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Hippocampal lesions impair prolonged titrated avoidance by rhesus monkeys
EXPERIMENTAL
NEUROLOGY
63, 28-34 (1979)
Hippocampal Lesions Impair Prolonged Avoidance by Rhesus Monkey9
Titrated
WILLIAM J. JACKSON AND QUENTIN R. REGESTEIN Department
of Physiology, Medical Division of Psychiatry, Brigham Hospital,
College of Georgia, Augusta, Georgia Department of Medicine, Peter Bent Boston, Massachusetts 02115
Received
May
30902
and
25, 1978
Performance on a 48-h, titrated avoidancetask was compared among groups of monkeys subtotal pocampal stopping, posterior,
with various hippocampal lesions. Unlike controls and monkeys with hippocampal lesions, three of four monkeys with large bilateral hiplesions suddenly stopped performing before the task ended. Prior to however, each animal performed comparably to animals with anterior, or no hippocampal lesions.
INTRODUCTION The limbic system is generally believed to subserve functions of emotion and emotional expression. Therefore, limbic ablations might modify the affective component of pain, and evidence that hippocampal ablations have altered either the perception of pain in human patients or avoidance thresholds in monkeys has been published (2, 3). The purpose of this study was to explore the effect of various hippocampal lesions on the performance of a titrated aversive schedule by monkeys. Performance on the titrated aversive schedule (11) has proven useful in animal research related to pain, because it shows sensitivity to many of the analgesic compounds known to be clinically useful for relieving pain. Although a large overlap exists between those stumuli which elicit pain in humans and those which serve as negative reinforcers for animals, analgesic drugs have generally failed to alter the threshold level of noxious stimulation above which avoidance behavior takes place. However, performance on the discrete-trials modification of the titrated aver1 Supported by U.S. Public Health Service grant MH16635-02 and by funds from the 6571st Aeromedical Research Laboratory at Holloman, Air Force Base, New Mexico. 28 0014-4886/79/010028-07$02.00/O Copyright All rights
0 1979 by Academic Press, of reproduction in any form
Inc. reserved.
IMPAIRMENT
AFTER HIPPOCAMPAL
DAMAGE
29
sive schedule is an exception to this rule, because animals administered analgesic agents, such as morphine and codeine, self-titrate at higher than normal levels of noxious stimulation (4). This result suggests that the titrated aversive schedule is a particularly useful model for assessing changes in pain sensation by animals. The present study was designed to provide additonal information about the possibility that performance of the titrated avoidance task might be mediated more by one region of the hippocampus than by another. This seemed possible because in monkeys of various species, anterior hippocampal lesions cause degeneration in different diencephalic and hypothalamic regions than do posterior hippocampal lesions, and lesions of the entire hippocampus result in yet a different degeneration pattern (7, 8). METHODS Subjects. Twenty adolescent rhesus monkeys of either sex, from 2.5 to 4.6 kg in weight (mean, 3.6 kg), and an estimated age of 31 to 42 months (mean, 36 months), as judged by dentition, were used in the study. The monkeys were assigned in a balanced manner to one of five surgical groups which were defined according to the following criteria: (A) bilateral lesions confined to the inferior temporal gyrus (which was also necessarily damaged in all animals with hippocampal lesions), (B) bilateral total hippocampal ablation, (C) bilateral lesions confined to the posterior hippocampus, (D) bilateral lesions confined to the anterior or uncal hippocampus, and (E) a group of unoperated monkeys. Surgery. Animals were deprived of water 24 h prior to surgery, anesthetized with Sernylan 14 mg intramuscularly and intravenous pentobarbital, and given 0.2 ml Koagamin intravenously for hemostasis. Under aseptic conditions, the inferior temporal gyrus was exposed through a zygomatic approach, the brain was gradually retracted, and the inferior pyriform cortex was visualized. An opening was then aspirated through the pyriform cortex, exposing the hippocampus. The designated hippocampal lesion was completed under direct visual guidance. Hemostasis was accomplished, and the head was repaired in layers. Bilateral lesions were done in a one-stage, 6-h procedure.2 Prophylactic ampicillin was administered postoperatively, and the animals were returned to their home cages for at least 1 month of recovery. Apparatus and Procedure. During the 48-h session the animals were placed in a primate restraint chair within a sound-attenuated chamber supplied with 20-dB constant white noise. The chambers were lighted 2 We thank Dr. Karl H. Pribram for demonstrating
the surgical technique.
30
JACKSON
AND
REGESTEIN
from 7:30 AM to 6:00 PM in a light-dark schedule similar to that of the home cage area. The monkeys had free access to water and were fed as usual. Electrical shocks were delivered through 5-kfi resistance to two brass shoe-type electrodes (12) which firmly contained the monkey’s feet. At the beginning of the session the monkey’s feet were cleaned with acetone and rubbed with conductive jelly to ensure low electrical resistance between feet and electrodes. Resistance was monitored and remained constant at 5kfi throughout the 48-h session. After preliminary training had induced stable performance, the monkeys were required to perform according to the requirements of a discrete-trials version of the titrating aversive schedule for 48 consecutive hours. Each monkey received a shock every 7 s and each succeeding shock increased 1 mA in intensity unless the animal pressed a lever in front of him, in which case the succeeding shock became 1 mA less intense. Each monkey was thus able to select a level of shock. Only the first lever press within a given 7-s intershock interval was effective in reducing the succeeding shock in comparison with the original schedule (1 l), in which all lever presses reduced the level of the succeeding shock by a fixed amount. Hippocampal lesions are known to elevate lever-press rates in rats, and this modification was used to prevent one group from showing spuriously low thresholds as a result of hyperactivity, rather than difference in pain reactivity. Maximum shock intensity was 60 mA and the session always began at the lowest shock intensity, which was zero. These parameters evoked stable performance over long periods of time, as indicated by our own pilot work and data from standard titrating aversive schedules. RESULTS Anatomical Results. Representative lesions are illustrated by Fig. 1. The group with “total” hippocampal ablation showed lesions which encompassed approximately 90% of the hippocampus bilaterally. The group with an anterior hippocampectomy showed lesions restricted to the uncus and the most anterior knob of the hippocampal formation. The group with a posterior hippocampectomy showed lesions confined to more posterior portions. There did appear’to be some overlap between the anterior and posterior hippocampal lesions but there was no evidence of infection or unintentional trauma. Behavioral Results. The major finding was that three of the four monkeys with “total hippocampal damage” were unable to continue for the entire 48-h session, whereas all monkeys in the remaining groups were able to lever-press throughout the entire session. The first monkey with a total
IMPAIRMENT
Normal
LIO
AFTER HIPPOCAMPAL L12
Ll4
31
DAMAGE Ll6
FIG. 1. Illustration of representative lesions from each of the surgical groups. The cuts were made sagittally at 10, 12, 14, and 16 mm from the midline. The darkened areas represent tissue removed during surgery.
hippocampectomy and the third after without detectable clasped the lever
stopped lever-pressing after 11 h, the second after 36 h, 42 h. The onsets of these breakdowns were sudden and warning. At the onset of the breakdown the monkeys lightly as if “frozen” onto the mechanism, but no
32
JACKSON
AND REGESTEIN
longer continued to depress it. As the shock level began to intensify, the monkeys showed signs of great emotional distress by squealing and facial expression, but were incapable of organizing appropriate level pressing. Because the shock quickly reached inhumane levels following the breakdown, the affected monkeys were disconnected from the shock generators and given rest. However, even several hours rest failed to restore these monkeys’ ability to perform the titrating task for more than a few minutes at a time. Figure 2 illustrates the decline in mean rate of lever pressing by the group with the larger hippocampal lesions. The source of the group differences seen in Fig. 2 is the failure of three animals with total hippocampectomy to continue performing; zeros were entered at the subsequent data points for each particular animal after it stopped lever pressing. However, while these three monkeys were still able to lever press, they established a rate of lever pressing and selected shock levels comparable to the other monkeys. This was verified by an analysis of variance for unequal numbers. For this computation, all the data collected prior to the cessation of lever pressing were included but none for an animal after it RHESUS
100’
, l-4
,
, S-12
,
, 17-20
,
( 25-28 HOURS
,
, 33-36
,
, 41-44
,
FIG. 2. Mean number of lever presses for each group during the 48-h session. The reduction in the group with total hippocampectomy is a result of a performance breakdown by three of the four monkeys in that group; the first monkey stopped pressing after 11 h, the second after 36 h, and the third after 42 h.
IMPAIRMENT
AFTER
HIPPOCAMPAL
DAMAGE
33
stopped responding. The results of this computation showed no statistically significant differences between any of the surgical groups (F = 0.836, & = 4/15, NS). The finding that only one of four animals in the group with total hippocampectomy was able to complete the 48-h session, when the animals in all the remaining groups were able to do so, would not seem to require additional statistical description. DISCUSSION The results of these experiments indicate that various hippocampal lesions do not alter pain threshold in monkeys as measured by the prolonged titrated avoidance task. Instead, the monkeys with larger hippocampal lesions lacked sufficient endurance to perform the task for a prolonged period. The change in this group was not due to an inability to learn the task or in the level of shock selected, but was linked to the prolonged period during which the animals were required to perform. Similar experiments using monkeys with total hippocampectomy have not been reported, and therefore interpretation of the results remains speculative. That they were able to work several hours before the breakdown of performance suggests that other brain structures are also involved in maintaining prolonged titrated avoidance performance. Presumably the monkeys with total hippocampal damage were more dependent on cortical mediation of avoidance responses (9). When the monkeys were deprived of those hippocampal efferents that project widely to cortex (6), attention deficits may have been sustained that affected avoidance task performance and the effect of such deficits presumably became manifest after fatigue diminished cortical functioning (1, 5). Likewise, the “freezing” of our subjects within the prolonged task could be viewed as a blockage of voluntary motor capability. It is well known that hippocampal electroencephalogram synchrony appears just prior to voluntary movements in the rat (10) and hippocampal ablation prolonged immobility responses in rats and rabbits (13). Although such immobility may be a component of the breakdown in endurance found in this study, the behavior required for prolonged titrated avoidance is probably more complex than mobility alone. At present the limits of endurance for normal monkeys on a titrated avoidance task with these parameters are unknown. However, as a pilot project, four normal monkeys were tested on this task for 96 consecutive hours with no observable deterioration of performance. Additional work will be required to determine whether this breakdown of prolonged performance is specific to the titrating avoidance task, or whether there are other tasks which monkeys with such hippocampal damage would not be able to perform for a prolonged period of time.
34
JACKSON
AND
REGESTEIN
The finding that a lesion of some critical size is necessary to elicit a breakdown in performance indicates that the hippocampal cells which support prolonged titrating avoidance behavior are spread through the length of the hippocampus, rather than concentrated within a specified anterior or posterior location. The present data do not contribute to identifying the particular hippocampal cells which support the sort of “endurance” measured in this study. However, several studies showed that in monkeys lesions of the anterior hippocampus resulted in degeneration of the lateral septal nucleus and nucleus acumbens, whereas lesions of the posterior hippocampus resulted in degeneration of the medial portions of the septal nuclei. In squirrel monkeys all regions of the monkey hippocampus apparently project to the diagonal band, olfactory tubercle, anteroventral nucleus, and mammillary bodies (7). It remains unknown whether these diffusely projecting cells specifically affect endurance of task performance. REFERENCES J. C., AND L. L. MITNICK. 1959. Electroencephalogram and sleep deprivation. J. Appl. Physiol., 14: 247-250. GOL, A., AND G. M. FAIBISH. 1%7. Effects of human hippocampal ablation. J. Neurosurg. 26: 390-398. GOL, A., P. KELLAWAY, M. SHAPIRO, AND C. M. HURST. 1963. Studies of hippocampectomy in the monkey, baboon, and cat. Neurology, 13: 1031-1041. HALPERN, L. M., AND F. P. ALLEVA. 1964. Drug-induced changes in threshold for aversive stimulation in chronically implanted monkeys. Fed. Proc. 23: 284. JOHNSON, L. C., E. S. SELEY, AND W. DEMENT. 1965. Electroencephalographic and antonomic activity during and after sleep deprivation. Psychosom. Med. 27: 415-423. ROSENE, D. L., AND G. W. VAN HORSEN. 1977. Hippocampalefferents reach widespread area of cerebral cortex and amygdala in the rhesus monkey. Science 198: 315-317. SIEGEL, A., S. OHGAMI, AND H. EDINGER. 1975. Projections of the hippocampus to the septal area in the squirrel monkey. Brain Res. 99: 247-260. SIMPSON, D. A. 1952. The efferent fibers of the hippocampus in the monkey. J. Neurol. Neurosurg. Psychiat. 15: 79-92. THOMPSON, R. 1963. Thakmic structures critical for retention of an avoidance conditioned response. .I. Comp. Physiol. Psychol. 56: 261-267. VANDERWOLF, C. H. 1%9. Hippocampal electrical activity and voluntary movement in the rat. Electroenceph. Clin. Neurophysiol. 26: 407-418. WEISS, B., AND V. LATIES. 1%3. Characteristics of aversive thresholds measured by a titration schedule. J. Exp. Anal. Behav. 6: 563-572. WEISS, B., AND V. LATIES. 1962. A foot electrode for monkeys. J. Exp. Anal. Behav. 5: 535-536. WOODRUFF, M. L., D. C. HUTTON, AND M. E. MEYER. 1975. Hippocampal ablation prolongs immobility response in rabbits. J. Comp. Physiol. Psychol. 88: 329-334.
1. ARMINGTON,
2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13.
NEUROLOGY
63, 28-34 (1979)
Hippocampal Lesions Impair Prolonged Avoidance by Rhesus Monkey9
Titrated
WILLIAM J. JACKSON AND QUENTIN R. REGESTEIN Department
of Physiology, Medical Division of Psychiatry, Brigham Hospital,
College of Georgia, Augusta, Georgia Department of Medicine, Peter Bent Boston, Massachusetts 02115
Received
May
30902
and
25, 1978
Performance on a 48-h, titrated avoidancetask was compared among groups of monkeys subtotal pocampal stopping, posterior,
with various hippocampal lesions. Unlike controls and monkeys with hippocampal lesions, three of four monkeys with large bilateral hiplesions suddenly stopped performing before the task ended. Prior to however, each animal performed comparably to animals with anterior, or no hippocampal lesions.
INTRODUCTION The limbic system is generally believed to subserve functions of emotion and emotional expression. Therefore, limbic ablations might modify the affective component of pain, and evidence that hippocampal ablations have altered either the perception of pain in human patients or avoidance thresholds in monkeys has been published (2, 3). The purpose of this study was to explore the effect of various hippocampal lesions on the performance of a titrated aversive schedule by monkeys. Performance on the titrated aversive schedule (11) has proven useful in animal research related to pain, because it shows sensitivity to many of the analgesic compounds known to be clinically useful for relieving pain. Although a large overlap exists between those stumuli which elicit pain in humans and those which serve as negative reinforcers for animals, analgesic drugs have generally failed to alter the threshold level of noxious stimulation above which avoidance behavior takes place. However, performance on the discrete-trials modification of the titrated aver1 Supported by U.S. Public Health Service grant MH16635-02 and by funds from the 6571st Aeromedical Research Laboratory at Holloman, Air Force Base, New Mexico. 28 0014-4886/79/010028-07$02.00/O Copyright All rights
0 1979 by Academic Press, of reproduction in any form
Inc. reserved.
IMPAIRMENT
AFTER HIPPOCAMPAL
DAMAGE
29
sive schedule is an exception to this rule, because animals administered analgesic agents, such as morphine and codeine, self-titrate at higher than normal levels of noxious stimulation (4). This result suggests that the titrated aversive schedule is a particularly useful model for assessing changes in pain sensation by animals. The present study was designed to provide additonal information about the possibility that performance of the titrated avoidance task might be mediated more by one region of the hippocampus than by another. This seemed possible because in monkeys of various species, anterior hippocampal lesions cause degeneration in different diencephalic and hypothalamic regions than do posterior hippocampal lesions, and lesions of the entire hippocampus result in yet a different degeneration pattern (7, 8). METHODS Subjects. Twenty adolescent rhesus monkeys of either sex, from 2.5 to 4.6 kg in weight (mean, 3.6 kg), and an estimated age of 31 to 42 months (mean, 36 months), as judged by dentition, were used in the study. The monkeys were assigned in a balanced manner to one of five surgical groups which were defined according to the following criteria: (A) bilateral lesions confined to the inferior temporal gyrus (which was also necessarily damaged in all animals with hippocampal lesions), (B) bilateral total hippocampal ablation, (C) bilateral lesions confined to the posterior hippocampus, (D) bilateral lesions confined to the anterior or uncal hippocampus, and (E) a group of unoperated monkeys. Surgery. Animals were deprived of water 24 h prior to surgery, anesthetized with Sernylan 14 mg intramuscularly and intravenous pentobarbital, and given 0.2 ml Koagamin intravenously for hemostasis. Under aseptic conditions, the inferior temporal gyrus was exposed through a zygomatic approach, the brain was gradually retracted, and the inferior pyriform cortex was visualized. An opening was then aspirated through the pyriform cortex, exposing the hippocampus. The designated hippocampal lesion was completed under direct visual guidance. Hemostasis was accomplished, and the head was repaired in layers. Bilateral lesions were done in a one-stage, 6-h procedure.2 Prophylactic ampicillin was administered postoperatively, and the animals were returned to their home cages for at least 1 month of recovery. Apparatus and Procedure. During the 48-h session the animals were placed in a primate restraint chair within a sound-attenuated chamber supplied with 20-dB constant white noise. The chambers were lighted 2 We thank Dr. Karl H. Pribram for demonstrating
the surgical technique.
30
JACKSON
AND
REGESTEIN
from 7:30 AM to 6:00 PM in a light-dark schedule similar to that of the home cage area. The monkeys had free access to water and were fed as usual. Electrical shocks were delivered through 5-kfi resistance to two brass shoe-type electrodes (12) which firmly contained the monkey’s feet. At the beginning of the session the monkey’s feet were cleaned with acetone and rubbed with conductive jelly to ensure low electrical resistance between feet and electrodes. Resistance was monitored and remained constant at 5kfi throughout the 48-h session. After preliminary training had induced stable performance, the monkeys were required to perform according to the requirements of a discrete-trials version of the titrating aversive schedule for 48 consecutive hours. Each monkey received a shock every 7 s and each succeeding shock increased 1 mA in intensity unless the animal pressed a lever in front of him, in which case the succeeding shock became 1 mA less intense. Each monkey was thus able to select a level of shock. Only the first lever press within a given 7-s intershock interval was effective in reducing the succeeding shock in comparison with the original schedule (1 l), in which all lever presses reduced the level of the succeeding shock by a fixed amount. Hippocampal lesions are known to elevate lever-press rates in rats, and this modification was used to prevent one group from showing spuriously low thresholds as a result of hyperactivity, rather than difference in pain reactivity. Maximum shock intensity was 60 mA and the session always began at the lowest shock intensity, which was zero. These parameters evoked stable performance over long periods of time, as indicated by our own pilot work and data from standard titrating aversive schedules. RESULTS Anatomical Results. Representative lesions are illustrated by Fig. 1. The group with “total” hippocampal ablation showed lesions which encompassed approximately 90% of the hippocampus bilaterally. The group with an anterior hippocampectomy showed lesions restricted to the uncus and the most anterior knob of the hippocampal formation. The group with a posterior hippocampectomy showed lesions confined to more posterior portions. There did appear’to be some overlap between the anterior and posterior hippocampal lesions but there was no evidence of infection or unintentional trauma. Behavioral Results. The major finding was that three of the four monkeys with “total hippocampal damage” were unable to continue for the entire 48-h session, whereas all monkeys in the remaining groups were able to lever-press throughout the entire session. The first monkey with a total
IMPAIRMENT
Normal
LIO
AFTER HIPPOCAMPAL L12
Ll4
31
DAMAGE Ll6
FIG. 1. Illustration of representative lesions from each of the surgical groups. The cuts were made sagittally at 10, 12, 14, and 16 mm from the midline. The darkened areas represent tissue removed during surgery.
hippocampectomy and the third after without detectable clasped the lever
stopped lever-pressing after 11 h, the second after 36 h, 42 h. The onsets of these breakdowns were sudden and warning. At the onset of the breakdown the monkeys lightly as if “frozen” onto the mechanism, but no
32
JACKSON
AND REGESTEIN
longer continued to depress it. As the shock level began to intensify, the monkeys showed signs of great emotional distress by squealing and facial expression, but were incapable of organizing appropriate level pressing. Because the shock quickly reached inhumane levels following the breakdown, the affected monkeys were disconnected from the shock generators and given rest. However, even several hours rest failed to restore these monkeys’ ability to perform the titrating task for more than a few minutes at a time. Figure 2 illustrates the decline in mean rate of lever pressing by the group with the larger hippocampal lesions. The source of the group differences seen in Fig. 2 is the failure of three animals with total hippocampectomy to continue performing; zeros were entered at the subsequent data points for each particular animal after it stopped lever pressing. However, while these three monkeys were still able to lever press, they established a rate of lever pressing and selected shock levels comparable to the other monkeys. This was verified by an analysis of variance for unequal numbers. For this computation, all the data collected prior to the cessation of lever pressing were included but none for an animal after it RHESUS
100’
, l-4
,
, S-12
,
, 17-20
,
( 25-28 HOURS
,
, 33-36
,
, 41-44
,
FIG. 2. Mean number of lever presses for each group during the 48-h session. The reduction in the group with total hippocampectomy is a result of a performance breakdown by three of the four monkeys in that group; the first monkey stopped pressing after 11 h, the second after 36 h, and the third after 42 h.
IMPAIRMENT
AFTER
HIPPOCAMPAL
DAMAGE
33
stopped responding. The results of this computation showed no statistically significant differences between any of the surgical groups (F = 0.836, & = 4/15, NS). The finding that only one of four animals in the group with total hippocampectomy was able to complete the 48-h session, when the animals in all the remaining groups were able to do so, would not seem to require additional statistical description. DISCUSSION The results of these experiments indicate that various hippocampal lesions do not alter pain threshold in monkeys as measured by the prolonged titrated avoidance task. Instead, the monkeys with larger hippocampal lesions lacked sufficient endurance to perform the task for a prolonged period. The change in this group was not due to an inability to learn the task or in the level of shock selected, but was linked to the prolonged period during which the animals were required to perform. Similar experiments using monkeys with total hippocampectomy have not been reported, and therefore interpretation of the results remains speculative. That they were able to work several hours before the breakdown of performance suggests that other brain structures are also involved in maintaining prolonged titrated avoidance performance. Presumably the monkeys with total hippocampal damage were more dependent on cortical mediation of avoidance responses (9). When the monkeys were deprived of those hippocampal efferents that project widely to cortex (6), attention deficits may have been sustained that affected avoidance task performance and the effect of such deficits presumably became manifest after fatigue diminished cortical functioning (1, 5). Likewise, the “freezing” of our subjects within the prolonged task could be viewed as a blockage of voluntary motor capability. It is well known that hippocampal electroencephalogram synchrony appears just prior to voluntary movements in the rat (10) and hippocampal ablation prolonged immobility responses in rats and rabbits (13). Although such immobility may be a component of the breakdown in endurance found in this study, the behavior required for prolonged titrated avoidance is probably more complex than mobility alone. At present the limits of endurance for normal monkeys on a titrated avoidance task with these parameters are unknown. However, as a pilot project, four normal monkeys were tested on this task for 96 consecutive hours with no observable deterioration of performance. Additional work will be required to determine whether this breakdown of prolonged performance is specific to the titrating avoidance task, or whether there are other tasks which monkeys with such hippocampal damage would not be able to perform for a prolonged period of time.
34
JACKSON
AND
REGESTEIN
The finding that a lesion of some critical size is necessary to elicit a breakdown in performance indicates that the hippocampal cells which support prolonged titrating avoidance behavior are spread through the length of the hippocampus, rather than concentrated within a specified anterior or posterior location. The present data do not contribute to identifying the particular hippocampal cells which support the sort of “endurance” measured in this study. However, several studies showed that in monkeys lesions of the anterior hippocampus resulted in degeneration of the lateral septal nucleus and nucleus acumbens, whereas lesions of the posterior hippocampus resulted in degeneration of the medial portions of the septal nuclei. In squirrel monkeys all regions of the monkey hippocampus apparently project to the diagonal band, olfactory tubercle, anteroventral nucleus, and mammillary bodies (7). It remains unknown whether these diffusely projecting cells specifically affect endurance of task performance. REFERENCES J. C., AND L. L. MITNICK. 1959. Electroencephalogram and sleep deprivation. J. Appl. Physiol., 14: 247-250. GOL, A., AND G. M. FAIBISH. 1%7. Effects of human hippocampal ablation. J. Neurosurg. 26: 390-398. GOL, A., P. KELLAWAY, M. SHAPIRO, AND C. M. HURST. 1963. Studies of hippocampectomy in the monkey, baboon, and cat. Neurology, 13: 1031-1041. HALPERN, L. M., AND F. P. ALLEVA. 1964. Drug-induced changes in threshold for aversive stimulation in chronically implanted monkeys. Fed. Proc. 23: 284. JOHNSON, L. C., E. S. SELEY, AND W. DEMENT. 1965. Electroencephalographic and antonomic activity during and after sleep deprivation. Psychosom. Med. 27: 415-423. ROSENE, D. L., AND G. W. VAN HORSEN. 1977. Hippocampalefferents reach widespread area of cerebral cortex and amygdala in the rhesus monkey. Science 198: 315-317. SIEGEL, A., S. OHGAMI, AND H. EDINGER. 1975. Projections of the hippocampus to the septal area in the squirrel monkey. Brain Res. 99: 247-260. SIMPSON, D. A. 1952. The efferent fibers of the hippocampus in the monkey. J. Neurol. Neurosurg. Psychiat. 15: 79-92. THOMPSON, R. 1963. Thakmic structures critical for retention of an avoidance conditioned response. .I. Comp. Physiol. Psychol. 56: 261-267. VANDERWOLF, C. H. 1%9. Hippocampal electrical activity and voluntary movement in the rat. Electroenceph. Clin. Neurophysiol. 26: 407-418. WEISS, B., AND V. LATIES. 1%3. Characteristics of aversive thresholds measured by a titration schedule. J. Exp. Anal. Behav. 6: 563-572. WEISS, B., AND V. LATIES. 1962. A foot electrode for monkeys. J. Exp. Anal. Behav. 5: 535-536. WOODRUFF, M. L., D. C. HUTTON, AND M. E. MEYER. 1975. Hippocampal ablation prolongs immobility response in rabbits. J. Comp. Physiol. Psychol. 88: 329-334.
1. ARMINGTON,
2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13.