing the intensity (ZOO-SO pa) of lO/sec thalamic stimulation on the long-burst responses of a thalamic unit. Upper traces from anterior sigmoid gyrus, lower traces from a rostra1 thalamic cell at 3 mm from midline. Stimulation in IL region, successively of ZOO, 100, and SO pa. Calibrations: 100 msec; 0.5 mv (upper). 5 mv (lower).
response modalities as defined above. However, a comparativeIy large proportion of the long bursts had a short latency (21% were shorter than 3 msec and 11% shorter than 1 msec, versus 0% in the other group). Although latency measurements were possible only on a limited number of cells (119 cells), the difference is noteworthy since units responding so quickly were the most peripheral in the thalamus, i.e., farthest away from the sites of stimulation. The latencies shorter than 1 msec were extremely stable (no measurable “jittering”). They were obtained in all three kinds of stimulation (VL, CM, and IL). Over-all Activity. Finally, the two types of populations were compared from the viewpoint of the amount of activity generated by thalamic repetitive stimulation, i.e., the proportions of units active (in the process of bursting) at successive moments of the 100-msec stimulus intervals were computed for both groups. The distribution showed that, at any time before 50 msec, there were several times (two to 26 times) more long-burst units active than other cells. Of course, SO msec after each stimulus, only long-burst units were still discharging. Responses
to Tlzalamic
Stimulations
at Othrr
Frequencies
Although long bursts were easily evoked in certain cells by lO/sec thalamic stimulation, this particular frequency was not so selectively effective as it was found to be for provoking short bursts in this and previous studies (33). For instance, the unit presented in Fig. 4 discharged profusely even when the stimulus intervals were of the order of 1 sec. The difference
THALAMIC
RETICCLAR
NEURONS
FIG. 4. Responses of a thalamic unit to repetitive thalamic stimulation 21 to 0.77/set. Upper traces from anterior sigmoid gyrus. Stimulation recorded along one of the tracks represented in Fig. 1C. Calibrations
s7
varying from in CM. Unit as in Fig-. 3.
between the effects of the first and subsequent stimuli is conspicuous in all these records. For all of the cells tested, the duration and density of the long bursts remained unchanged at rates down to .5/set, but they were still considerable at frequencies definitely lower than those of spontaneous spindles. In contrast, there was no increase in duration of short bursts at such low frequencies. At frequencies above lO,/sec. the firing always tended to become continuous. Average discharge rates as high as 350-450/set were usual; they were often accompanied by spike attenuation (Figs. 4-7 ) One of the most remarkable features was the capacity of many of these neurons to sustain such an intense firing for a considerable time. The unit presented in Fig. 5 discharged at 320/set for 3 set under 30/set CM stimulation. This kind of feat, to our knowledge, has never heen reported for any dorsal thalamic cells (e.g., 18. 25 ). In this example. the very long activation was followed by a long pause. Almost half of the cells, however, did not show any postreactional depression (Fig. 6). Thev continued firing after the last stimu-
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lus of a train, in contrast to dorsal thalamic neurons which were regularly inhibited after a period of excitation (also 25, 33). Thirty-two neurons responding by long bursts to lO/sec thalamic stimulation were tested to 40-250/set stimulation. All of them were activated very strongly in a prolonged manner. In contrast, of 19 neurons responding by short bursts to lO/sec stimulation, 12 were silenced by high-frequency stimulation, four were accelerated for less than 400 msec, and three remained apparently unaffected. Responses
to Cortical
Stiwmlation
It is known from several anatomical studies that different sectors of the thalamic reticular complex have topographical relations with definite cortical regions (7, 8, 25). Since it was impossible to place stimulating electrodes everywhere on the hemispheres, explorations were limited to rostra1 thalamic cells and, accordingly, sites of stimulation were selected only within the frontal lobe cortex : anterior and posterior sigmoid, anterior cingulate, orbital gyri; and the mesial cortex under the cruciate sulcus (27,
FIG. 5. Sustained high-frequency firing of a thalamic cell evoked by IO/set stimulation in CM lasting for 3 set (between the arrows). Continuous record. Note spike attenuation and postreactional depression. Upper trace from anterior sigmoid gyrus. Unit recorded along one of the tracks represented in Fig. 1C (different from unit illustrated in Fig. 4). Calibration marks : 100 msec; 500 ,uv (upper), 2 mv (lower).
THALAMIC
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NEURONS
37). The number of responsive cells studied (48 cells) was too small to analyze these cases separately. The most significant finding was that 12 of 14 units (86%) responding with long bursts to lO/sec thalamic stimulation responded in exactly the same way to lO/sec cortical stimulation. The median duration of the fully developed bursts (after the fifth or sixth stimulus of a train) was 50 msec. The other two units (l-l% ) were progressively silenced. responding with short bursts to In contrast, 15 out of 3-l units (44%) lO/sec thalamic stimulation also responded with short bursts to lO/sec cortical stimulation, whereas the other 19 units (56% ) stopped firing (also 2, 21). This depression could be obtained even more easily by high-freyuency (-FO-250/set) cortical stimulation (S-l% j, Conversely, most cells of the long-burst type (76% ) were strongly activated by this stimulation. Respomes
to Midbrain
arid Caztdntr
Nuclezts
Stimulation
High-frequency (10&250/sec) stinutli applied to the mesencephalic tegmentum, ventrolaterally to the central gray matter (reticular formation), either reduced the activity of the cells characterized by their long-burst responses to thalamic stimulation (66%. Figs. 7 and 9) or had no effect (3-l%). This was not due to high-frequency spike attenuation. In sharp contrast, 78% of units of the short-burst type were activated, and only 22% showed a depression in firing. The results obtained by stimulation of the head of the caudate nucleus were comparable. Clear-cut effects were best obtained with the highest fre-
FIG. 6. Persistence of high-frequency firing after termination of thalamic stimulation in two conditions. ,4, continuous record during and following lO/sec stimulation in IL. Upper record from anterior sigmoid gyrus. B, 40/set stimulation in IL in another animal. This cell had a very low spontaneous activity. Calibration marks: 100 msec ; 1 mv (upper tracings), 10 mv (lower tracings).
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quencies (lOO-250/see) which, in 75% of of cells of the type illustrated in Fig. 7. At 40/set), there could be a slowing down or, the discharges. Sometimes both occurred train (Fig. 7) or alternatively in different 2.5% of the cases. There were not enough cells to provide a comparison.
Spontaneous Activity
the cases, depressed the firing lower frequencies (e.g., 10 and on the contrary, a grouping of in succession during the same trains. Activation was seen in tests of the short-burst type of
and Relations with EEG Activity
The spontaneous firing of cells characterized by their long-burst responses to thalamic stimulation was extremely variable. The range of variation was from complete silence to levels of more than 120/set maintained for several seconds, a value not attained by other uninjured thalamic cells (maximum actually observed : 70/set). IL
10
FIG. 7. Comparison between responses to stimulations at different sites: IL, Cd, and RF, and with different frequencies: 10, 40, and 25O/sec. Unit recorded along track in rostra1 part of thalamic reticular cortex. Upper traces from anterior sigmoid gyrus. Note the high-frequency discharges induced by thalamic stimulation, and the arrest of firing caused by RF stimulation and by Cd stimulation, especially at 40 and 250jsec. Time 100 msec; but record RF taken at slower speed. Vertical calibrations : 0.5 mv (upper), 20 mv (lower).
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;\lany of these cells were found to fire spontaneously in long bursts as they did in response to lO/sec thalan~ic stimulation (also 20). On several occasions when simultaneous EEG recordings had been made by chance from an adequate position on the cerebra1 cortex, the bursts were found to correspond to the occurrence of surface-negative waves, either evoked or spontaneous (Fig. S ). They were generally composed of more than 10 spikes and lasted for 30-120 msec. Kegishi ct al. (22) and Mukhametov c‘f al. ( 20 ) carried on (spontaneous activity of reticularis cells in the vicinity of the lateral geniculate body ) quantitative analyses similar to ours and fount1 similar figures. Burst durations of 132 nlsec (22) have been reported. as compared to 20 nxec for lateral geniculate cells (22) or IO-25 nlsec for dorsal thalamic cells in general ( 1). Reciprocally, the intervals between the groups of prolonged discharges were shorter. Since the lmrsts were long, their separation short, and the tiring rate high, these cells tended to he much more active during than 1)etween EEG spindle trains (Fig. 9). This observation refers to individual spindle trains, for, as Mukhametov Et al. (20) mentioned. the over-all average activity may be less in periods of spindling than during EEG fast rhythms in arousal or REM sleep. In Fig. 9C, a high-frequency stimulation of the midbrain reticular formation is shown to stop the cortical spindling and the activity of the thalamic unit simultaneously recorded. Although many similar okrvations were made, the relation with the EEG activity was not always as clear. Other factors certainly were involved. Indeed, when the EEG desynchronization was produced by thalamic high-frequency stinmlation. it was accompanied, on the contrary, hy an intensification of the firing.
8. Comparison of evoked and spontaneous bursts in a rostra1 thalamic unit. record: end of a lO/sec train of stimuli applied in IL. Louver record: spontaneous activity of the same cell during cortical spindles (upper trace from anterior sigmoid gyrus). Note the similarity of the bursts and their timing in relation x&h cortical surface-negative \I-aves. Calibrations: 100 msec; 0.5 mv (upper), 10 mv ( lower ). FIG. Upper
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Discussion
A group of thalamic cells in this study has been characterized by : (i) their long high-frequency bursts evoked by lO/sec thalamic stimulation ; (ii) their long high-frequency bursts evoked by lO/sec cortical stimulation, in 86% of the cases; (ii;) their sustained high-frequency firing induced by 40-250isec stimulation of thalamic sites ; (iv) their sustained high-frequency firing induced by 44-25O/sec stimulation of cortical sites, in 76% of the cases; (zt) the depression of their firing by high-frequency stimulation of the midbrain reticular formation; (vi) the depression of their firing by high-frequency stimulation of the head of the caudate nucleus, in 75% of the cases ; (vi;) their tendency to be more active during EEG spindles ; and (z&) their location along tracks histologically found crossing the thalamic reticular complex. Most peculiar was the ability of these cells to sustain high frequencies of discharge (up to 350/set) for long periods (up to 3 set). First, we shall discuss the arguments indicating that these were reticularis neurons. On the basis of parameter measurements (especially length of bursts), the cells exhibiting property i were shown to form a separate population, Thus, property i was chosen as a criterion for differentiation and was found to be shared only by units which satisfied the anatomical require-
FIG. 9. Relation between the firing the thalamic reticular complex, and different times. Upper traces from first trace, lOO/sec stimulation of cortical spindling. Calibrations: 100
of a cell found along a track passing through the EEG. A, B, and C from the same unit at anterior sigmoid gyrus. In C at the end of the RF for 400 msec and subsequent cessation of msec; 0.5 mv (upper), 20 mv (lower).
ment ~iii. Conversely, the other cells located within the limits of the dorsal thalamus behaved quite differently in the situations in which properties i to zqii. revealed themselves. Our observations on these other cells, in fact, agree with those of previous studies escept on one point: the high-frequency firing patterns assumed to represent the activity of small interneurolls in specific thalamic nuclei (4. 6, IS) were never observed in the present experiments probably hecause our microelectrodes had different characteristics. Whatever the case, records from such interneurons were said to form only a small percentage in the populations explored (1, 18)) in contrast to our long-bursting units which were easy to find in clusters in the region of the thalamic reticular complex. ,4s far as neurons of the medial thalamus and region of the internal meclullary lamina are concerned. strong bursts obtained under similar conditions have been occasionally reported ( 10, 25 ) but. apparently, the discharges did not reach such a high frequency and were, by far, never so long-lasting. The correlation between property i on one hand, and properties ii, izj. and vi on the other hand was not absolute. Kamely. knowing that a given unit responded by long bursts to thalamic stimulation, the responses evoked from the cerebral cortex or caudate nucleus were not as predictable as the effect of stimulating the midbrain reticular formation (property v). Nevertheless. these observations ii, izf, and zli deserve consideration as they extend the range of experimental conditions under which a differentiation was possible-at least statistically. Considering these results altogether, we submit that the cells characterized hy property i helonged to the thalamic reticular complex. For convenience. they will be referred to from now on as reticularis neurons. Quite possibly. some reticularis neurons have not been recognized in this study and. therefore, have been wrongly classified because the test stimulations were not adequate for revealing their particularities. Conversely, it is less likely that nonreticularis neurons have been wrongly classified. unless they were cells of the close by medial sector of VA which have the same structural organization as reticularis cells (30 31 j. This study suggests that reticularis neurons are excitable from a variety of places. Even those of the lateral wing of the nucleus (as far as 7.5 mm lateral to the midline) were able to respond strongly to CM stimulation. Eleven per cent could fire within a very short and stable delay (less than 1 msec ) after VL. CM, or IL stimulation. Such characteristics strongly suggest the possibility of antidromic invasion, though further studies are necessary for confirmation. The reticularis Lmit responses to lO/sec thalamic stimulation were analyzed in order to estimate the proportion of these cells active (i.e., in the process of bursting) at successive moments. The distribution showed that several times more reticularis cells than other cells were activated at anv
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time during the 100 msec separating the stimuli. The difference became, of course, the most dramatic in the second half of the lOO-msec intervals when all dorsal thalamic cells were inhibited. Since the firing rate of reticularis cells was the highest in the middle of their bursts, it can be said that the peak of reticularis activity corresponded to the beginning of the inhibition of dorsal thalamic cells. Since reticularis neurons distribute their axons diffusely in the dorsal thalamus (29), the thalamic structures must receive the vigorous reticularis output. As just pointed out, most of the dorsal thalamic neurons underwent a long phase of inhibition when the reticularis volleys were fully developed. It is, thus, implausible that reticularis neurons are the source of an excitatory action. Were they ultimately excitatory, either their output, although massive, must be rather ineffectual, or else could only serve to generate activity resembling rebound when the inhibition of dorsal thalamic cells has subsided. The converse hypothesis : that reticularis neurons are directly or indirectly (i.e., through intercalated interneurons) inhibitory elements is more consistent with the facts observed. In this connection, one cannot fail to be impressed by the capacity of these cells to discharge at very high-frequency as do many inhibitory neurons ( 11). In the elaboration of this inhibitory hypothesis, it would be possible to regard the reticularis neurons as responsible for the individual inhibitory pauses phasing the thalamic activity at around lO/sec (3). However, this seems questionable since the lO/sec rate of stimulation was not more selective than lower rates in driving these neurons and since their firing could be sustained for much longer than 100 msec. Another possibility is suggested by previous demonstrations that rhythmic postsynaptic inhibitory potential (IPSP) of dorsal thalamic cells, either spontaneous (1) or evoked by thalamic stimulation (26), often tend to increase progressively in amplitude. This phennmenon, that we have also observed (Waszak. cited in Ref. 32), may be due to the partial overlapping of consecutive IPSP, or may be caused by a slow hyperpolarizing drift on which successive waves are superimposed. If the latter interpretation is valid, the longlasting firing of reticularis neurons could be considered as the source of this very long underlying hyperpolarization, whereas briefer recurrent inhibitory phases would be produced by local interneuronal circuits in the various dorsal thalamic nuclei (4, 6, 18). Indeed, there is a difference in duration of bursts : compared with reticularis neurons, the small interneurons fire for shorter periods and they are tonically much less active (18). Under favorable conditions, the maximal activity of reticularis neurons could be correlated with the presence of individual spindle bursts in the EEG (also Refs. 12, 20). Such spindles have been shown by Andersen and Andersson (1) to be accompanied for their whole duration hy a SUS-
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NEURONS
95
tained hyperpolarization of dorsal thalamic neurons. This suggests the possibility of a tonic role of reticularis cells in regulating the occurrence of spindles. In fact, lesions destroying the rostra1 pole of the thalamus-ineluding the reticular complex-strongly interfere with the spindling process (5. 9, 13, 38). But, since the impairment is reversible by extensive decorticntion (36’)) it seems that the rostra1 thalamic lesions only affect a controlling factor, leaving intact the oscillatory mechanism itself. This is but one aspect of the possible role plnyed by reticularis neurons. More specific aspects of their interactions with other thalamic nuclei should be investigated. References Basis of the Alpha 1. ?ISIERSEN. P., and S. A. ANDERSON. 1968. “Physiological Rhythm. .Appleton-Century-Crofts, New York. 235 pp. 2. .~SIERSES, P., C. Beooh-s, J. C. ECCLES, and T. .A. SEARS. 1964. The ventro-basal nucleus of the thalamus : potential fields, synaptic transmission and excitability of hoth presynaptic and postsynaptic components. J. Pk>qsiol. Lorfdo+f 174 : 34% 369. 3. .ZNIIEKSEK. P.. and J. C. E~CLBS. 1962. Inhibitory phasing of neuronal discharge. .Votrtrc Lodm 196 : 645447. 4. \ NIXRSEK, P.. J. C. ECCLFS, and T. A. SEARS. 1964. The ventro-basal complex of the thalamus: types of cells, their responses and their functional organization. J. Pltysiol. Loufor 174: 370-399. 5. &l.H-Y-RTT.4, G.. C. BAGRAKD, and A. CHRISTOLOMRIE. 1969. A comparison of EEG modifications induced hy coagulation of subthalamus, preoptic region and mesenrephalic reticular formation. Elcrtr-o~,~rccphalonv. C/it?. Kcwoplf~si~~l. 26 : 393-502. 0. RL.RKE, \I’.. and A. J. SEFTON. 1966. Discharge patterns of principal cells and interneurons in lateral geniculate nucleus of rat. I. Ph?vioi. Lordon 187 : 201212. 7. C.z~;nr.\s. J. B., \V. M. C~WAX. and T. P. S. POWELL. 1964. Cortical conncsions of the thalamlc rctlcular nucleus. J. . Iunf. 98 : 587-598. S. C~IO\\, K. L. 1954. Regional degeneration of the thalamic reticular nucleus following -ortical ablations in monkeys. J. C‘owp. N~rrrol. 97 : 37-59. 9. CHOLV. K. I,.. L%'. C. DEMEKT, and S. A. MITC.HEI,L JR. 1959. Effects of lesions of the rostra1 thalamus on hrain waves and behavior in cats. Elrrtloc~~ccphlogr.
!I). 11. I.?.
13.
Ilir~.
.l’curnphysiol.
11 : 107-120.
T., and 1). P. Pc~rurc~. 1970. Organization of specific-nonspecific thalaniic internuclear synaptic pathways. Hvnirz Rcs. 21 : 169-181. E(.(.LEs, J. C. 1969. “The Inhibitory Pathways of the Central Nervous System.” Thomas, Springfield, Illinois. 135 pp. FILIOS, 31.. Y. LAMAKRE, and J. P. CORDEAU. 1969. Plctivites unitaires du noyau lateralis du thalamus au tours de la veille et du sommeil. J. Physiol. Paris 61: 290. HANBERRY, J., C. AJMOKE-MARSAN, and M. DILR.~RTH. 1954. Pathways of nonspecific thalamo-cortical projection system. EII,cirorllcrphlllunr. (‘/in. A:t*~tr-oI)SsIlARu.
/‘lt.vsiol.
6 : 103-l
18.
96
SCIILAG
AND
WASZAK
T., and S. TERASHI~IIA. 1966. Correlation between activity of the visual cortex and the somatovisual interaction in the lateral thalamus of cats. Brain Kcs. 2 : 160-172. 15. JASPER, H. H., and C. AJMOKE-MARSAN. 1954. “A Stereotaxic Atlas of the Diencephalon of the Cat.” National Research Council of Canada, Ottawa. 16. MACLEAN, P. D., T. YOKOTA, and M. A. KINNARD. 1968. Photically sustained on-responses of units in posterior hippocampal gyrus of awake monkey. .I. Neuro~ltysiol. 31 : 870-883. 17. MAEKAWA, K., and D. P. PURPURA. 1967. Intracellular study of lemniscal and non-specific synaptic interactions in thalamic ventrobasal neurons. Brairz XC-S 4: 308-323. 18. MARCO, L. A., T. S. BROWN, and M. E. ROUSE. 1967. Unitary responses in ventrolateral thalamus upon intranuclear stimulation. J. Neurophysiol. 30 : 482493. 19. MASSION, J. 1968. “Etude d’une structure motrice thalamique, le noyau ventrolateral, et de sa regulation par les afferences sensorielles.” These de Doctorat, Paris. 134 pp. 20. MUKHAMETOV, L. M., G. RIZZOLATTI, and V. TRADARDI. 1970. Spontaneous activity of neurons of nucleus reticularis thalami in freely moving cats. J. Physiol. Loadon 210 : 651-667. 21. NAKAMURA, Y., and J. SCHLAG. 1968. Cortically induced rhythmic activities in the tha!amic ventrolateral nucleus of the cat. Exp. Ncztrol. 22: 209-221. 22. NEGISHI, Ii., E. S. Lu, and M. VER~EANO. 1962. Neuronal activity in the lateral geniculate body and the nucleus reticularis of the thalamus. Visiorz Rcs. 1 : 343-353. 23. NEGISHI, K., and M. VERZEANO. 1961. Recordings with multiple microelectrodes from the lateral geniculate and the visual cortex of the cat, pp. 288295. IO “The Visual System: Neurophysiology and Psychophysics.” R. Jung and H. Kornhuber [Eds.]. Springer-Verlag, Berlin. 24. PWPURA, D. P., and B. COHEN. 1962. Intracellular recordings from thalamic neurons during recruiting responses. J. Neurophysiol. 25 : 62163.5. 25. PURPUXA, D. P., and R. J. SHOFER. 1963. Intracellular recordings from thalamic neurons during reticula-cortical activation. J. Ncwoplzysiol. 26 : 494-505. 26. PURPURA, D. P., T. SCARFF, and J. G. MCM~JRTY. 1965. Intracellular study of internuclear inhibition in ventrolateral thalamic neurons. J. Nezr~o~hystol. 28 : 487-496. 27. RIIYVIK, E. 1968. The corticothalamic projection from the gyrus proreus and the medial wall of the rostra1 hemisphere in the cat. ,4n experimental study with silver impregnation methods. Exp. Brailz Rcs. 5 : 129-152. 28. ROSE, J. E. 1952. The cortical connections of the reticular complex of the thalamus. Res. I’&. Ass. Nerv. Med. Uis. 30 : 454479. 29. SCHEIBEL, M. E., and A. B. SCHEIBEL. 1966. The organization of the nucleus reticularis thalami : a Golgi study. Brain Rcs. 1 : 43-62. 30. SCHEIBEL, M. E., and A. B. SCIIEIBEL. 1966. The organization of the ventral anterior nucleus of the thalamus : a Golgi study. Brcrin Rcs. 1 : 25&268. 31. SCHEIBEL, M. E., and A. B. SCHEIBEIL. 1967. Structural organization of nonspecific thalamic nuclei and their projection toward cortex. Brain Res. 6: 60-94. 32. SCHLAG, J. 1970. Physiologie du thalamus. Acta NEZ(I.O/. Ps~~rhiat. Belg. 70: 6155 645. 14.
HOTTA,
THALAMIC
33.
34. 35. 36. 37. 38.
39.
RETICULAR
NEURONS
97
1968. A quantitative study of temporal and J.. and J. VILI.ABLANCA. spatial response patterns in a thalamic cell population electrically stimulated. Brairt Res. 8 : 255-270. SCHLAG, J., and M. WASZAK. 1970. Characteristics of unit responses in nucleus reticularis thalami. Brain Kes. 21 : 28&X% VERZEANO, M., and I<. NEGISHI. 1960. Neuronal activity in cortical and thalamic networks. I. Gen. Physiol. 43 : 177-195. VILLABLANCA, J., and J. SCHLAG. 1968. Cortical control of thalamic spindle waves. Exp. Nezwol. 20 : 432-442. WASZAK, M., J. SCHLAG, and D. M. FEENEY. 1970. Thalamic incremental responses to prefrontal cortical stimulation in the cat. Bruin Res. 21: 105-113. WEINBERGER, N. M., M. VELASCO, and D. B. LINDSLEY. 1965. Effects of lesions upon thalamically induced electrocortical desynchronization and recruiting. Electroerlcepkalogr. Clk Neurophysiol. 18 : 369-377, YOKOTA, T., and P. D. MACLEAN. 1968. Fornix and fifth-nerve interaction on thalamic unit in awake, sitting squirrel monkeys. J. Newophysiol. 31 : 358-370.
SCHLAG,
SEIIROL0C.Y
32, 79-97
Electrophysiological The Thalamic
(1971)
Properties Reticular
of Units Complex
of
Unit activity was recorded in and close to the thalamic reticular complex in of units was characterized by their long high-frecwCphale isol: cats. A group quency burst responses to lO/sec thalamic and cortical stimulations. their sustained high-frequency firing induced by 4&250/sec thalamic and cortical stimulations, the depression of their firing by high-frequency stimulations of the midbrain reticular fortration and caudate nucleus, and their tendency to he more active during EEIG spindles. These units were located along tracks histologically found crossing the thalamic reticular complex. They differed from cells collected along tracks not crossing the reticular complex. on all four electro-physiological properties mentioned above. These properties are shown to be intrinsic for a class of neurons, presumably of the reticular complex. The timing of firing of rcticularis and nonreticularis neurons is compared and it is suggested that reticularis neurons arc at the origin of inhibition of dorsal thalamic cells. It is also postulated that they play a role in the control of thalamic spindle \vaves. Introduction
The thalamic reticular complex is a thin shell of the ventral thalamus surrounding the cellular mass of the dorsal thalamus on its rostra1 and lateral aspects. Electrophysiological recordings from its neurons have been made (12, 14, 16, 19, 20, 22, 2.3. 3.5, 39), 1XIt most often incidentally while exploring a nearby nucleus. From these studies, three features emerge. First, Negishi, Lu, and I’erzeano (22) observed that reticularis neurons in the vicinity of the lateral geniculate body spontaneously discharged in bursts of long duration. This has heen confirmed recently by Rlukhametov, Kizzolatti, and Tradardi (20). Second, Massion (19) noticed that reticular% cells tended to fire when cells of the nucleus ventralis lateralis 1 This work has been supported by U.S. Public Health Service Grants NB-04955 and NB-21633. Dr. Waszak’s present address is: V.% Hospital, Irving -Avenue and University Place, Syracuse, New York 13210. \\:e express our thanks to Mr. D. Kuroda for his technical assistance. and to Miss C. Xucker for the histological preparations. 79
80
SCHLAG
An-D
WASZAK
(\‘L) were silent. Third, Filion, Lamarre, and Cordeau (12) extended this observation on the reciprocity of firing behaviors by showing that rostral reticularis cells were more active and VL cells less active during cortical EEG spindling. These findings deserve attention in view of the particular physical orientation of the reticularis neurons. Their dendritic fields are traversed by most of the thalamocortical and corticothalamic projections. Synaptic contacts are made on this occasion and, as demonstrated by the Scheibels (29) with the Golgi method, most axons project caudally upon the thalamus and the midbrain. The confrontation of these anatomical and electrophysiological data led to the suggestion that reticularis neurons, strategically situated to receive a variety of inputs, may play back on dorsal thalamic cells (31), most probably by inhibiting them directly or indirectly. The present investigation was undertaken to examine this hypothesis. A number of experimental conditions of stimulation were used, under which the behavior of neurons belonging to various dorsal thalamic nuclei has been extensively studied and is now rather well known. This is especially the case for thalamic and cortical stimulations which induce powerful synaptic drives when applied repetitively at low frequencies (6-12/set.) ( 1, 2, 4, 10, 17, 21, 24-26. 33). Unit activity recorded with microelectrodes aimed at the thalamic reticular complex was compared to that of other thalamic units under these conditions. Preliminary results obtained on this problem have been presented in a short paper (34). Materials
and
Methods
The experiments were performed on 22 cats surgically prepared under ether and Brevital anesthesia. The neuraxis was completely transected by suction at the spinomedullary junction and artificial respiration was provided. The cerebral cortex was widely exposed and immediately covered with mineral oil continuously warmed to about 38 C. The body temperature was maintained by a heating pad. All sites of incision and the pressure points of the stereotaxic headholder were infiltrated with 1% lidoCaine. The general anesthesia was interrupted l-2 hr prior to recording and Flaxedil was injected. The cats’ pupils remained fissurated throughout the experiments, including the periods of stimulation. Except in one case, unit recordings were made with glass micropipettes filled with 3 M KCl. The tips of these electrodes were 2 ,u or less in diameter. The potentials were led into a Tektronix 502 oscilloscope (CRO) through a cathode follower without amplification. Photographic records were obtained for all data reported: lo-30 pictures were taken for every test, depending on the stability of the unit behavior observed; and all measurements were made on films. Electrical stimuli (ordinarily 0.5 msec.
TNALAMIC
RETICI.LAR
NEGROSS
Sl
200-450 pa, square pulses) were applied through concentric stainless-steel electrodes. The inner wire was 0.15 mm in diameter ; it was exposed only at the tip and protruded 0.4-0.8 mm from a 22-gauge needle. Stereotaxic placements were made according to the atlas of Jasper and Ajmone-Marsan ( 15,). Micropipette insertions were irregularly distributed in order to permit identification of individual tracks upon examination of the histological material. Confusion could he avoided by varying the number of tracks on successive frontal planes. The sites of stimulation were marked by iron deposits and sul)sequent ferrocyanide reaction. The SO-p histological sections were stained with thionine.’ Results
A+lato/r/ical
Comidrratiocs
On histological sections, a number of electrode tracks were found crossing the thalamic reticular complex on at least parts of their trajectory, as illustrated by different examples in Fig. 1. In A, a track is seen penetrating the lateral sector of the reticular shell. In B. the micropipette was inserted obliquely and the first unit observed differed, in the manner described below, from those encountered subsequently in the dorsal thalamus. In C, five tracks are situated in the rostra1 pole of the reticular complex and all five yielded similar results. D refers to the sole experiment in which a metal microelectrode was used, thereby permitting a marking of the site of unit recording closeto the transition with the zona incerta. In such cases,conditions were satisfied to contact reticularis cells. However, because of the shape of the complex (e.g.. Fig. 1A). possibly neurons from adjacent dorsal thalamic nuclei or from the subthalamic region could also be encountered. Since depth measurements have some imprecision, we could not assert with absolute confidence that given units were reticular. Therefore, we shall objectively refer to them as “found along tracks crossing the thalamic reticular complex.” Other tracks were directed entirely within the confines of the dorsal thalamus (‘namely, in the VL, VPL, T,P, and lateral part of the VZ\) and the results collected there could be used for comparison, since certainly, no reticularis neurons were situated in the electrode path. Still other tracks traversed the internal capsule on their entire course, recording rare and always sharp spikes (of probable asoual origin). During the esperiments, 2 pII1 anatomical locations given in this report refer to actual histological findings. The following anatomical abbreviations will be used in the text: Cd, caudate nucleus; CM, centrum medianum comp!ex; IL, internal medullary lamina of the thalamus ; LP, nucleus lateralis posterior ; RF, mesencephalic reticular formation : VA, nucleus ventralis anterior : VT,. nucleus ventralis lateralis ; \7PI., nucleus ventropcsterolateI-alis.
82
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AND
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such indications of “misses” helped in adjusting the next insertions of microelectrodes toward the thalamic reticular target. Once the target was located, as judged by the electrophysiological results, close by tracks tended to yield the same type of records (as in the case illustrated by Fig. 1C). No explorations of more medial sectors of the thalamus were attempted in this study, since data on more than 200 cells observed in and around the VL nucleus under similar conditions were available for comparison from previous works from this laboratory (21, 33).
FIG.
showing the text.
1. Thionine-stained tracks passing
histological sections of thalamus in four different animals, through the thalamic reticular complex. Other explanations in
THAL.-\MIC
Responsesto Rrprfitive
RETICCLAR
XETROKS
s3
Thalawic Stimulation at TM i)cr Sccoml
Defi&olt of R~spome Paftcrns. Thalamic stimulation at the rate of naturally occurring spindles is known to he particularly effective on thalamic neurons (10, 17, 24, 26, 33 ). Therefore, lO/sec rates were used routinely. Unit responses to stimulation in the region of CM (59 observations j, of IL (75 observations), or in the center of VL (56 observations) yielded similar results: irrespective of the site of recording, the responses were either an immediate cessation of firing or. more often, one of the two patterns illustrated in Fig. 2. As illustrated in records A and B of Fig. 2, the number of discharges after each stimulus tended to increase progressively during the early part of the train. Except for this common feature, the traces differed in the density and duration of the bursts. In Fig. ZA, the unit fired one to three spikes with a constant latency of less than 30 msec. \Vhen units of this type were spontaneously active, lO/sec thalamic stimulation resulted in an over-all depression during and following the train. In particular. discharges were suppressed during the second half of the 100~msec interval between the stimuli. Seventy-seven cells fell in this category: The latencies varied from 3.5 to 10 msec and the number of spikes per response from one to six. Short bursts evoked in the same conditions were obtained from \*I~-identified neurons in our previous study (33 ) . Although recorded only O..; mm away from the first, the unit presented in Fig. 2B differed considerably in the length of its bursts. For cells of this second type, the IO/set stimulation increased the average firing rate up to 350,/set with peaks as high as .SOO/sec. \I’hen the background activity was already intense. the individuality of responses could be lost, and the effect was more adequately described as a frequency modulation at the rate of stimulation (Fig. 6). M’e found 85 cells behaving in this manner. Neasurements were possible in 77: the latencies varied from less than 1 to 36 msec and the nrml)er of spikes per response from seven to 30. The two types of evoked activity illustrated in Fig. 2 could he distinguished with little ambiguity when viewed on the CR0 screen. They were respectively called “short-burst” and “long-burst” for convenience. In order to verify the objectivity of this differentiation, parameters of the firing patterns were analyzed (duration, number of spikes, frequency, and latency). Measurements were made on fully developed responses after stahilization (i.e., the fifth or sixth response in the lO/sec trains) in 151 units. DI4ratiolz of Rlt~.sts. As seen in Fig. 2C. the distribution of all cells according to the duration of the bursts confirmed the impression of two populations. The thick line (between the two white arrows) indicates where the division beetween short-bursts and long-bursts had been subjectively
84
SCHLAG
AND
WASZAK
placed before resorting to any quantitative analysis. Although this separation was quite arbitrary, it was kept in order to form two groups, because, whatever the criterion adopted, the classification would have been the same except for only three or four units (in the range of 15 to 30-msec bursts). Nzt~!~r of Spikes. The distribution according to the number of spikes per response was also bimodal. It is not presented since it has practically the same shape as the histogram of Fig. 2. In fact, the dividing line in Fig.
20
*
40
60
80
too
120
FIG. 2. Example of short-burst (A) and long-burst (B) responses to 1Ojsec thalamic stimulation. Calibration marks : 100 msec; 1 mv (upper), 10 mv (other recordings). C. Distribution of cells according to the duration of their thalamically evoked bursts. In A and B, upper traces from anterior sigmoid gyrus, lower traces from thalamic units. Stereotaxic coordinates of unit in B were 0.2 mm more anterior, 0.3 mm more lateral, and 0.1 mm more ventral than for unit in A, in the same animal. In this and all following figures, focal positivity indicated by a downward deflection, cortical surface recordings always monopolar. Stimulation in the IL region. In C, abscissa is duration of bursts in msec, ordinate is number of cells. Hatching: cells found in tracks crossing thalamic reticular complex. Black: cells found in tracks away from reticular complex. White: cells in track of uncertain course. Heavy line (between white arrows) : arbitrary division made for quantitative comparison of two groups of cells.
THALAMIC
RETICrLAR
NEUROKS
S3
2C was found to separate cells having less and more than six spikes per burst. Comparison of Rcsponsc Patterm and Location. In the histogram of Fig. 2C, it can be noticed that no cells found in tracks entirely situated outside the thalamic reticular complex discharged in long bursts in response to thalamic stimulation. Conversely, only a few cells found in tracks passing through the reticular complex responded by short bursts. This confrontation of electrophysiological with anatomical data indicates that the response modalities were definitely correlated with the sites of recordings. This conclusion is further supported by the fact that units exhibiting different response modes were never interspersed along the same track. They were always clustered: for instance, up to seven units responding by long bursts could be recorded in succession over a 2.5111111 span at the rostra1 pole of the reticular complex, in the region illustrated by Fig. 1C. Sflecijicit~~ of Rcspo~~ Pattems. The production of long high-frequency bursts was an intrinsic property of a class of neurons. Three of these units were tested with thalamic stimulations at two different places (~CM and IL) and responded in the same profuse manner to both. Fourteen units were also tested with cortical stimulations (see below), and 12 responded with long bursts whereas two were progressively silenced. In another unit, lO/sec stimulation of the CM, anterior sigmoid gyrus, and cingulate gyrus evoked SO-msec bursts, whereas lO/sec stimulation in the depth of the presylvian sulcus stopped the spontaneous discharges. Thus, depression of ongoing activity seemed to be the only alternative response modality. No short bursts were ever produced in these cells, under any conditions tested. except when the intensity of stimulation was lowered. It would have been surprising, indeed, if the number of spikes triggered did not depend also on the strength of stimulation. To explore this possibility, in a few instances, the voltage of thalamic stimuli was reduced: this drastically decreased the number of discharges as shown in Fig. 3. But, in comparison with the short bursts described above, such responses were always unstable in latency and duration. It was clear that the long-burst characteristic could be lost when the drive was insufficient, thus preventing a correct identification on the basis of the criterion adopted. admittedly. this may have occurred in our experiments, thereby confusing the distinction or biasing the classification of cells systematically in favor of the short-burst type. Frequency of Fihg. The average frequency of firing could be about the same in short-burst and long-burst responses. But the maximum frequency was always reached immediately in short bursts. whereas it came in the middle of the long bursts [Figs. 2B. 5, 6A. 7, and S). Latelzcy. No obvious difference in latency could he associated with the
86
SCHLAG
AND
WASZAK
FIG. 5. Effect of reducing the intensity (ZOO-SO pa) of lO/sec thalamic stimulation on the long-burst responses of a thalamic unit. Upper traces from anterior sigmoid gyrus, lower traces from a rostra1 thalamic cell at 3 mm from midline. Stimulation in IL region, successively of ZOO, 100, and SO pa. Calibrations: 100 msec; 0.5 mv (upper). 5 mv (lower).
response modalities as defined above. However, a comparativeIy large proportion of the long bursts had a short latency (21% were shorter than 3 msec and 11% shorter than 1 msec, versus 0% in the other group). Although latency measurements were possible only on a limited number of cells (119 cells), the difference is noteworthy since units responding so quickly were the most peripheral in the thalamus, i.e., farthest away from the sites of stimulation. The latencies shorter than 1 msec were extremely stable (no measurable “jittering”). They were obtained in all three kinds of stimulation (VL, CM, and IL). Over-all Activity. Finally, the two types of populations were compared from the viewpoint of the amount of activity generated by thalamic repetitive stimulation, i.e., the proportions of units active (in the process of bursting) at successive moments of the 100-msec stimulus intervals were computed for both groups. The distribution showed that, at any time before 50 msec, there were several times (two to 26 times) more long-burst units active than other cells. Of course, SO msec after each stimulus, only long-burst units were still discharging. Responses
to Tlzalamic
Stimulations
at Othrr
Frequencies
Although long bursts were easily evoked in certain cells by lO/sec thalamic stimulation, this particular frequency was not so selectively effective as it was found to be for provoking short bursts in this and previous studies (33). For instance, the unit presented in Fig. 4 discharged profusely even when the stimulus intervals were of the order of 1 sec. The difference
THALAMIC
RETICCLAR
NEURONS
FIG. 4. Responses of a thalamic unit to repetitive thalamic stimulation 21 to 0.77/set. Upper traces from anterior sigmoid gyrus. Stimulation recorded along one of the tracks represented in Fig. 1C. Calibrations
s7
varying from in CM. Unit as in Fig-. 3.
between the effects of the first and subsequent stimuli is conspicuous in all these records. For all of the cells tested, the duration and density of the long bursts remained unchanged at rates down to .5/set, but they were still considerable at frequencies definitely lower than those of spontaneous spindles. In contrast, there was no increase in duration of short bursts at such low frequencies. At frequencies above lO,/sec. the firing always tended to become continuous. Average discharge rates as high as 350-450/set were usual; they were often accompanied by spike attenuation (Figs. 4-7 ) One of the most remarkable features was the capacity of many of these neurons to sustain such an intense firing for a considerable time. The unit presented in Fig. 5 discharged at 320/set for 3 set under 30/set CM stimulation. This kind of feat, to our knowledge, has never heen reported for any dorsal thalamic cells (e.g., 18. 25 ). In this example. the very long activation was followed by a long pause. Almost half of the cells, however, did not show any postreactional depression (Fig. 6). Thev continued firing after the last stimu-
88
SCHLAG
AND
WASZAK
lus of a train, in contrast to dorsal thalamic neurons which were regularly inhibited after a period of excitation (also 25, 33). Thirty-two neurons responding by long bursts to lO/sec thalamic stimulation were tested to 40-250/set stimulation. All of them were activated very strongly in a prolonged manner. In contrast, of 19 neurons responding by short bursts to lO/sec stimulation, 12 were silenced by high-frequency stimulation, four were accelerated for less than 400 msec, and three remained apparently unaffected. Responses
to Cortical
Stiwmlation
It is known from several anatomical studies that different sectors of the thalamic reticular complex have topographical relations with definite cortical regions (7, 8, 25). Since it was impossible to place stimulating electrodes everywhere on the hemispheres, explorations were limited to rostra1 thalamic cells and, accordingly, sites of stimulation were selected only within the frontal lobe cortex : anterior and posterior sigmoid, anterior cingulate, orbital gyri; and the mesial cortex under the cruciate sulcus (27,
FIG. 5. Sustained high-frequency firing of a thalamic cell evoked by IO/set stimulation in CM lasting for 3 set (between the arrows). Continuous record. Note spike attenuation and postreactional depression. Upper trace from anterior sigmoid gyrus. Unit recorded along one of the tracks represented in Fig. 1C (different from unit illustrated in Fig. 4). Calibration marks : 100 msec; 500 ,uv (upper), 2 mv (lower).
THALAMIC
RETICL-LAR
89
NEURONS
37). The number of responsive cells studied (48 cells) was too small to analyze these cases separately. The most significant finding was that 12 of 14 units (86%) responding with long bursts to lO/sec thalamic stimulation responded in exactly the same way to lO/sec cortical stimulation. The median duration of the fully developed bursts (after the fifth or sixth stimulus of a train) was 50 msec. The other two units (l-l% ) were progressively silenced. responding with short bursts to In contrast, 15 out of 3-l units (44%) lO/sec thalamic stimulation also responded with short bursts to lO/sec cortical stimulation, whereas the other 19 units (56% ) stopped firing (also 2, 21). This depression could be obtained even more easily by high-freyuency (-FO-250/set) cortical stimulation (S-l% j, Conversely, most cells of the long-burst type (76% ) were strongly activated by this stimulation. Respomes
to Midbrain
arid Caztdntr
Nuclezts
Stimulation
High-frequency (10&250/sec) stinutli applied to the mesencephalic tegmentum, ventrolaterally to the central gray matter (reticular formation), either reduced the activity of the cells characterized by their long-burst responses to thalamic stimulation (66%. Figs. 7 and 9) or had no effect (3-l%). This was not due to high-frequency spike attenuation. In sharp contrast, 78% of units of the short-burst type were activated, and only 22% showed a depression in firing. The results obtained by stimulation of the head of the caudate nucleus were comparable. Clear-cut effects were best obtained with the highest fre-
FIG. 6. Persistence of high-frequency firing after termination of thalamic stimulation in two conditions. ,4, continuous record during and following lO/sec stimulation in IL. Upper record from anterior sigmoid gyrus. B, 40/set stimulation in IL in another animal. This cell had a very low spontaneous activity. Calibration marks: 100 msec ; 1 mv (upper tracings), 10 mv (lower tracings).
90
SCHLAG
AND
WASZAK
quencies (lOO-250/see) which, in 75% of of cells of the type illustrated in Fig. 7. At 40/set), there could be a slowing down or, the discharges. Sometimes both occurred train (Fig. 7) or alternatively in different 2.5% of the cases. There were not enough cells to provide a comparison.
Spontaneous Activity
the cases, depressed the firing lower frequencies (e.g., 10 and on the contrary, a grouping of in succession during the same trains. Activation was seen in tests of the short-burst type of
and Relations with EEG Activity
The spontaneous firing of cells characterized by their long-burst responses to thalamic stimulation was extremely variable. The range of variation was from complete silence to levels of more than 120/set maintained for several seconds, a value not attained by other uninjured thalamic cells (maximum actually observed : 70/set). IL
10
FIG. 7. Comparison between responses to stimulations at different sites: IL, Cd, and RF, and with different frequencies: 10, 40, and 25O/sec. Unit recorded along track in rostra1 part of thalamic reticular cortex. Upper traces from anterior sigmoid gyrus. Note the high-frequency discharges induced by thalamic stimulation, and the arrest of firing caused by RF stimulation and by Cd stimulation, especially at 40 and 250jsec. Time 100 msec; but record RF taken at slower speed. Vertical calibrations : 0.5 mv (upper), 20 mv (lower).
THALAMIC
RETICYLAR
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91
;\lany of these cells were found to fire spontaneously in long bursts as they did in response to lO/sec thalan~ic stimulation (also 20). On several occasions when simultaneous EEG recordings had been made by chance from an adequate position on the cerebra1 cortex, the bursts were found to correspond to the occurrence of surface-negative waves, either evoked or spontaneous (Fig. S ). They were generally composed of more than 10 spikes and lasted for 30-120 msec. Kegishi ct al. (22) and Mukhametov c‘f al. ( 20 ) carried on (spontaneous activity of reticularis cells in the vicinity of the lateral geniculate body ) quantitative analyses similar to ours and fount1 similar figures. Burst durations of 132 nlsec (22) have been reported. as compared to 20 nxec for lateral geniculate cells (22) or IO-25 nlsec for dorsal thalamic cells in general ( 1). Reciprocally, the intervals between the groups of prolonged discharges were shorter. Since the lmrsts were long, their separation short, and the tiring rate high, these cells tended to he much more active during than 1)etween EEG spindle trains (Fig. 9). This observation refers to individual spindle trains, for, as Mukhametov Et al. (20) mentioned. the over-all average activity may be less in periods of spindling than during EEG fast rhythms in arousal or REM sleep. In Fig. 9C, a high-frequency stimulation of the midbrain reticular formation is shown to stop the cortical spindling and the activity of the thalamic unit simultaneously recorded. Although many similar okrvations were made, the relation with the EEG activity was not always as clear. Other factors certainly were involved. Indeed, when the EEG desynchronization was produced by thalamic high-frequency stinmlation. it was accompanied, on the contrary, hy an intensification of the firing.
8. Comparison of evoked and spontaneous bursts in a rostra1 thalamic unit. record: end of a lO/sec train of stimuli applied in IL. Louver record: spontaneous activity of the same cell during cortical spindles (upper trace from anterior sigmoid gyrus). Note the similarity of the bursts and their timing in relation x&h cortical surface-negative \I-aves. Calibrations: 100 msec; 0.5 mv (upper), 10 mv ( lower ). FIG. Upper
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Discussion
A group of thalamic cells in this study has been characterized by : (i) their long high-frequency bursts evoked by lO/sec thalamic stimulation ; (ii) their long high-frequency bursts evoked by lO/sec cortical stimulation, in 86% of the cases; (ii;) their sustained high-frequency firing induced by 40-250isec stimulation of thalamic sites ; (iv) their sustained high-frequency firing induced by 44-25O/sec stimulation of cortical sites, in 76% of the cases; (zt) the depression of their firing by high-frequency stimulation of the midbrain reticular formation; (vi) the depression of their firing by high-frequency stimulation of the head of the caudate nucleus, in 75% of the cases ; (vi;) their tendency to be more active during EEG spindles ; and (z&) their location along tracks histologically found crossing the thalamic reticular complex. Most peculiar was the ability of these cells to sustain high frequencies of discharge (up to 350/set) for long periods (up to 3 set). First, we shall discuss the arguments indicating that these were reticularis neurons. On the basis of parameter measurements (especially length of bursts), the cells exhibiting property i were shown to form a separate population, Thus, property i was chosen as a criterion for differentiation and was found to be shared only by units which satisfied the anatomical require-
FIG. 9. Relation between the firing the thalamic reticular complex, and different times. Upper traces from first trace, lOO/sec stimulation of cortical spindling. Calibrations: 100
of a cell found along a track passing through the EEG. A, B, and C from the same unit at anterior sigmoid gyrus. In C at the end of the RF for 400 msec and subsequent cessation of msec; 0.5 mv (upper), 20 mv (lower).
ment ~iii. Conversely, the other cells located within the limits of the dorsal thalamus behaved quite differently in the situations in which properties i to zqii. revealed themselves. Our observations on these other cells, in fact, agree with those of previous studies escept on one point: the high-frequency firing patterns assumed to represent the activity of small interneurolls in specific thalamic nuclei (4. 6, IS) were never observed in the present experiments probably hecause our microelectrodes had different characteristics. Whatever the case, records from such interneurons were said to form only a small percentage in the populations explored (1, 18)) in contrast to our long-bursting units which were easy to find in clusters in the region of the thalamic reticular complex. ,4s far as neurons of the medial thalamus and region of the internal meclullary lamina are concerned. strong bursts obtained under similar conditions have been occasionally reported ( 10, 25 ) but. apparently, the discharges did not reach such a high frequency and were, by far, never so long-lasting. The correlation between property i on one hand, and properties ii, izj. and vi on the other hand was not absolute. Kamely. knowing that a given unit responded by long bursts to thalamic stimulation, the responses evoked from the cerebral cortex or caudate nucleus were not as predictable as the effect of stimulating the midbrain reticular formation (property v). Nevertheless. these observations ii, izf, and zli deserve consideration as they extend the range of experimental conditions under which a differentiation was possible-at least statistically. Considering these results altogether, we submit that the cells characterized hy property i helonged to the thalamic reticular complex. For convenience. they will be referred to from now on as reticularis neurons. Quite possibly. some reticularis neurons have not been recognized in this study and. therefore, have been wrongly classified because the test stimulations were not adequate for revealing their particularities. Conversely, it is less likely that nonreticularis neurons have been wrongly classified. unless they were cells of the close by medial sector of VA which have the same structural organization as reticularis cells (30 31 j. This study suggests that reticularis neurons are excitable from a variety of places. Even those of the lateral wing of the nucleus (as far as 7.5 mm lateral to the midline) were able to respond strongly to CM stimulation. Eleven per cent could fire within a very short and stable delay (less than 1 msec ) after VL. CM, or IL stimulation. Such characteristics strongly suggest the possibility of antidromic invasion, though further studies are necessary for confirmation. The reticularis Lmit responses to lO/sec thalamic stimulation were analyzed in order to estimate the proportion of these cells active (i.e., in the process of bursting) at successive moments. The distribution showed that several times more reticularis cells than other cells were activated at anv
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time during the 100 msec separating the stimuli. The difference became, of course, the most dramatic in the second half of the lOO-msec intervals when all dorsal thalamic cells were inhibited. Since the firing rate of reticularis cells was the highest in the middle of their bursts, it can be said that the peak of reticularis activity corresponded to the beginning of the inhibition of dorsal thalamic cells. Since reticularis neurons distribute their axons diffusely in the dorsal thalamus (29), the thalamic structures must receive the vigorous reticularis output. As just pointed out, most of the dorsal thalamic neurons underwent a long phase of inhibition when the reticularis volleys were fully developed. It is, thus, implausible that reticularis neurons are the source of an excitatory action. Were they ultimately excitatory, either their output, although massive, must be rather ineffectual, or else could only serve to generate activity resembling rebound when the inhibition of dorsal thalamic cells has subsided. The converse hypothesis : that reticularis neurons are directly or indirectly (i.e., through intercalated interneurons) inhibitory elements is more consistent with the facts observed. In this connection, one cannot fail to be impressed by the capacity of these cells to discharge at very high-frequency as do many inhibitory neurons ( 11). In the elaboration of this inhibitory hypothesis, it would be possible to regard the reticularis neurons as responsible for the individual inhibitory pauses phasing the thalamic activity at around lO/sec (3). However, this seems questionable since the lO/sec rate of stimulation was not more selective than lower rates in driving these neurons and since their firing could be sustained for much longer than 100 msec. Another possibility is suggested by previous demonstrations that rhythmic postsynaptic inhibitory potential (IPSP) of dorsal thalamic cells, either spontaneous (1) or evoked by thalamic stimulation (26), often tend to increase progressively in amplitude. This phennmenon, that we have also observed (Waszak. cited in Ref. 32), may be due to the partial overlapping of consecutive IPSP, or may be caused by a slow hyperpolarizing drift on which successive waves are superimposed. If the latter interpretation is valid, the longlasting firing of reticularis neurons could be considered as the source of this very long underlying hyperpolarization, whereas briefer recurrent inhibitory phases would be produced by local interneuronal circuits in the various dorsal thalamic nuclei (4, 6, 18). Indeed, there is a difference in duration of bursts : compared with reticularis neurons, the small interneurons fire for shorter periods and they are tonically much less active (18). Under favorable conditions, the maximal activity of reticularis neurons could be correlated with the presence of individual spindle bursts in the EEG (also Refs. 12, 20). Such spindles have been shown by Andersen and Andersson (1) to be accompanied for their whole duration hy a SUS-
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tained hyperpolarization of dorsal thalamic neurons. This suggests the possibility of a tonic role of reticularis cells in regulating the occurrence of spindles. In fact, lesions destroying the rostra1 pole of the thalamus-ineluding the reticular complex-strongly interfere with the spindling process (5. 9, 13, 38). But, since the impairment is reversible by extensive decorticntion (36’)) it seems that the rostra1 thalamic lesions only affect a controlling factor, leaving intact the oscillatory mechanism itself. This is but one aspect of the possible role plnyed by reticularis neurons. More specific aspects of their interactions with other thalamic nuclei should be investigated. References Basis of the Alpha 1. ?ISIERSEN. P., and S. A. ANDERSON. 1968. “Physiological Rhythm. .Appleton-Century-Crofts, New York. 235 pp. 2. .~SIERSES, P., C. Beooh-s, J. C. ECCLES, and T. .A. SEARS. 1964. The ventro-basal nucleus of the thalamus : potential fields, synaptic transmission and excitability of hoth presynaptic and postsynaptic components. J. Pk>qsiol. Lorfdo+f 174 : 34% 369. 3. .ZNIIEKSEK. P.. and J. C. E~CLBS. 1962. Inhibitory phasing of neuronal discharge. .Votrtrc Lodm 196 : 645447. 4. \ NIXRSEK, P.. J. C. ECCLFS, and T. A. SEARS. 1964. The ventro-basal complex of the thalamus: types of cells, their responses and their functional organization. J. Pltysiol. Loufor 174: 370-399. 5. &l.H-Y-RTT.4, G.. C. BAGRAKD, and A. CHRISTOLOMRIE. 1969. A comparison of EEG modifications induced hy coagulation of subthalamus, preoptic region and mesenrephalic reticular formation. Elcrtr-o~,~rccphalonv. C/it?. Kcwoplf~si~~l. 26 : 393-502. 0. RL.RKE, \I’.. and A. J. SEFTON. 1966. Discharge patterns of principal cells and interneurons in lateral geniculate nucleus of rat. I. Ph?vioi. Lordon 187 : 201212. 7. C.z~;nr.\s. J. B., \V. M. C~WAX. and T. P. S. POWELL. 1964. Cortical conncsions of the thalamlc rctlcular nucleus. J. . Iunf. 98 : 587-598. S. C~IO\\, K. L. 1954. Regional degeneration of the thalamic reticular nucleus following -ortical ablations in monkeys. J. C‘owp. N~rrrol. 97 : 37-59. 9. CHOLV. K. I,.. L%'. C. DEMEKT, and S. A. MITC.HEI,L JR. 1959. Effects of lesions of the rostra1 thalamus on hrain waves and behavior in cats. Elrrtloc~~ccphlogr.
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T., and 1). P. Pc~rurc~. 1970. Organization of specific-nonspecific thalaniic internuclear synaptic pathways. Hvnirz Rcs. 21 : 169-181. E(.(.LEs, J. C. 1969. “The Inhibitory Pathways of the Central Nervous System.” Thomas, Springfield, Illinois. 135 pp. FILIOS, 31.. Y. LAMAKRE, and J. P. CORDEAU. 1969. Plctivites unitaires du noyau lateralis du thalamus au tours de la veille et du sommeil. J. Physiol. Paris 61: 290. HANBERRY, J., C. AJMOKE-MARSAN, and M. DILR.~RTH. 1954. Pathways of nonspecific thalamo-cortical projection system. EII,cirorllcrphlllunr. (‘/in. A:t*~tr-oI)SsIlARu.
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6 : 103-l
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