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Corticifugal influences on the activity of reticular formation neurons in cats
EXPERIMEKTAL
D.
36,
h-EUROLOGY
250-262
Corticifugal
Influences Formation
F. LINDSLEY,
S. K. RANF,
Depart?ncnt of Ph~uiology,
(1972)
on the Neurons
M. J. SHERWOOD,
University illageles,
Los
Activity of in Cats
Received
AND W.
of Southern California California 90033 March
Reticular
G.
Medical
PRESTON ’ School,
31, 1972
Corticifugal influences descending through the subthalamus have been shown to regulate the excitability of the reticular formation (RF) and maintain attentive behavior. Previous work demonstrated that cooling the secondary somatosensory cortex (SSII) modified RF sensory-evoked potentials. The present experiments indicate that the primary sensorimotor cortex (SSI) also projects to single neurons at those levels of the RF which have been shown to receive subthalamic influences. In acutely prepared, unanesthetized, immobilized cats, bilateral cooling of SSI caused a reduction in the response of midbrain and medullary RF neurons to sciatic stimulation. In some RF cells which responded to both sciatic and forepaw stimulation, cortical cooling decreased responses to both inputs. The generalized, tonic nature of these corticifugal influences was also illustrated by showing that cooling reduced spontaneous activity. Rewarming led to a recovery of reticular responsiveness and background activity. If care was taken to prevent cortical
deterioration, cooling could be repeated with subsequent response recovery back to control levels upon rewarming. In some reticular neurons which had both early and late responses it was possible to show that the cortex could also exert differential effects on these responses. Thus, corticifugal and SSII are important in determining the excitability of the RF to somatosensory input. Although these
and generalized specific
in nature. in some cases they
projections from both SSI of neurons along the length influences were usually tonic could be shown to exert more
effects. Introduction
The role of the cortex in the modulation of subcortical activity has been the subject of considerable anatomical and physiological work (5, 6, 10, 13-15, 21, 25, 27, 32). Numerous studies have shown that sensory cortical areas can exert facilitatory and inhibitory influences on the responses of subcortical, somatosensory nuclei (4, 9, 12, 23, 28). Recently these same cortical areas have been demonstrated to influence the development of sen1 The research was supported by Grants GB 31540 from the National Science Foundation and NS 07865 from the National Institutes of Health. The authors gratefully acknowledge the histological assistance of Mrs. Joan Higgins. 250 Copyright All rights
0 1972 hy Academic Press, of reproduction in any form
Inc. reserved.
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FORMATION
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sory-evoked potentials (EP ) in the reticular formation (RF) and adjacent midbrain (19, 24, 26). Rabin (26) has even proposed that “the second somatosensory zone of the cortex controls responses of the so-called nonspecific structures of the brain.” However other work indicates that the primary somatosensory cortex (SSI) a 1so has important projections to the RF (7, 19, 21, 33), although the secondary somatosensory cortex (SSII ) may exert a more powerful influence (23). Because tonic influences descending through the subthalamus can also modify reticular excitability (l), it has been suggested that these influences include projections from SSI and SSII (19) and from limbic areas (2). The present experiments were designed to extend the work of Lindsley, Ranf, and Barton (19) to SSI and to study the effects of its projections on single neurons at various levels of the RF which have been shown to receive subthalamic influences. Methods
The results were obtained in acute experiments on 13 cats. All surgical maneuvers were performed under ether anesthesia. All surgical incisions and pressure points were infiltrated with procaine in peanut oil (Zyljectin, Abbott) after which the animals were immobilized with gallamine triethiodide (Flaxedil, Davis and Geck. about 0.13 mg/min).2 The experiments were conducted in a sound-shielded room (Industrial Acoustics Co.). No recordings were taken for at least 2 hr after the conclusion of the ether anesthesia. Stainless-steel microelectrodes made according to the technique of Green ( 11) were used to record the activity of single neurons. The microelectrode was oriented stereotaxically in a micrometer-drive apparatus (Kopf microdrive), and records were kept of the depth of each unit studied. The unit activity was led into a Grass high impedance probe and then into a Grass P511 preamplifier. The amplified signals were sent into a Schmitt trigger to produce standardized, square-wave pulses (7 v, 0.5 msec) which were displayed with the unit activity on an oscilloscope. Unit activity and trigger pulses were monitored throughout the experiment, and an exact correspondence between the two was maintained by adjusting the Schmitt trigger. Unit activity, Schmitt trigger pulses, and the stimulus output of the master stimulator (Tektronix 161 and 162 pulse and waveform generators) serving as a stimulus-triggering pulse, were also recorded on a Honeywell 7600 tape recorder for later processing. The Schmitt trigger pulses and the stimulus-triggering pulse were also led into a LAB-S computer (Digital Equipment Corp.) for on-line, poststimulus time histo2 Heart rate and pupillary size were monitored throughout the experiment; they gave no indication that the animals were suffering pain or discomfort. The animals periodically showed a constricted pupil which could be reversed by loud clapping or pinching the animal.
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ET
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gram (PST) analysis. The PST for the LAB-S (DECUS No. S-339) has a bin size of 1.5 msec. The output of the LAB-S was displayed on a Tektronix 503 oscilloscope and photographed with a Polaroid camera. Sciatic stimuli as used in these experiments (2-3 v, 1 msec, once per 3 set) do not evoke painful responses (16, 17). The body temperature was maintained at 38 C by using an infant heating blanket. When an RF neuron was found that gave a clearcut response to sciatic stimulation, the cell was allowed to stabilize for approximately half an hour. Such care was taken because a period of l-2 hr was required to study each unit completely. It was also important to minimize the possibility of losing the unit during the first cooling period, as subsequent toolings were not felt to be as effective, due perhaps to cortical deterioration. Cooling of the primary sensorimotor cortex (SSI) was performed bilaterally by placing physiological saline ice slush over the intact dura; the cortex was kept warm before cooling and rewarmed by application of physiological saline at body temperature. Although the main aim of this study was to determine the effects of cooling SSI on RF neurons, this area in the cat is difficult to separate from neighboring “motor” areas and perhaps is more appropriately called the primary sensorimotor cortex (7). Also because the cooling procedure undoubtedly influenced “motor” areas immediately adjacent to SSI, the cortical area involved in the present experiments should be properly considered to be the primary sensorimotor cortex. Since sciatic stimulation was continued for a long period of time, control PST were photographed only after some 15 min of stimulation. When it was clear that the response had stabilized, cooling of the cortex was initiated. The PST were monitored continuously during cooling and when major changes were ohserved. cooling was terminated, the cortex was rewarmed, and monitoring of PST was resumed. Recovery during rewarming was followed for 30 min and sometimes longer. To minimize cortical deterioration produced by repeated toolings and by the time-consuming experimental procedure outlined above, a number of animals were killed after completing cooling studies on one cell. This reduced the population of cells that could be studied, but led to a more reliable assessment of corticifugal effects. After each experiment direct current was passed through the microelectrode to mark the point of the last recorded unit ; the brain of the animal was perfused with a mixture of potassium ferricyanide in 10% formalin which produced a Prussian blue spot where the electrode point had been. All brains were cut in frozen coronal sections and stained with neutral red : they were examined and the position of the unit within the RF was determined either from the location of the marked spot or by calculating the distance back from the lesions along the electrode track using the micrometer-drive readings corrcsponding to the unit.
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Results
Eflects of Cortical Cooling on the Responses of Reticular Formation Neurons to Sciatic Stiwdation. Sciatic-evoked responses of cells in both the midbrain and medullary RF were reduced by bilateral cooling of the sensorimotor cortex. Figure 1 shows poststimulus time histogram (PST) displays of sciatic responses of two neurons in the midbrain RF. The response of the unit to the left (Fig. la) consisted of an initial inhibition of firing followed by a peak of activity. Cooling the cortex bilaterally led to a disintegration of the basic pattern of the response, although the effect on the activity peak was more marked. The response of the cell to the right (Fig. lb) consisted of a single peak of activity. Cooling led to a decrease of the response. For both units, rewarming of the sensorimotor cortex led to almost total recovery of the control response. Complete recovery of the response was difficult to obtain even after periods of 30 min perhaps due to alterations of the cortex. In this figure and all other PST displays the vertical calibration represents five spikes and the horizontal 25 msec; each PST is the sum of 2-l responses to sciatic stimulation at the rate of once per 3 sec. Figure 2 shows the actual response of a single unit in the medullary RF to repetitive sciatic stimulation at once per 3 sec. This figure was obtained b.
a.
CCNTROL
COOL
FIG. 1. Effects of bilateral cooling of the primary sensorimotor cortex (SSI) on the responses of two midbrain reticular formation neurons to sciatic stimulation. Each trace is a poststimulus time histogram (PST) representing the sum of 24 responses of the cell to sciatic stimulation at the rate of once per 3 sec. Note that for both cells (a and b) cooling of SSI led to disintegration of the responses and with rewarming the responses returned to control levels. In all PST displays the bin size is 1.5 msec. In all figures the arrows indicate onset of stimulus. All vertical calibrations represent five spikes and all horizontal are 25 msec.
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by using Z-axis modulation of the oscilloscope, photographing each sweep with a Polaroid camera, and moving the sweep down along the Y-axis of the scope in small steps. Each dot represents a single spike, and each horizontal row of dots is the response of the cell to one sciatic stimulus. Before cooling (Fig. 2a) the cell had a double-peaked response followed by a period of inhibition and then gradually returned to spontaneous firing levels. Cooling of the cortex for 2 min (Fig. 2b j caused a general break-up of the response, and by the end of 5 min (Fig. 2c ) the cell had completely stopped firing. After 15-min recovery (Fig. 2d), the cell’s response had returned to control levels. Thus cooling of the sensorimotor tortes was effective for neurons at both midbrain (A2-4, according to the atlas of Snider and Niemer, 29) and medullary (Pll-13) levels of the RF. There appeared to be no striking differences in the effects of cooling on neurons at different levels of the RF, but comparisons were difficult because of different durations of cooling. Altogether 18 neurons in 13 cats were studied completely and histologically verified as being in the RF; sis in the midbrain and 12 in the medullary RF. Most of the reticular cells studied showed some response alteration as a result of cooling, although about half of the midbrain and two-thirds of the medullary cells were more severely affected. In those cases in which the response alterations were not dramatic, it is possible that increasing the duration of cooling would have led to
FIG. 2. Effects of cooling the primary sensorimotor cortex on the response of a medullary reticular formation neuron to sciatic stimulation. Each dot represents a single spike and each horizontal row of dots is the response of the cell to one sciatic stimulus. (a) The response of the cell before cooling. After 2 min of cooling the response had begun to decrease (b) and after 5 min of cooling the cell stopped firing completely (c). Rewarming of the cortex (d) led to recovery of the control response.
1
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FORRI.1TION
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greater effects. However, in order to insure good response recovery and minimize cortical deterioration rewarming was begull shortly after changes in response were seen. Effects of Cortical Cooling on Specific Cowponrnts of the Reticular Response to Sciatic Stinrulution. The sciatic responses of the RF cells illustrated in Figs. 1 and 2 showed a generalized decrease or disintegration during cooling of the sensorimotor cortex. However in some neurons that had a definitive early and late response it was possible to demonstrate that cooling could have a differential effect on the two responses. Figure 3 shows two cells in the medullary RF with early and late responses. The unit on the left (Fig. 3a) responded to sciatic stimulation with an initial burst of activity followed by a weaker late response. Cooling of the sensorimotor cortex was terminated when the late response was ahnost completely abolished. Despite the change in the late response the early response showed little alteration in latency. duration, or amplitude. Rewarming of the cortex led to some recovery of the late response. Another example of the differential effect of cooling is shown in the cell on the right (Fig. 3b). This unit responded to sciatic stimulation with an initial peak of activity followed by an inhibitory period. Cooling led to a decrease of the inhibitory period. Measurement of its duration showed that it changed from about 13 msec during control to S msec at the time cooling was
FIG. 3. Effects of cooling the primary sensorimotor cortex on specific components of the reticular unit response to sciatic stimulation. PST displays from two medullary RF cells. Same description as in Fig. 1. Note that cooling in (a) caused almost total loss of the late response but little change in the early response. Rewarming led to partial recovery of the late response. In another neuron (b) cooling resulted in a decrease in the duration of the inhibitory period after the initial response. The early response showed little change in latency or duration, although there was some decrease in amplitude. Rewarming restored the original inhibitory period.
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ET
AL.
terminated, and with rewarming recovered to control levels of about 13 msec. This alteration in the later component of the sciatic response occurred despite little change in the latency and duration of the early response even after 6 min of cooling, although there was some decrease in amplitude. Efects of Co&-al Cooling on Reticular Cell Responses to Dijfevent Sonzatosensory Inputs and on Spontaneous Activity. The previous figures show the effects of cortical cooling on the response of a cell to stimulation of a single sensory input. In some reticular neurons which responded to stimulation of two different somatosensory inputs experiments were performed to determine whether cortical cooling could alter both responses. Figure 4 shows the results of such an experiment on a cell in the midbrain RF ; the actual responses of the neuron are displayed in a manner similar to that described in Fig. 2. The control records of the responses to single shock stimulation of the left forepaw and the right sciatic nerve are presented to the left of the figure; the neuron was located in the left midbrain RF at A4.5 and about 3 mm from the midline. After 5 min of bilateral cortical cooling both responses were almost completely abolished as shown to the right of the figure. Thus, responses of RF cells to widely divergent somatosensory inputs could be altered by cooling of the sensorimotor cortex. Stimulation of other sensory modalities was not attempted.
FIG. 4. Effects of cooling the primary sensorimotor cortex on cell responses to different somatosensory inputs. Dot displays of the responses of a midbrain RF cell to left forepaw and right sciatic nerve stimulation. Same description as Fig. 2. Control responses are shown to the left of the figure. Responses to both inputs were virtually abolished by cortical cooling.
RETICUL.4R
257
FORMATION
In addition to examining the results of cortical cooling on the responses to different somatosensory inputs, the effects on background activity were also studied. Figure 5 indicates that cortical cooling not only influences the response of the neuron to stimulation but can also alter its spontaneous activity. At the top of the figure (Fig. 5A) is a record of the spontaneous firing of the cell which was obtained in the same way as the other PST displays but without peripheral stimulation. Figure 5B represents the control response to sciatic nerve stimulation. After 5 min of cortical cooling (Fig. SC) spontaneous activity was significantly decreased. Immediately after obtaining the spontaneous record the sciatic response was observed of the to have almost completely disappeared (Fig. 5Dj. Rewarming sensorimotor cortex led to a return of the spontaneous activity and moderate recovery of the sciatic response (Fig. SE). Effects of Repeated Cooling of the Primary Sensoriwzotor Cortex. In order to maximize the possibility of recovery during rewarming of the cortex, cooling was terminated when a definite change in response was first observed. If cooling was not prolonged, it was possible to cool the
SPONLWEOUS
CoNlROL
SKIN.-
cca
COOL
REWARM
FIG. 5. Effects of cooling the primary sensorimotor cortex on spontaneous activity. PST displays from a medullary RF cell. Same description as Fig. 1. Control PSTs of the spontaneous activity of the cell (A) and the response to sciatic stimulation (B) are shown at the top of the figure. Note that cooling reduced both the background activity of the unit (C) and the response to sciatic stimulation CD). Rewarming led to moderate recovery of the control response (E).
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ET
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cortex twice and still obtain good recovery of the original response. Figure 6 is an illustration of such a retooling experiment. Figure 6A is a PST display of the control response; cortical cooling produced a significant decrease in the initial response (Fig. 6B) and rewarming led to recovery of the response (Fig, 6C). Retooling of the tortes (Fig. 6D) resulted in almost complete disappearence of the initial response. Cortical rewarming led to recovery of the sciatic response (Fig. 6E), although the amplitude of the response was less than that of the original response (Fig. 6A). This decrease in recovery was due presumably to some deterioration in the state of the cortex, as prolonged rewarming for periods of lo-30 min did not lead to complete return of the control response, Because of the problem of cortical deterioration from successive cooling periods, the results reported in the previous figures represent only the effects of the initial cooling. This presumed cortical deterioration also restricted the number of units that could be studied in any one animal. In many animals the experiment was terminated after the first cooling and rewarming periods to minimize the effects of cortical deterioration.
CoNlRoL
COOL
REWARM
COOL
FfwARM
FIG. 6. Effects of cooling and retooling the primary sensorimotor cortex. PST displays from a medullary RF neuron. Same description as Fig. 1. The control response of the cell to sciatic stimulation is shown at the top of the figure. If cooling was terminated as soon as a change in response was seen (B), it was possible to restore the response (C), then repeat the cooling procedure (U), and still obtain moderate recovery of the original response with rewarming (E).
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Discussion
The present results indicate that corticifugal influences from SSI (primary sensorimotor cortex in the cat) play an important part in regulating the responsiveness of RF neurons to entering sensory input. Adey and Lindsley (1) postulated that corticifugal influences passing through the subthalamus have a significant role in determining the excitability of the RF and maintaining the attentive behavior of the animal. Buser, Richard and Lescop (7) by cooling the cortex and Zilo\- (33) in cortical stimulation studies demonstrated that the primary sensorimotor cortex can influence the activity of midbrain RF cells. Also Ostrich and Polster (24) observed that cooling of SSI led to a decrease of midbrain evoked potentials. There has been some controversy recently as to the extent of involvement of the somatosensory cortex in control of somatic responses in the RF. Rabin (26) concluded that the responsiveness of the RF to contralateral somatic nerve stimulation, “depends directly on the functional state of second somatosensory cortex.” Lindsley, Ranf. and Barton (19) also found that cooling of SSII reduced sciatic EP in the RF but concluded that wider areas of the cortex were involved in controlling reticular responsiveness. The unit data reported here and the single neuron and EP work of others (7, 19, 24, 33) support the conclusion that both SSI and SSII are important in determining reticular excitability. When the degree of involvement of SSI and SSII were compared, Ostrich and Polster (24) observed that cooling of SSII led to a greater decrease of evoked potentials at the midbrain periaqueductal gray-RF junction than cooling of SSI, but cooling of both produced still more reduction. Thus, more extensive areas of the cortex are involved in maintaining the responsiveness of the RF to entering somatic input than originally proposed by Rabin (26). Not only is there a greater cortical projection than previously suggested by Rabin (26), but these corticifugal influences are distributed along the length of the RF. The EP data of Lindsley, Ranf. and Barton (19) showed that cooling of SSII reduced midbrain and medullary RF EP. The results reported here indicate that SSI is also capable of influencing both midbrain and medullary RF neurons. Although the EP experiments (19) suggested that SSII projected more powerfully to the midbrain than to the medullary RF, such differential effects from cooling of SSI were not obvious at the unit level. Most of the reticular neurons studied showed some change in response with bilateral cooling of the primary sensorimotor cortex; about half of the midbrain and two-thirds of the medullary cells were more severelv affected. However, midbrain and medullary neurons did not demonstrate any dramtic differences in response modification as a result of
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AL.
cortical cooling. Either SSI has no such differential RF projections or single cell, PST analysis is not a good means of manifesting them. Buser, Richard and Lescop (7) in an extensive study of midbrain RF neurons found that 75% of cells had altered somatic responses consequent to cortical cooling. In addition to the questions of the origin and distribution of corticifugal effects to the RF, it was also of interest to determine the nature of these influences. The work of Adey and Lindsley on subthalamic lesions (1) and the studies of Lindsley, Ranf, and Barton on cooling of SSII (19) indicate that there are both tonic facilitatory and phasic inhibitory corticifugal influences. The present results show that cortical cooling in most cases alters the overall response pattern of the neuron, is effective on different inputs to the same cell and decreases spontaneous activity. Thus this data supports the concept that there are tonic, facilitatory, corticifugal influences to the RF. In the present unit studies it was more difficult to demonstrate the existence of specific and phasic inhibitory corticifugal projections. In most cases bilateral cortical cooling produced a general reduction in the RF unit response. In some neurons with a definitive early and late response to sciatic stimulation it was possible to show that cortical cooling could exert differential effects on these components of the reticular response. As in previous work on the modification of the response of lateral geniculate cells (8)) the later components of the response appear to be more susceptible to alteration than earlier components. However, in the present cooling study there is not enough evidence to draw any conclusion. Possihly more examples of the specificity of corticifugal influences might have been found if unilateral or more restricted cortical cooling had been attempted. Also paired sensory stimulation which has been used previously to demonstrate specificity and the phasic inhibitory nature of corticifugal projections was not tried in the present study. Work by Chow, Lindsley and Gollender (8) using paired visual stimuli suggested that corticifugal effects might be responsible for modifying specific components of the lateral geniculate unit response. The paired sciatic shock studies of Adey and Lindsley (1) and Lindsley, Ranf, and Barton (19) showed the existence of phasic, inhibitory corticifugal influences to the RF. In the unit experiments reported here there was no obvious evidence of corticifugal inhibition, although it has been reported by others (9, 21, 33). The present experiments together with the unit and EP studies of others ( 1, 2, 7, 15-20, 24, 26, 33) indicate that influences from various neocortical (including SSI and SSII) and limbic areas are distributed to widespread regions of the RF and are important in determining the availability of the RF to entering sensory input. In general these influences are bilateral in origin and tonic and facilitatory in nature; in some cases they have been
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shown to alter specific components of the reticular response to afferent input. In addition there is evidence for phasic, inhibitory influences. These as suggested previously from the subthalamic corticifugal projections, work of Adey and Lindsley (1) and Adey, Walter, and Lindsley (3), together with lateral midbrain regions and the lateral hypothalamus studied by Sprague et al. (30. 31) and Marshall, Turner, and Teitelbaum (22) respectively, play an important role in determining the responsiveness of the animal to sensory stimuli and maintaining attentive, affective. and motor behavior. References 1. ADEY, W. R., and D. F. LINDSLEY. 1959. On the role of subthalamic areas in the maintenance of brain stem reticular excitability. Exp. Nczr~al. 1 : 407-426. 2. ADEY, W. R., J. P. SEGUNDO, and R. B. LIVINCSTOS. 1957. Corticifugal influences on intrinsic brain stem conduction in cat and monkey. J. Nerwaphysial. 20: l-16. 3. ADEY, W. R.. D. 0. WALTER, and D. F. LIXDSLEY. 1962. Subthalamic lesions. Effects on learned behavior and correlated hippocampal and subcortical slowwave activity. Arch. Newal. 6 : 194-207. 4. ANGEL, A. 1963. Evidence for cortical inhibition of transmission at the tha!amic sensory relay nucleus in the rat. J. Ph.ysio/. Lorzdorz 169 : 108P. 5. BORENSTEIN, P., and P. BUSER. 1960. Observations sur les projections du cortex dans la formation reticulee mesencephalique chez le chat. C. R. Sot. Biol. 154: 38-42. 6. BURES, J., 0. BURESOVA, T. WEISS, and E. FIFKOVA. 1963. Excitability changes in non-specific thalamic nuclei during cortical spreading depression in the rat. Electvarncephalagr. C&t. Ncztraph~~siol. 15 : 73-83. 7. BUSER, P., D. RICHARD, and J. LESCOP. 1969. Controle. par le cortex sensorimoteur, de la reactivite de cellules reticularies mesencephaliques chez le chat. Esp. l?rain Rcs. 9 : 83-95. 8. CHOW, K. L., D. F. LINDSLEY, and M. GOLLENDER. 1968. Modification of response patterns of lateral geniculate neurons after paired stimulation of contralateral and ipsilateral eyes. 1. Nctrraphysiol. 31 : 729-739. 9. DARIAN-SMITH. I., and T. YOKOTA. 1966. Corticofugal effects on different neuron types within the cat’s brain stem activated by tactile stimulation of the face. .I. Nruvophysiol. 29 : 185-206. 10. FRENCH, J. D., R. HERNANDEZ-PEON, and R. B. LIVINGSTON. 1955. Projections from cortex to cephalic brain stem (RF) in monkey. 1. Ncrrrophysiol. 16 : 7495. 11. GREEN, J. D. 1958. A simple microelectrode for recording from the central nervous system. Natwc Londolt 162 : 962. 12. IWAMA, K., and C. YAMAMOTO. 1961. Impulse transmission of thalamic somatosensory relay nuclei as modified by electrical stimulation of the cerebral cortex. Jap. J. Physial. 11: 169-182. 13. JASPER, H., C. AJMONE-MARSAN, and J. STOLL. 1952. Corticofugal projections to the brain stem. .4rch. hTcacrol. Psgchiat. 67 : 155-171. 14. KUYPERS, H. G. J. M. 1958. .4 n anatomical analysis of corticobulbar connecticns to the pons and the lower brain stem in the cat. J. .
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16. LINDSLEY, D. F., and W. R. ADEY. 1961. Availability of midbrain reticular formation. Exp. Ncurol. 4 : 358-376. 17. LINDSLEU, D. F., R. J. BARTON, and R. J. ATKINS. 1970. lesions on peripheral and central arousal thresholds in 109-119. 18. LINDSLEY, D. F., T. H. MORTON, and T. ZAROODNY. 1%7. stimulation on sensory-evoked potentials in the reticular Exp.
Ncurol.
peripheral
input to the
Effects of subthalamic cats. Exp. Ncztrol. 26: Effects of subthalamic formation and cortex.
17 : 439-150.
19. LINDSLEY, D. F., S. K. RANF, and R. J. BARTON. 1972. Corticifugal influences on reticular formation evoked activity in cats. Exp. Neural. 34: 511-521. 20. LINDSLEY, D. F., T. ZAROODNY, and T. H. MORTON. 1967. Effects of subthalamic lesions on sensory-evoked potentials in the reticular formation and sensorimotor cortex. Exp. Newel. 17 : 210-220. 21. MAGNI, F., and W. D. WILLIS. 1964. Cortical control of brain stem reticular neurons. ilrch. Ital. Biol. 102 : 418-133. 22. MARSHALL, J. F., B. H. TURNER, and P. THITELBAUM. 1971. Sensory neglect produced by lateral hypothalamic damage. Science 174 : 523-525. 23. OGDEN, T. E. 1960. Cortical control of thalamic somatosensory relay nuclei. Electroencephulogr. Clin. hrcurophysiol. 12 : 621-634. 24. OSTRICH, J. H., and D. F. POLSTER. 1968. Cortical influences on midbrain evoked activity in cat. Med. Coil. Virgitzia f&art. 4 : 195. 25. PEARCE, G. W. 1960. Some cortical projections to the midbrain reticular formation, pp. 131-137. In “Structure and Function of the Cerebral Cortex.” S. Tower and J. P. Schade [Eds.]. Elsevier, Amsterdam. 26. RABIN, A. G. 1%6. Selective cortical control of evoked activity in the reticular structures of the brain. Fed. Proc. (Translatioft Sz~ppl.) 25: Tl-T4. Translated from Fiziol. Zh. SSSR 51: 159, 1965. 27. Rossr, G. F., and A. BRODAL. 1956. Corticofugal fibers to the brain stem reticular formation. An experimental study in the cat. J. Aftat. London. 60: 42-62. 28. SHIMAZU, H., N. YANAGISA~VA, and B. GAROUTTE. 1965. Corticopyramidal influences on thalamic somato-sensory transmission in the cat. Jap. J. Physiol 15: 101-124. 29. SNIDER, R. S., and W. T. NIEMER. 1961. “A Stereotaxic Atlas of the Cat Brain.” Univ. of Chicago Press, Chicago. 30. SPRAGUE, J. M., W. \I:. CHA~~BERS, and E. STELLAR. 1961. Attentive, affective and adaptive behavior in the cat. Sensory deprivation of the forebrain by lesions in the brain stem results in striking behavioral abnormalities. Science 133: 165173. 31. SPRAGUE, J. M., M. LEVITT, Ii. ROBSON, C. N. LIU, E. N. STELLAR, and W. W. CHAMBERS. 1963. -4 neuroanatomical and behavioral analysis of the syndromes resulting from midbrain lemniscal and reticular lesions in the cat. Arch. Ital. Biol. 101: 225-295. 32. ZERNICKI, B., R. W. DOTY, and G. SANTIBANEZ-H. 1970. Isolated midbrain in cats. Electvoencephalogr. Clin. Neztrophysiol. 26 : 221-235. 33. ZILOV, V. G. 1970. Cortical and hypothalamic influences on single neurons of mesencephalic reticular formation. Neurosc. Trattslatiorzs 13 : 75-83. Translated from Fiziol. ZII. SSSR 55 : 1326-1333, 1969.
D.
36,
h-EUROLOGY
250-262
Corticifugal
Influences Formation
F. LINDSLEY,
S. K. RANF,
Depart?ncnt of Ph~uiology,
(1972)
on the Neurons
M. J. SHERWOOD,
University illageles,
Los
Activity of in Cats
Received
AND W.
of Southern California California 90033 March
Reticular
G.
Medical
PRESTON ’ School,
31, 1972
Corticifugal influences descending through the subthalamus have been shown to regulate the excitability of the reticular formation (RF) and maintain attentive behavior. Previous work demonstrated that cooling the secondary somatosensory cortex (SSII) modified RF sensory-evoked potentials. The present experiments indicate that the primary sensorimotor cortex (SSI) also projects to single neurons at those levels of the RF which have been shown to receive subthalamic influences. In acutely prepared, unanesthetized, immobilized cats, bilateral cooling of SSI caused a reduction in the response of midbrain and medullary RF neurons to sciatic stimulation. In some RF cells which responded to both sciatic and forepaw stimulation, cortical cooling decreased responses to both inputs. The generalized, tonic nature of these corticifugal influences was also illustrated by showing that cooling reduced spontaneous activity. Rewarming led to a recovery of reticular responsiveness and background activity. If care was taken to prevent cortical
deterioration, cooling could be repeated with subsequent response recovery back to control levels upon rewarming. In some reticular neurons which had both early and late responses it was possible to show that the cortex could also exert differential effects on these responses. Thus, corticifugal and SSII are important in determining the excitability of the RF to somatosensory input. Although these
and generalized specific
in nature. in some cases they
projections from both SSI of neurons along the length influences were usually tonic could be shown to exert more
effects. Introduction
The role of the cortex in the modulation of subcortical activity has been the subject of considerable anatomical and physiological work (5, 6, 10, 13-15, 21, 25, 27, 32). Numerous studies have shown that sensory cortical areas can exert facilitatory and inhibitory influences on the responses of subcortical, somatosensory nuclei (4, 9, 12, 23, 28). Recently these same cortical areas have been demonstrated to influence the development of sen1 The research was supported by Grants GB 31540 from the National Science Foundation and NS 07865 from the National Institutes of Health. The authors gratefully acknowledge the histological assistance of Mrs. Joan Higgins. 250 Copyright All rights
0 1972 hy Academic Press, of reproduction in any form
Inc. reserved.
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sory-evoked potentials (EP ) in the reticular formation (RF) and adjacent midbrain (19, 24, 26). Rabin (26) has even proposed that “the second somatosensory zone of the cortex controls responses of the so-called nonspecific structures of the brain.” However other work indicates that the primary somatosensory cortex (SSI) a 1so has important projections to the RF (7, 19, 21, 33), although the secondary somatosensory cortex (SSII ) may exert a more powerful influence (23). Because tonic influences descending through the subthalamus can also modify reticular excitability (l), it has been suggested that these influences include projections from SSI and SSII (19) and from limbic areas (2). The present experiments were designed to extend the work of Lindsley, Ranf, and Barton (19) to SSI and to study the effects of its projections on single neurons at various levels of the RF which have been shown to receive subthalamic influences. Methods
The results were obtained in acute experiments on 13 cats. All surgical maneuvers were performed under ether anesthesia. All surgical incisions and pressure points were infiltrated with procaine in peanut oil (Zyljectin, Abbott) after which the animals were immobilized with gallamine triethiodide (Flaxedil, Davis and Geck. about 0.13 mg/min).2 The experiments were conducted in a sound-shielded room (Industrial Acoustics Co.). No recordings were taken for at least 2 hr after the conclusion of the ether anesthesia. Stainless-steel microelectrodes made according to the technique of Green ( 11) were used to record the activity of single neurons. The microelectrode was oriented stereotaxically in a micrometer-drive apparatus (Kopf microdrive), and records were kept of the depth of each unit studied. The unit activity was led into a Grass high impedance probe and then into a Grass P511 preamplifier. The amplified signals were sent into a Schmitt trigger to produce standardized, square-wave pulses (7 v, 0.5 msec) which were displayed with the unit activity on an oscilloscope. Unit activity and trigger pulses were monitored throughout the experiment, and an exact correspondence between the two was maintained by adjusting the Schmitt trigger. Unit activity, Schmitt trigger pulses, and the stimulus output of the master stimulator (Tektronix 161 and 162 pulse and waveform generators) serving as a stimulus-triggering pulse, were also recorded on a Honeywell 7600 tape recorder for later processing. The Schmitt trigger pulses and the stimulus-triggering pulse were also led into a LAB-S computer (Digital Equipment Corp.) for on-line, poststimulus time histo2 Heart rate and pupillary size were monitored throughout the experiment; they gave no indication that the animals were suffering pain or discomfort. The animals periodically showed a constricted pupil which could be reversed by loud clapping or pinching the animal.
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gram (PST) analysis. The PST for the LAB-S (DECUS No. S-339) has a bin size of 1.5 msec. The output of the LAB-S was displayed on a Tektronix 503 oscilloscope and photographed with a Polaroid camera. Sciatic stimuli as used in these experiments (2-3 v, 1 msec, once per 3 set) do not evoke painful responses (16, 17). The body temperature was maintained at 38 C by using an infant heating blanket. When an RF neuron was found that gave a clearcut response to sciatic stimulation, the cell was allowed to stabilize for approximately half an hour. Such care was taken because a period of l-2 hr was required to study each unit completely. It was also important to minimize the possibility of losing the unit during the first cooling period, as subsequent toolings were not felt to be as effective, due perhaps to cortical deterioration. Cooling of the primary sensorimotor cortex (SSI) was performed bilaterally by placing physiological saline ice slush over the intact dura; the cortex was kept warm before cooling and rewarmed by application of physiological saline at body temperature. Although the main aim of this study was to determine the effects of cooling SSI on RF neurons, this area in the cat is difficult to separate from neighboring “motor” areas and perhaps is more appropriately called the primary sensorimotor cortex (7). Also because the cooling procedure undoubtedly influenced “motor” areas immediately adjacent to SSI, the cortical area involved in the present experiments should be properly considered to be the primary sensorimotor cortex. Since sciatic stimulation was continued for a long period of time, control PST were photographed only after some 15 min of stimulation. When it was clear that the response had stabilized, cooling of the cortex was initiated. The PST were monitored continuously during cooling and when major changes were ohserved. cooling was terminated, the cortex was rewarmed, and monitoring of PST was resumed. Recovery during rewarming was followed for 30 min and sometimes longer. To minimize cortical deterioration produced by repeated toolings and by the time-consuming experimental procedure outlined above, a number of animals were killed after completing cooling studies on one cell. This reduced the population of cells that could be studied, but led to a more reliable assessment of corticifugal effects. After each experiment direct current was passed through the microelectrode to mark the point of the last recorded unit ; the brain of the animal was perfused with a mixture of potassium ferricyanide in 10% formalin which produced a Prussian blue spot where the electrode point had been. All brains were cut in frozen coronal sections and stained with neutral red : they were examined and the position of the unit within the RF was determined either from the location of the marked spot or by calculating the distance back from the lesions along the electrode track using the micrometer-drive readings corrcsponding to the unit.
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Results
Eflects of Cortical Cooling on the Responses of Reticular Formation Neurons to Sciatic Stiwdation. Sciatic-evoked responses of cells in both the midbrain and medullary RF were reduced by bilateral cooling of the sensorimotor cortex. Figure 1 shows poststimulus time histogram (PST) displays of sciatic responses of two neurons in the midbrain RF. The response of the unit to the left (Fig. la) consisted of an initial inhibition of firing followed by a peak of activity. Cooling the cortex bilaterally led to a disintegration of the basic pattern of the response, although the effect on the activity peak was more marked. The response of the cell to the right (Fig. lb) consisted of a single peak of activity. Cooling led to a decrease of the response. For both units, rewarming of the sensorimotor cortex led to almost total recovery of the control response. Complete recovery of the response was difficult to obtain even after periods of 30 min perhaps due to alterations of the cortex. In this figure and all other PST displays the vertical calibration represents five spikes and the horizontal 25 msec; each PST is the sum of 2-l responses to sciatic stimulation at the rate of once per 3 sec. Figure 2 shows the actual response of a single unit in the medullary RF to repetitive sciatic stimulation at once per 3 sec. This figure was obtained b.
a.
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FIG. 1. Effects of bilateral cooling of the primary sensorimotor cortex (SSI) on the responses of two midbrain reticular formation neurons to sciatic stimulation. Each trace is a poststimulus time histogram (PST) representing the sum of 24 responses of the cell to sciatic stimulation at the rate of once per 3 sec. Note that for both cells (a and b) cooling of SSI led to disintegration of the responses and with rewarming the responses returned to control levels. In all PST displays the bin size is 1.5 msec. In all figures the arrows indicate onset of stimulus. All vertical calibrations represent five spikes and all horizontal are 25 msec.
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by using Z-axis modulation of the oscilloscope, photographing each sweep with a Polaroid camera, and moving the sweep down along the Y-axis of the scope in small steps. Each dot represents a single spike, and each horizontal row of dots is the response of the cell to one sciatic stimulus. Before cooling (Fig. 2a) the cell had a double-peaked response followed by a period of inhibition and then gradually returned to spontaneous firing levels. Cooling of the cortex for 2 min (Fig. 2b j caused a general break-up of the response, and by the end of 5 min (Fig. 2c ) the cell had completely stopped firing. After 15-min recovery (Fig. 2d), the cell’s response had returned to control levels. Thus cooling of the sensorimotor tortes was effective for neurons at both midbrain (A2-4, according to the atlas of Snider and Niemer, 29) and medullary (Pll-13) levels of the RF. There appeared to be no striking differences in the effects of cooling on neurons at different levels of the RF, but comparisons were difficult because of different durations of cooling. Altogether 18 neurons in 13 cats were studied completely and histologically verified as being in the RF; sis in the midbrain and 12 in the medullary RF. Most of the reticular cells studied showed some response alteration as a result of cooling, although about half of the midbrain and two-thirds of the medullary cells were more severely affected. In those cases in which the response alterations were not dramatic, it is possible that increasing the duration of cooling would have led to
FIG. 2. Effects of cooling the primary sensorimotor cortex on the response of a medullary reticular formation neuron to sciatic stimulation. Each dot represents a single spike and each horizontal row of dots is the response of the cell to one sciatic stimulus. (a) The response of the cell before cooling. After 2 min of cooling the response had begun to decrease (b) and after 5 min of cooling the cell stopped firing completely (c). Rewarming of the cortex (d) led to recovery of the control response.
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greater effects. However, in order to insure good response recovery and minimize cortical deterioration rewarming was begull shortly after changes in response were seen. Effects of Cortical Cooling on Specific Cowponrnts of the Reticular Response to Sciatic Stinrulution. The sciatic responses of the RF cells illustrated in Figs. 1 and 2 showed a generalized decrease or disintegration during cooling of the sensorimotor cortex. However in some neurons that had a definitive early and late response it was possible to demonstrate that cooling could have a differential effect on the two responses. Figure 3 shows two cells in the medullary RF with early and late responses. The unit on the left (Fig. 3a) responded to sciatic stimulation with an initial burst of activity followed by a weaker late response. Cooling of the sensorimotor cortex was terminated when the late response was ahnost completely abolished. Despite the change in the late response the early response showed little alteration in latency. duration, or amplitude. Rewarming of the cortex led to some recovery of the late response. Another example of the differential effect of cooling is shown in the cell on the right (Fig. 3b). This unit responded to sciatic stimulation with an initial peak of activity followed by an inhibitory period. Cooling led to a decrease of the inhibitory period. Measurement of its duration showed that it changed from about 13 msec during control to S msec at the time cooling was
FIG. 3. Effects of cooling the primary sensorimotor cortex on specific components of the reticular unit response to sciatic stimulation. PST displays from two medullary RF cells. Same description as in Fig. 1. Note that cooling in (a) caused almost total loss of the late response but little change in the early response. Rewarming led to partial recovery of the late response. In another neuron (b) cooling resulted in a decrease in the duration of the inhibitory period after the initial response. The early response showed little change in latency or duration, although there was some decrease in amplitude. Rewarming restored the original inhibitory period.
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terminated, and with rewarming recovered to control levels of about 13 msec. This alteration in the later component of the sciatic response occurred despite little change in the latency and duration of the early response even after 6 min of cooling, although there was some decrease in amplitude. Efects of Co&-al Cooling on Reticular Cell Responses to Dijfevent Sonzatosensory Inputs and on Spontaneous Activity. The previous figures show the effects of cortical cooling on the response of a cell to stimulation of a single sensory input. In some reticular neurons which responded to stimulation of two different somatosensory inputs experiments were performed to determine whether cortical cooling could alter both responses. Figure 4 shows the results of such an experiment on a cell in the midbrain RF ; the actual responses of the neuron are displayed in a manner similar to that described in Fig. 2. The control records of the responses to single shock stimulation of the left forepaw and the right sciatic nerve are presented to the left of the figure; the neuron was located in the left midbrain RF at A4.5 and about 3 mm from the midline. After 5 min of bilateral cortical cooling both responses were almost completely abolished as shown to the right of the figure. Thus, responses of RF cells to widely divergent somatosensory inputs could be altered by cooling of the sensorimotor cortex. Stimulation of other sensory modalities was not attempted.
FIG. 4. Effects of cooling the primary sensorimotor cortex on cell responses to different somatosensory inputs. Dot displays of the responses of a midbrain RF cell to left forepaw and right sciatic nerve stimulation. Same description as Fig. 2. Control responses are shown to the left of the figure. Responses to both inputs were virtually abolished by cortical cooling.
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In addition to examining the results of cortical cooling on the responses to different somatosensory inputs, the effects on background activity were also studied. Figure 5 indicates that cortical cooling not only influences the response of the neuron to stimulation but can also alter its spontaneous activity. At the top of the figure (Fig. 5A) is a record of the spontaneous firing of the cell which was obtained in the same way as the other PST displays but without peripheral stimulation. Figure 5B represents the control response to sciatic nerve stimulation. After 5 min of cortical cooling (Fig. SC) spontaneous activity was significantly decreased. Immediately after obtaining the spontaneous record the sciatic response was observed of the to have almost completely disappeared (Fig. 5Dj. Rewarming sensorimotor cortex led to a return of the spontaneous activity and moderate recovery of the sciatic response (Fig. SE). Effects of Repeated Cooling of the Primary Sensoriwzotor Cortex. In order to maximize the possibility of recovery during rewarming of the cortex, cooling was terminated when a definite change in response was first observed. If cooling was not prolonged, it was possible to cool the
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SKIN.-
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FIG. 5. Effects of cooling the primary sensorimotor cortex on spontaneous activity. PST displays from a medullary RF cell. Same description as Fig. 1. Control PSTs of the spontaneous activity of the cell (A) and the response to sciatic stimulation (B) are shown at the top of the figure. Note that cooling reduced both the background activity of the unit (C) and the response to sciatic stimulation CD). Rewarming led to moderate recovery of the control response (E).
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cortex twice and still obtain good recovery of the original response. Figure 6 is an illustration of such a retooling experiment. Figure 6A is a PST display of the control response; cortical cooling produced a significant decrease in the initial response (Fig. 6B) and rewarming led to recovery of the response (Fig, 6C). Retooling of the tortes (Fig. 6D) resulted in almost complete disappearence of the initial response. Cortical rewarming led to recovery of the sciatic response (Fig. 6E), although the amplitude of the response was less than that of the original response (Fig. 6A). This decrease in recovery was due presumably to some deterioration in the state of the cortex, as prolonged rewarming for periods of lo-30 min did not lead to complete return of the control response, Because of the problem of cortical deterioration from successive cooling periods, the results reported in the previous figures represent only the effects of the initial cooling. This presumed cortical deterioration also restricted the number of units that could be studied in any one animal. In many animals the experiment was terminated after the first cooling and rewarming periods to minimize the effects of cortical deterioration.
CoNlRoL
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FfwARM
FIG. 6. Effects of cooling and retooling the primary sensorimotor cortex. PST displays from a medullary RF neuron. Same description as Fig. 1. The control response of the cell to sciatic stimulation is shown at the top of the figure. If cooling was terminated as soon as a change in response was seen (B), it was possible to restore the response (C), then repeat the cooling procedure (U), and still obtain moderate recovery of the original response with rewarming (E).
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Discussion
The present results indicate that corticifugal influences from SSI (primary sensorimotor cortex in the cat) play an important part in regulating the responsiveness of RF neurons to entering sensory input. Adey and Lindsley (1) postulated that corticifugal influences passing through the subthalamus have a significant role in determining the excitability of the RF and maintaining the attentive behavior of the animal. Buser, Richard and Lescop (7) by cooling the cortex and Zilo\- (33) in cortical stimulation studies demonstrated that the primary sensorimotor cortex can influence the activity of midbrain RF cells. Also Ostrich and Polster (24) observed that cooling of SSI led to a decrease of midbrain evoked potentials. There has been some controversy recently as to the extent of involvement of the somatosensory cortex in control of somatic responses in the RF. Rabin (26) concluded that the responsiveness of the RF to contralateral somatic nerve stimulation, “depends directly on the functional state of second somatosensory cortex.” Lindsley, Ranf. and Barton (19) also found that cooling of SSII reduced sciatic EP in the RF but concluded that wider areas of the cortex were involved in controlling reticular responsiveness. The unit data reported here and the single neuron and EP work of others (7, 19, 24, 33) support the conclusion that both SSI and SSII are important in determining reticular excitability. When the degree of involvement of SSI and SSII were compared, Ostrich and Polster (24) observed that cooling of SSII led to a greater decrease of evoked potentials at the midbrain periaqueductal gray-RF junction than cooling of SSI, but cooling of both produced still more reduction. Thus, more extensive areas of the cortex are involved in maintaining the responsiveness of the RF to entering somatic input than originally proposed by Rabin (26). Not only is there a greater cortical projection than previously suggested by Rabin (26), but these corticifugal influences are distributed along the length of the RF. The EP data of Lindsley, Ranf. and Barton (19) showed that cooling of SSII reduced midbrain and medullary RF EP. The results reported here indicate that SSI is also capable of influencing both midbrain and medullary RF neurons. Although the EP experiments (19) suggested that SSII projected more powerfully to the midbrain than to the medullary RF, such differential effects from cooling of SSI were not obvious at the unit level. Most of the reticular neurons studied showed some change in response with bilateral cooling of the primary sensorimotor cortex; about half of the midbrain and two-thirds of the medullary cells were more severelv affected. However, midbrain and medullary neurons did not demonstrate any dramtic differences in response modification as a result of
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cortical cooling. Either SSI has no such differential RF projections or single cell, PST analysis is not a good means of manifesting them. Buser, Richard and Lescop (7) in an extensive study of midbrain RF neurons found that 75% of cells had altered somatic responses consequent to cortical cooling. In addition to the questions of the origin and distribution of corticifugal effects to the RF, it was also of interest to determine the nature of these influences. The work of Adey and Lindsley on subthalamic lesions (1) and the studies of Lindsley, Ranf, and Barton on cooling of SSII (19) indicate that there are both tonic facilitatory and phasic inhibitory corticifugal influences. The present results show that cortical cooling in most cases alters the overall response pattern of the neuron, is effective on different inputs to the same cell and decreases spontaneous activity. Thus this data supports the concept that there are tonic, facilitatory, corticifugal influences to the RF. In the present unit studies it was more difficult to demonstrate the existence of specific and phasic inhibitory corticifugal projections. In most cases bilateral cortical cooling produced a general reduction in the RF unit response. In some neurons with a definitive early and late response to sciatic stimulation it was possible to show that cortical cooling could exert differential effects on these components of the reticular response. As in previous work on the modification of the response of lateral geniculate cells (8)) the later components of the response appear to be more susceptible to alteration than earlier components. However, in the present cooling study there is not enough evidence to draw any conclusion. Possihly more examples of the specificity of corticifugal influences might have been found if unilateral or more restricted cortical cooling had been attempted. Also paired sensory stimulation which has been used previously to demonstrate specificity and the phasic inhibitory nature of corticifugal projections was not tried in the present study. Work by Chow, Lindsley and Gollender (8) using paired visual stimuli suggested that corticifugal effects might be responsible for modifying specific components of the lateral geniculate unit response. The paired sciatic shock studies of Adey and Lindsley (1) and Lindsley, Ranf, and Barton (19) showed the existence of phasic, inhibitory corticifugal influences to the RF. In the unit experiments reported here there was no obvious evidence of corticifugal inhibition, although it has been reported by others (9, 21, 33). The present experiments together with the unit and EP studies of others ( 1, 2, 7, 15-20, 24, 26, 33) indicate that influences from various neocortical (including SSI and SSII) and limbic areas are distributed to widespread regions of the RF and are important in determining the availability of the RF to entering sensory input. In general these influences are bilateral in origin and tonic and facilitatory in nature; in some cases they have been
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shown to alter specific components of the reticular response to afferent input. In addition there is evidence for phasic, inhibitory influences. These as suggested previously from the subthalamic corticifugal projections, work of Adey and Lindsley (1) and Adey, Walter, and Lindsley (3), together with lateral midbrain regions and the lateral hypothalamus studied by Sprague et al. (30. 31) and Marshall, Turner, and Teitelbaum (22) respectively, play an important role in determining the responsiveness of the animal to sensory stimuli and maintaining attentive, affective. and motor behavior. References 1. ADEY, W. R., and D. F. LINDSLEY. 1959. On the role of subthalamic areas in the maintenance of brain stem reticular excitability. Exp. Nczr~al. 1 : 407-426. 2. ADEY, W. R., J. P. SEGUNDO, and R. B. LIVINCSTOS. 1957. Corticifugal influences on intrinsic brain stem conduction in cat and monkey. J. Nerwaphysial. 20: l-16. 3. ADEY, W. R.. D. 0. WALTER, and D. F. LIXDSLEY. 1962. Subthalamic lesions. Effects on learned behavior and correlated hippocampal and subcortical slowwave activity. Arch. Newal. 6 : 194-207. 4. ANGEL, A. 1963. Evidence for cortical inhibition of transmission at the tha!amic sensory relay nucleus in the rat. J. Ph.ysio/. Lorzdorz 169 : 108P. 5. BORENSTEIN, P., and P. BUSER. 1960. Observations sur les projections du cortex dans la formation reticulee mesencephalique chez le chat. C. R. Sot. Biol. 154: 38-42. 6. BURES, J., 0. BURESOVA, T. WEISS, and E. FIFKOVA. 1963. Excitability changes in non-specific thalamic nuclei during cortical spreading depression in the rat. Electvarncephalagr. C&t. Ncztraph~~siol. 15 : 73-83. 7. BUSER, P., D. RICHARD, and J. LESCOP. 1969. Controle. par le cortex sensorimoteur, de la reactivite de cellules reticularies mesencephaliques chez le chat. Esp. l?rain Rcs. 9 : 83-95. 8. CHOW, K. L., D. F. LINDSLEY, and M. GOLLENDER. 1968. Modification of response patterns of lateral geniculate neurons after paired stimulation of contralateral and ipsilateral eyes. 1. Nctrraphysiol. 31 : 729-739. 9. DARIAN-SMITH. I., and T. YOKOTA. 1966. Corticofugal effects on different neuron types within the cat’s brain stem activated by tactile stimulation of the face. .I. Nruvophysiol. 29 : 185-206. 10. FRENCH, J. D., R. HERNANDEZ-PEON, and R. B. LIVINGSTON. 1955. Projections from cortex to cephalic brain stem (RF) in monkey. 1. Ncrrrophysiol. 16 : 7495. 11. GREEN, J. D. 1958. A simple microelectrode for recording from the central nervous system. Natwc Londolt 162 : 962. 12. IWAMA, K., and C. YAMAMOTO. 1961. Impulse transmission of thalamic somatosensory relay nuclei as modified by electrical stimulation of the cerebral cortex. Jap. J. Physial. 11: 169-182. 13. JASPER, H., C. AJMONE-MARSAN, and J. STOLL. 1952. Corticofugal projections to the brain stem. .4rch. hTcacrol. Psgchiat. 67 : 155-171. 14. KUYPERS, H. G. J. M. 1958. .4 n anatomical analysis of corticobulbar connecticns to the pons and the lower brain stem in the cat. J. .
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16. LINDSLEY, D. F., and W. R. ADEY. 1961. Availability of midbrain reticular formation. Exp. Ncurol. 4 : 358-376. 17. LINDSLEU, D. F., R. J. BARTON, and R. J. ATKINS. 1970. lesions on peripheral and central arousal thresholds in 109-119. 18. LINDSLEY, D. F., T. H. MORTON, and T. ZAROODNY. 1%7. stimulation on sensory-evoked potentials in the reticular Exp.
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19. LINDSLEY, D. F., S. K. RANF, and R. J. BARTON. 1972. Corticifugal influences on reticular formation evoked activity in cats. Exp. Neural. 34: 511-521. 20. LINDSLEY, D. F., T. ZAROODNY, and T. H. MORTON. 1967. Effects of subthalamic lesions on sensory-evoked potentials in the reticular formation and sensorimotor cortex. Exp. Newel. 17 : 210-220. 21. MAGNI, F., and W. D. WILLIS. 1964. Cortical control of brain stem reticular neurons. ilrch. Ital. Biol. 102 : 418-133. 22. MARSHALL, J. F., B. H. TURNER, and P. THITELBAUM. 1971. Sensory neglect produced by lateral hypothalamic damage. Science 174 : 523-525. 23. OGDEN, T. E. 1960. Cortical control of thalamic somatosensory relay nuclei. Electroencephulogr. Clin. hrcurophysiol. 12 : 621-634. 24. OSTRICH, J. H., and D. F. POLSTER. 1968. Cortical influences on midbrain evoked activity in cat. Med. Coil. Virgitzia f&art. 4 : 195. 25. PEARCE, G. W. 1960. Some cortical projections to the midbrain reticular formation, pp. 131-137. In “Structure and Function of the Cerebral Cortex.” S. Tower and J. P. Schade [Eds.]. Elsevier, Amsterdam. 26. RABIN, A. G. 1%6. Selective cortical control of evoked activity in the reticular structures of the brain. Fed. Proc. (Translatioft Sz~ppl.) 25: Tl-T4. Translated from Fiziol. Zh. SSSR 51: 159, 1965. 27. Rossr, G. F., and A. BRODAL. 1956. Corticofugal fibers to the brain stem reticular formation. An experimental study in the cat. J. Aftat. London. 60: 42-62. 28. SHIMAZU, H., N. YANAGISA~VA, and B. GAROUTTE. 1965. Corticopyramidal influences on thalamic somato-sensory transmission in the cat. Jap. J. Physiol 15: 101-124. 29. SNIDER, R. S., and W. T. NIEMER. 1961. “A Stereotaxic Atlas of the Cat Brain.” Univ. of Chicago Press, Chicago. 30. SPRAGUE, J. M., W. \I:. CHA~~BERS, and E. STELLAR. 1961. Attentive, affective and adaptive behavior in the cat. Sensory deprivation of the forebrain by lesions in the brain stem results in striking behavioral abnormalities. Science 133: 165173. 31. SPRAGUE, J. M., M. LEVITT, Ii. ROBSON, C. N. LIU, E. N. STELLAR, and W. W. CHAMBERS. 1963. -4 neuroanatomical and behavioral analysis of the syndromes resulting from midbrain lemniscal and reticular lesions in the cat. Arch. Ital. Biol. 101: 225-295. 32. ZERNICKI, B., R. W. DOTY, and G. SANTIBANEZ-H. 1970. Isolated midbrain in cats. Electvoencephalogr. Clin. Neztrophysiol. 26 : 221-235. 33. ZILOV, V. G. 1970. Cortical and hypothalamic influences on single neurons of mesencephalic reticular formation. Neurosc. Trattslatiorzs 13 : 75-83. Translated from Fiziol. ZII. SSSR 55 : 1326-1333, 1969.