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Choice bias from unilateral hippocampal or frontal lesions in the rat
EXPERIMENTAL
NEUROLOGY
Choice
534-545
29,
Bias
from
Frontal
(1970)
Unilateral Lesions
ERNEST GREENE, SAMUEL Department
in the
University
Los Angeles,
California August
or
Rat
SAPORTA, AND JOHN WALTERS
of Psychology, Received
Hippocampal
of So&hertz 90007
1
California,
30, 1970
Rats with unilateral lesions of the hippocampus or of frontal cortex tended to choose the arm of a T maze that was ipsilateral to the lesion, and in some cases exhibited forced circling toward the ipsilateral side. Lesions of parietal or occipital cortex did not produce these effects. Other investigators have reported similarity of behavioral impairment with hippocampal and frontal damage. The anatomical and behavioral evidence indicates that the frontal cortical area serves motor functions; the present findings support McCleary’s suggestion that the hippocampus also is part of a motor control system. Introduction
Bilateral hippocampal lesions in the rat produce a variety of behavioral deficits. Examples of these include impairments in passive avoidance, discrimination-reversal, alternation-learning, and extinction. The animal appears to have difficulty inhibiting its response tendencies in the face of punishment or lack of reward, and thus tends to repeat the same act in a fixed manner. Often animals with hippocampal lesions have been described as being “perseverative.” There have been a number of theories of the function served by the hippocampus. Herrick (6) proposed that it is the sensory cortex for olfaction. Papez (21) suggestedthat it evaluates affective or emotional significance of events, and Penfield and Milner (23) argued that in man it plays a key role in the storage of memories. In general, recent studies have not supported these suggestions,and several alternative hypotheses have been proposed. Douglas and Pribram (4, 5) argued that the hippocampus operates essentially as an attentional device. They viewed the hippocampus as one part of a system which selectively admits stimuli that provide appropriate cues for behavior-an “error evaluate system.” Without the hippocampus an animal fixates on certain stimuli, even though these stimuli may cease 1 This investigation was supported by PHS Research Grant MH 18371 from the National Institute of Mental Health, Ernest Greene, principal investigator. 534
HIPPOCAMPUS
AND
FRONTAL
CORTEX
535
to be appropriate for adequate task performance. Kimble (10) suggested that the hippocampus mediates the condition of “internal inhibition,” which was first formulated and characterized by Pavlov (22). Although Pavlov based the concept of internal inhibition mainly on classical conditioning phenomena, Kimble argued that the concept applies equally well to such tasks as habituation to novelty, discrimination-reversal, and operant extinction. Kimble stressed the anatomical relations of the hippocampus with the mesencephalic and diencephalic arousal systems, and like Douglas and Pribram, suggested that this system serves to direct the animal’s attention. McCleary (20) proposed that the limbic system provides a balanced circuit for the facilitation or inhibition of response tendency. In this system, the hippocampus acts to inhibit responses. He drew support for his theory from Kaada’s (7) findings that stimulation of various brain regions, and especially limbic structures, resulted in facilitation or inhibition of autonomic motor activity, somatic reflexes, or movement elicited by stimulation of motor cortex. The possibility that the hippocampus serves as a system for motor control rather than as an attentional system is further reinforced by the similarity of behavioral impairments produced from lesions in motor areas of frontal cortex to those seen with hippocampal lesion. Passive avoidance deficits have been reported for frontal (17) and hippocampal lesions alike (11). Difficulty in extinction (2, 10) and habit reversal (9, 19) has been reported with either lesion. In the rat, hippocampal lesions produce virtually a complete inability to learn an alternation task (25). Likewise, difficulties in alternation learning as a consequence of frontal damage have been reported in the rat ( IS), cat (31)) and monkey (30). Teitelbaum (28) drew attention to these similarities of behavioral impairment, and in the cat studied the effects of orbitofrontal and hippocampal lesions. He reported that these treatments were similar in producing an impairment for tactile discrimination-reversal, while having no effect on the initial discrimination learning. The present experiments developed from studies of the effects of unilateral brain lesions on choice bias. They provide further evidence of the similarity of effect of lesions of the hippocampus and lesions of frontal motor systems. Method
The subjects of the first experiment were 32 male albino rats, 59-64 days old at the start of testing. Each day for 12 days these were tested in a standard T maze. Each rat was allowed three choices of the maze arms, and no reward or punishment was provided as a consequence of any choice. The first 6 days of testing were used to indicate the natural choice
536
GREENE,
SAPORTA,
AND
WALTERS
tendencies of each animal. The side chosen most often over the 6 days was designated the preferred side (though the actual score of each rat was the number of choices against that preference, to be consistant with postoperative scoring). Once the choice preference of each subject was established, the rats were randomly divided into four treatment groups, designated Frontal, Parietal, Occipital, and Sham, according to whether the animals sustained damage to frontal cortex, parietal cortex, occipital cortex, or removal of the skull over the region of the frontal cortex. In each case the lesion (or skull removal) was to the side opposite of the initial choice preference. Thus, if in the first 6 days of testing the rat chose the right side of the maze most often, the lesion was placed on the left. The rat’s subsequent score of choices against the preferred side may, therefore, be interpreted as choices toward the side of the lesion. In a separate study, the effect of unilateral hippocampal lesion on choice bias was examined. The subjects were 33 male albino rats, 120-124 days old at the start of the experiment. Initial choice preference was determined using 3 days of testing, rather than 6. Surgery was performed on day 4, and the animals were not tested on that day. They were randomly divided into groups which received lesions of the hippocampus, of the cortex overlying the hippocampus, or received no surgical treatment (designated Hippocampal, Cortical Control, and Normal, respectively). As in the first experiment the lesions were placed on the side opposite the rat’s initial choice preference. Beginning on day 5, each was tested for 7 more days. Throughout testing, four choices were given each test day (instead of three choices as in the first study) to increase the sensitivity of each day’s test. A 30-min interval was used between trials to increase the independence of each trial. At the end of each of the two experiments, the animals were killed under Nembutal anesthesia. The brains were removed and sectioned to determine the location and extent of each lesion. Results
Figure 1 shows the choices of the Frontal, Parietal, Occipital, and Sham groups over preoperative and postoperative test periods. There was no significant difference among the groups during the preoperative period of testing. After surgery the Frontal subjects alone showed a significant choice bias toward the side of the lesion. Comparison of the choices of Frontal subjects before and after the operation yielded a t = 3.65, p < .Ol. No other group showed a significant change from initial choice bias as a result of the surgical treatment. The effectiveness of the frontal lesion in producing an ipsilateral choice
HIPPOCAMPUS
AND
FRONTAL
CORTEX
537
bias was further supported by a comparison of postoperative scores among the groups. An analysis of variance between the groups yielded an F = 9.53, p<.OOl. Detailed comparison showed this difference to be due to the extreme scores of Frontal subjects. Frontal subjects differed significantly from Sham controls (t = 3.65, p<.Ol), and from the other groups. The smallest difference was between Frontal and Parietal subjects (t = 2.26, p<.O5). Neither of the other groups differed significantly from Sham controls. Figure 2 shows the choices for the groups of the first experiment with the choices shown separately for each test day. It is clear that the major change in choice bias is for Frontal subjects on the first day after surgery. From that day forward, there was a gradual decline toward control levels of choice preference. There were no obvious differences among the groups in their motivation or willingness to be handled and tested. The experimentors did observe, however, that most of the animals with lesions in the frontal area would circle toward the side of the lesion. Typically the animal would bend its head toward the lesioned side, and its locomotion would carry it in small circles. The circling was most conspicuous at the choice point in the T maze. With the rats that showed circling tendencies, the arm of the maze chosen most often was invariably ipsilateral to the lesion, and in some FRONTAL
12.1 PARIETAL
11 , ! 11.1
OCCIPITAL
lo.! 10.t SHAM
9.5
cl
9.
9.c
8.
8.5
8.
8.0
7.
7.5
7.
7.0
6.
6.5
6.
6.0
5.
5.5 PRE-OPERATIVE
FIG. 1. Mean
POST-OPERATIVE
number of choices by the groups of the first experiment. The lesions were placed in the hemisphere opposite to the preoperative choice bias. Only the frontal lesion produced a significant change in bias toward the side of the lesion.
538
GREENE,
3.0
SAPORTA,
AND
WALTERS
-
.
2.8
----
2.6
-. -
FRONTAL PARIETAL --
OCCIPITAL SHAM
2.4 2.2 2.0 1.8 1.6 1.4 1.2 1.0 0.8 0.6 0.4
SURCtRY
0.2 I Tl :st da YS
1
2
3
4
5
I 6
7
a
9
10
11
FIG. 2. Mean number of daily choices by the groups of the first experiment. frontal lesion had the greatest influence on choices the first few days after surgery.
12
The
casesthe animal was able to enter the other arm only by spinning in backward. Figure 3 shows the choices of Hippocampal, Cortical Control, and Normal groups over preoperative and postoperative test periods. Again, there HIPPOCAMPAL
CORTICAL CONTROL
10 9 8
1
20 NORMAL CONTROL
19
7 6 5 4 3 2 1 PRE-OPERATIVE
POST-OPERATIVE
FIG. 3. Mean number of choices against bias by the groups of the second experiment. Only the hippocampal lesion produced a significant change in bias toward the side of the lesion.
HIPPOCAMPUS
AND
FRONTAL
539
CORTEX
was no significant difference among the groups during preoperative testing. After surgery, the Hippocampal subjects showed a dramatic change to a bias which was ipsilateral to the lesion. An analysis of variance among the groups of the second experiment demonstrated a significant treatment effect (F = 6.44, p < ,005 ‘) . The Cortical Controls were not significantly different from Normals, therefore the scores of these control groups were pooled for comparison with Hippocampal scores. The ipsilateral choice bias of the Hippocampal subjects was found to differ significantly from the choices of these control rats (t = 3.61, p<.OOl). Figure 4 shows the choices of the groups of the second experiment for each of the test days. Unlike the performance of the Frontal subjects of the first experiment, the Hippocampal subjects did not show as dramatic a change in bias on the first day after surgery. However, they did remain more stable in their bias, and did not return to the response levels of the control groups over the 7-clay test period. Forced circling was also observed in a number of rats with hippocampal lesions. In fact, two animals were eliminated from testing because they were totally unable to move through the T maze. These animals would spin about in the start box, but were not able to move out of the start box into the stem or goal arms. Any disturbance of these animals in their home cages would also produce circling. Figure 5 illustrates the extent of damage in Frontal, Parietal, and Occipital groups. The lesions are shown from the dorsal view and in cross 3.0 2.8 2.6 2.4 2.2 2.0 1.8 1.6 1.4
-
HIPPOCAMPAL
-----
CORTICAL
-
NORMAL
FIG. 4. Mean number of daily choices by the groups of the second hippocampal lesions produced a small but consistent ipsilateral bias.
CONTROL CONTROL
experiment.
The
540
GREENE,
SAt’ORTA,
AND
WALTERS
Frc. 5. Maximum and minimum da.mage is shown in the upper diagram for each group; and total extent of damage in the lower diagrams. A. Frontal ; cross section at de Groot coordinate A 7.5 mm. B. Parietal; cross section at de Groot coordinate A 2.6 mm. C. Occipital ; cross section at de Groot coordinate A 1.0 mm.
RIPPOCAMP~S
AND
FROKTAL
CORTEX
541
section. ;\Iaximum and minimum damage from each perspective are illustrated, along with the total extent of damage. Total extent of damage was determined by overlapping the diagrams of all the lesions of a group. Illustrations of the lesions are all shown on the right hemisphere, even though many of the lesions were on the left. The frontal lesions were located in Krieg area 19 (13). The average lesion size was 12 mm’. range 23 mm wide by 3-7 mm long. They typically extended through the cortex down to the corpus callosum. In several cases the corpus callosum was damaged. Parietal and occipital lesions were approximately the same size, and were smaller than frontal lesions. The average size of the lesions was 7-S mm”, range 2-3 mm wide by 3-4 mm long. Parietal lesions typically extended through the corpus callosum. In only one case was there damage to the hippocampus, and this animal showed no abnormal choice or circling tendencies. The lesions generally fell at the intersection of Krieg areas 1, 2, 3, and 7. The occipital lesions extended down to the corpus callosum, and there appeared to be no damage to the callosum. The lesions centered on Krieg area 17. Figure 6 illustrates the damage in Hippocampal and Cortical Control groups. In most of the former, the ventral portion of the hippocampus was not damaged, comparable to the hippocampal lesions performed in other laboratories. Hippocampal and cortical control lesions alike were generally larger than the lesions of the first experiment. In both cases (and especially in several hippocampal lesions) there was considerable damage to the cortical visual areas. However, there was no clear indication that the bias was a function of lesion size, and the first experiment showed no sign of bias as a result of damage to visual cortex. Discussion
It is likely that the choice bias produced by unilateral lesions of the hippocampus and frontal cortex reflect an impairment of motor rather than sensory systems. Whatever might have been the sensory impairments produced by the parietal and occipital lesions of the first experiment, or by the parietotemporal lesion of the second experiment, there was no evidence of a choice bias as a consequence of that damage. Various observations indicate that the area of the frontal cortex involved in the lesion in the first experiment serves for motor control. Using morphological criteria, this region has been shown to contain a large population of pyramidal cells (14)) and lesions of it result in extensive degeneration in the pyramidal tract (13. 16). M ovement of the head and forelimb has been reported with electrical stimulation of this region (15), and Peterson (24) has found that unilateral lesions near this area can produce a shift of hand preference.
542
GREENE,
SAPORTA,
AND
WALTERS
FIG. 6. Maximum and minimum damage is shown in the upper diagrams for each of the groups, and total extent of damage is shown in the lower diagrams. A. Hippocampal. B. Cortical control. For both groups the cross sections were taken at de Groot coordinates A 3.4 mm and A 2.6 mm.
Laterality of motor control has been reported with damage to frontal cortex in monkeys. Kennard and Ectors (8) found that monkeys with unilateral lesions to the rostra1 bank of the arcuate sulcus (the frontal eyefields) circled to the ipsilateral side, and tended to disregard objects appearing in the contralateral visual field. Denny-Brown and Chambers (3) reported that monkeys with lesions of the posterior half of the parietal lobe would not reach out and grasp objects approaching from that side, and termed the deficit an “attention heminopia.” If, in addition to the parietal lesion, precentral pyramidal fields were removed, there was a tendency to turn the head toward the side of the lesion. The monkey’s head and eyes appeared to be attracted to that side.
HIPPOCAMPUS
AND
FRONTAL
CORTEX
543
The behavioral effects of lesions to the orbitofrontal cortex in higher animals may be especially relevant. It seems clear that the orbitofrontal region has some role in motor control, since stimulation of it has been shown to inhibit monosynaptic and polysynaptic somatomotor (7, 12, 27) and autonomic reflexes (7). Several investigators have observed deficits after orbitofrontal lesions which are similar to the deficits produced by hippocampal lesions. For example, Teitelbaum (28) directly compared the effects of both lesions in cats and found an impairment of tactile discrimination reversal, while there was no indication of a disability in original learning with either lesion. Warren, Warren and Akert (31) studied the behavior of cats with orbitofrontal lesions, found deficits in alternation learning, and found that these animals had difficulty in learning to inhibit response tendencies. These deficits are like those which characterize the “hippocampal syndrome.” The results of the present study also suggest that the hippocampus performs functions similar to those performed by frontal cortex, and therefore complement the studies of the orbitofrontal area. However, the issue of homology of function across species must be considered. One defining feature of orbitofrontal cortex is that it receives a projection from the mediodorsal nucleus of the thalamus (26). The area of the cortex in the rat which receives a mediodorsal projection, lies on the dorsal lip of the rhinal sulcus and along the medial wall of the frontal pole (16), and in only two instances did the lesions of the present study include any damage to this region. Generally the area damaged in the present study corresponds to premotor cortex in carnivores and primates. Since Allen (1) found that lesions in premotor cortex or in the presylvian SU~CUS of the dog produced losses in conditioned responses similar to the losses produced by orbitofrontal lesion, one might argue that damage to any of the motor control systems may produce a similar behavioral impairment. It is not likely that the choice bias observed in the present study reflects impairment of an “attentional device.” Although a perceptual imbalance certainly could produce biased choices in the T maze, it would not produce a compulsive circling of the animals toward the side of the lesion. However, in the fina analysis a rapprochement between theories of attentional gating and motor control may be in order. Teuber (29) surveyed many studies of behavioral impairment in rodents, carnivores, subhuman primates, and man after damage to the frontal lobes. He has concluded that the common element in each behavior dysfunction is a lack of sensorymotor coordination, and that the function of the frontal systems is to signal the sensory systems of impending motor activity. If the hippocampus performs operations similar to these frontal systems, perhaps it also serves to coordinate sensory processing with the animal’s ongoing behavior.
544
GREENE,
SAPORTA,
AND
WALTERS
References
1. 2. 3. 4. 5.
6. 7.
8.
9. 10. 11. 12.
13. 14. 15. 16. 17. 18. 19. 20.
21. 22.
W. F. 1949. Effects of prefrontal brain lesions on conditioned differential responses in dogs. Amer. J. Physiol. 159 : 525-532. BUTTER, C. M., M. MISHKIN, and H. E. ROSEVOLD. 1963. Conditioning and extinction of a food rewarded response after selective ablations of the frontal cortex in Rhesus monkeys. E.zp. Neural. 7 : 65-75. DENNY-BROWN, D., and R. A. CHAMBERS. 1958. The parietal lobe and behavior. Res. Publ. Ass. New. Mewt. Dis. 36 : 37-117. DOUGLAS, R. J. 1967. The hippocampus and behavior. Psychol. Bull. 67:.416442. DOUGLAS, R. J., and K. H. PRIBR!.M. 1966. Learning and limbic lesions. NcuroPsychologia 4 : 197-220. HERRICK, C. J. 1933. The function of the olfactory parts of the cortex. Proceedings of the National Academy of Sciences 19 : 7-17. KAADA, B. R. 1951. Somato-motor, autonomic and electrocorticographic responses to electrical stimulation of ‘rhinencephalic’ and other structures in primates, cat and dog. Acta Physiol. Stand. Suppl. 83 24: l-285. KENNARD, M. A., and L. ECTORS. 1938. Forced circling in monkeys following lesions of the frontal lobes. J. Neurophysiol. 1 : 45-54. KIMBLE. D. P. 1963. The effects of bilateral hippocampal lesions in rats. Z. Camp. Physiol. Psyrhol. 56 : 273-283. KIMBLE, D. P. 1968. Hippocampus and internal inhibition. Psychol. Bull. 70: 285-295. KIMURA, D. 1958. Effects of selective hippocampal damage on avoidance behavior of the rat. Can. J. Psychol. 12: 213-217. KNAUSS, T., E. K. SAUERLAND, and C. D. CLEMENTE. 1968. Cortically induced reflex inhibition following ablation of sensorimotor cortex in the cat. Brain Res. 6: 373-375. KRIEG, W. J. S. 1946. Connections of the cerebral cortex. I. The albino rat. A. Topography of the cortical areas. J. Camp. Neural. 64: 221-275. KRIEG, W. J. S. 1946. Connections of the cerebral cortex. I. The albino rat. B. Structure of the cortical areas. J. Con~p. Neurol. 64 : 277-323. LASHLEY, K. S. 1921. Studies of cerebral function in learning. 111. The motor areas. Brain 44 : 255-286. LEONARD, C. M. 1969. The prefrontal cortex of the rat. I. Cortical projection of the mediodorsal nucleus. II. Efferent connections. Brain Res. 12: 321-343. LICHTENSTEIN, P. E. 1950. Studies of anxiety. 11. The effects of lobotomy on a feeding inhibition in dogs. J. Camp. Physiol. Psychol. 43 : 419-427. LOUCSS, R. B. 1931. Efficacy of the rat’s motor cortex in delayed alternation. J. Camp. Newel. 53 : 511-567. MAHUT, H., and J. P. CORDEAU. 1963. Spatial reversal deficit in monkeys with amygdalohippocampal ablations. E.rp. Neural. 7 : 426-434. MCCLEARY, R. A. 1966. Response-modulating functions of the limbic system: Initiation and suppression, pp. 210-266. In “Progress in Physiological Psychology” E. Stellar and J. M. Sprague [Eds.], Academic Press, New York. PAPEZ, J. W. 1937. A proposed mechanism of emotion. Arch Neural. Psychiat. 36 : 725-744. PAVLOV, I. P. 1927. “Conditioned Reflexes, an Investigation of the Physiological Activity of the Cerebral Cortex,” G. V. Anrep [Trans.] Oxford Univ. Press, Oxford, England. ALLEN,
HIPPOCAMPUS
AXD
FRONTAL
CORTEX
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23. PENFIELD, 24. 25. 26. 27.
28.
W., and B. MILNER. 1958. Memory deficit produced by bilateral lesions in the hippocampal zone. A.M.A. Arch. Neural. Psychiat. 79 : 475-497. PETERSON, G. M. 1934. Mechanisms of handedness in the rat. Conzp. Psychol. Monogr. 9: l-67. RACII\‘E, R. J., and D. P. KIMBLE. 1965. Hippocampal lesions and delayed alternation in the rat. Psychonow. Sci. 3 : 285-286. ROSE, J. E., and C. N. WOOLSEY. 1948. The orbitofrontal cortex and its connections with the mediodorsal nucleus in rabbit, sheep, and cat. Res. Publ. Ass. New. Me&. Dis. 27 : 210-232. SAUERLAND, E. K., T. KNAUSS, Y. NAECAMURA, and C. D. CLEMENTE. 1967. Inhibition of monosynaptic and polysynaptic reflexes and muscle tone by electrical stimulation of the cerebral cortex. E.rp. Nezcvol. 17 : 159-171. TEITELBAUM, H. 1964. A comparison of effects of orbitofrontal and hippocampal lesions upon discrimination learning and reversal in the cat. Exp. Neural. 9:
452-462. 29. TEUBER, H. L. 1966. The frontal 30. 31.
lobes and their function: Further observations on rodents, carnivores, subhuman primates, and man. Int. J. Neural. Montevideo 5: 282300. WARREN, J. M., R. W. LEARY, H. F. HARLOW, and G. M. FRENCH. 1957. Function of association cortex in monkey. h-it. J. A&z. Behav. 5 : 131-138. WARREN, J. M., H. B. WARREN, and K. AKERT. 1962. Orbitofrontal cortical lesions and learning in cats. J. Covzp. Neural. 118 : 17-39.
NEUROLOGY
Choice
534-545
29,
Bias
from
Frontal
(1970)
Unilateral Lesions
ERNEST GREENE, SAMUEL Department
in the
University
Los Angeles,
California August
or
Rat
SAPORTA, AND JOHN WALTERS
of Psychology, Received
Hippocampal
of So&hertz 90007
1
California,
30, 1970
Rats with unilateral lesions of the hippocampus or of frontal cortex tended to choose the arm of a T maze that was ipsilateral to the lesion, and in some cases exhibited forced circling toward the ipsilateral side. Lesions of parietal or occipital cortex did not produce these effects. Other investigators have reported similarity of behavioral impairment with hippocampal and frontal damage. The anatomical and behavioral evidence indicates that the frontal cortical area serves motor functions; the present findings support McCleary’s suggestion that the hippocampus also is part of a motor control system. Introduction
Bilateral hippocampal lesions in the rat produce a variety of behavioral deficits. Examples of these include impairments in passive avoidance, discrimination-reversal, alternation-learning, and extinction. The animal appears to have difficulty inhibiting its response tendencies in the face of punishment or lack of reward, and thus tends to repeat the same act in a fixed manner. Often animals with hippocampal lesions have been described as being “perseverative.” There have been a number of theories of the function served by the hippocampus. Herrick (6) proposed that it is the sensory cortex for olfaction. Papez (21) suggestedthat it evaluates affective or emotional significance of events, and Penfield and Milner (23) argued that in man it plays a key role in the storage of memories. In general, recent studies have not supported these suggestions,and several alternative hypotheses have been proposed. Douglas and Pribram (4, 5) argued that the hippocampus operates essentially as an attentional device. They viewed the hippocampus as one part of a system which selectively admits stimuli that provide appropriate cues for behavior-an “error evaluate system.” Without the hippocampus an animal fixates on certain stimuli, even though these stimuli may cease 1 This investigation was supported by PHS Research Grant MH 18371 from the National Institute of Mental Health, Ernest Greene, principal investigator. 534
HIPPOCAMPUS
AND
FRONTAL
CORTEX
535
to be appropriate for adequate task performance. Kimble (10) suggested that the hippocampus mediates the condition of “internal inhibition,” which was first formulated and characterized by Pavlov (22). Although Pavlov based the concept of internal inhibition mainly on classical conditioning phenomena, Kimble argued that the concept applies equally well to such tasks as habituation to novelty, discrimination-reversal, and operant extinction. Kimble stressed the anatomical relations of the hippocampus with the mesencephalic and diencephalic arousal systems, and like Douglas and Pribram, suggested that this system serves to direct the animal’s attention. McCleary (20) proposed that the limbic system provides a balanced circuit for the facilitation or inhibition of response tendency. In this system, the hippocampus acts to inhibit responses. He drew support for his theory from Kaada’s (7) findings that stimulation of various brain regions, and especially limbic structures, resulted in facilitation or inhibition of autonomic motor activity, somatic reflexes, or movement elicited by stimulation of motor cortex. The possibility that the hippocampus serves as a system for motor control rather than as an attentional system is further reinforced by the similarity of behavioral impairments produced from lesions in motor areas of frontal cortex to those seen with hippocampal lesion. Passive avoidance deficits have been reported for frontal (17) and hippocampal lesions alike (11). Difficulty in extinction (2, 10) and habit reversal (9, 19) has been reported with either lesion. In the rat, hippocampal lesions produce virtually a complete inability to learn an alternation task (25). Likewise, difficulties in alternation learning as a consequence of frontal damage have been reported in the rat ( IS), cat (31)) and monkey (30). Teitelbaum (28) drew attention to these similarities of behavioral impairment, and in the cat studied the effects of orbitofrontal and hippocampal lesions. He reported that these treatments were similar in producing an impairment for tactile discrimination-reversal, while having no effect on the initial discrimination learning. The present experiments developed from studies of the effects of unilateral brain lesions on choice bias. They provide further evidence of the similarity of effect of lesions of the hippocampus and lesions of frontal motor systems. Method
The subjects of the first experiment were 32 male albino rats, 59-64 days old at the start of testing. Each day for 12 days these were tested in a standard T maze. Each rat was allowed three choices of the maze arms, and no reward or punishment was provided as a consequence of any choice. The first 6 days of testing were used to indicate the natural choice
536
GREENE,
SAPORTA,
AND
WALTERS
tendencies of each animal. The side chosen most often over the 6 days was designated the preferred side (though the actual score of each rat was the number of choices against that preference, to be consistant with postoperative scoring). Once the choice preference of each subject was established, the rats were randomly divided into four treatment groups, designated Frontal, Parietal, Occipital, and Sham, according to whether the animals sustained damage to frontal cortex, parietal cortex, occipital cortex, or removal of the skull over the region of the frontal cortex. In each case the lesion (or skull removal) was to the side opposite of the initial choice preference. Thus, if in the first 6 days of testing the rat chose the right side of the maze most often, the lesion was placed on the left. The rat’s subsequent score of choices against the preferred side may, therefore, be interpreted as choices toward the side of the lesion. In a separate study, the effect of unilateral hippocampal lesion on choice bias was examined. The subjects were 33 male albino rats, 120-124 days old at the start of the experiment. Initial choice preference was determined using 3 days of testing, rather than 6. Surgery was performed on day 4, and the animals were not tested on that day. They were randomly divided into groups which received lesions of the hippocampus, of the cortex overlying the hippocampus, or received no surgical treatment (designated Hippocampal, Cortical Control, and Normal, respectively). As in the first experiment the lesions were placed on the side opposite the rat’s initial choice preference. Beginning on day 5, each was tested for 7 more days. Throughout testing, four choices were given each test day (instead of three choices as in the first study) to increase the sensitivity of each day’s test. A 30-min interval was used between trials to increase the independence of each trial. At the end of each of the two experiments, the animals were killed under Nembutal anesthesia. The brains were removed and sectioned to determine the location and extent of each lesion. Results
Figure 1 shows the choices of the Frontal, Parietal, Occipital, and Sham groups over preoperative and postoperative test periods. There was no significant difference among the groups during the preoperative period of testing. After surgery the Frontal subjects alone showed a significant choice bias toward the side of the lesion. Comparison of the choices of Frontal subjects before and after the operation yielded a t = 3.65, p < .Ol. No other group showed a significant change from initial choice bias as a result of the surgical treatment. The effectiveness of the frontal lesion in producing an ipsilateral choice
HIPPOCAMPUS
AND
FRONTAL
CORTEX
537
bias was further supported by a comparison of postoperative scores among the groups. An analysis of variance between the groups yielded an F = 9.53, p<.OOl. Detailed comparison showed this difference to be due to the extreme scores of Frontal subjects. Frontal subjects differed significantly from Sham controls (t = 3.65, p<.Ol), and from the other groups. The smallest difference was between Frontal and Parietal subjects (t = 2.26, p<.O5). Neither of the other groups differed significantly from Sham controls. Figure 2 shows the choices for the groups of the first experiment with the choices shown separately for each test day. It is clear that the major change in choice bias is for Frontal subjects on the first day after surgery. From that day forward, there was a gradual decline toward control levels of choice preference. There were no obvious differences among the groups in their motivation or willingness to be handled and tested. The experimentors did observe, however, that most of the animals with lesions in the frontal area would circle toward the side of the lesion. Typically the animal would bend its head toward the lesioned side, and its locomotion would carry it in small circles. The circling was most conspicuous at the choice point in the T maze. With the rats that showed circling tendencies, the arm of the maze chosen most often was invariably ipsilateral to the lesion, and in some FRONTAL
12.1 PARIETAL
11 , ! 11.1
OCCIPITAL
lo.! 10.t SHAM
9.5
cl
9.
9.c
8.
8.5
8.
8.0
7.
7.5
7.
7.0
6.
6.5
6.
6.0
5.
5.5 PRE-OPERATIVE
FIG. 1. Mean
POST-OPERATIVE
number of choices by the groups of the first experiment. The lesions were placed in the hemisphere opposite to the preoperative choice bias. Only the frontal lesion produced a significant change in bias toward the side of the lesion.
538
GREENE,
3.0
SAPORTA,
AND
WALTERS
-
.
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OCCIPITAL SHAM
2.4 2.2 2.0 1.8 1.6 1.4 1.2 1.0 0.8 0.6 0.4
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0.2 I Tl :st da YS
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I 6
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a
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FIG. 2. Mean number of daily choices by the groups of the first experiment. frontal lesion had the greatest influence on choices the first few days after surgery.
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The
casesthe animal was able to enter the other arm only by spinning in backward. Figure 3 shows the choices of Hippocampal, Cortical Control, and Normal groups over preoperative and postoperative test periods. Again, there HIPPOCAMPAL
CORTICAL CONTROL
10 9 8
1
20 NORMAL CONTROL
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7 6 5 4 3 2 1 PRE-OPERATIVE
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FIG. 3. Mean number of choices against bias by the groups of the second experiment. Only the hippocampal lesion produced a significant change in bias toward the side of the lesion.
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was no significant difference among the groups during preoperative testing. After surgery, the Hippocampal subjects showed a dramatic change to a bias which was ipsilateral to the lesion. An analysis of variance among the groups of the second experiment demonstrated a significant treatment effect (F = 6.44, p < ,005 ‘) . The Cortical Controls were not significantly different from Normals, therefore the scores of these control groups were pooled for comparison with Hippocampal scores. The ipsilateral choice bias of the Hippocampal subjects was found to differ significantly from the choices of these control rats (t = 3.61, p<.OOl). Figure 4 shows the choices of the groups of the second experiment for each of the test days. Unlike the performance of the Frontal subjects of the first experiment, the Hippocampal subjects did not show as dramatic a change in bias on the first day after surgery. However, they did remain more stable in their bias, and did not return to the response levels of the control groups over the 7-clay test period. Forced circling was also observed in a number of rats with hippocampal lesions. In fact, two animals were eliminated from testing because they were totally unable to move through the T maze. These animals would spin about in the start box, but were not able to move out of the start box into the stem or goal arms. Any disturbance of these animals in their home cages would also produce circling. Figure 5 illustrates the extent of damage in Frontal, Parietal, and Occipital groups. The lesions are shown from the dorsal view and in cross 3.0 2.8 2.6 2.4 2.2 2.0 1.8 1.6 1.4
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FIG. 4. Mean number of daily choices by the groups of the second hippocampal lesions produced a small but consistent ipsilateral bias.
CONTROL CONTROL
experiment.
The
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Frc. 5. Maximum and minimum da.mage is shown in the upper diagram for each group; and total extent of damage in the lower diagrams. A. Frontal ; cross section at de Groot coordinate A 7.5 mm. B. Parietal; cross section at de Groot coordinate A 2.6 mm. C. Occipital ; cross section at de Groot coordinate A 1.0 mm.
RIPPOCAMP~S
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541
section. ;\Iaximum and minimum damage from each perspective are illustrated, along with the total extent of damage. Total extent of damage was determined by overlapping the diagrams of all the lesions of a group. Illustrations of the lesions are all shown on the right hemisphere, even though many of the lesions were on the left. The frontal lesions were located in Krieg area 19 (13). The average lesion size was 12 mm’. range 23 mm wide by 3-7 mm long. They typically extended through the cortex down to the corpus callosum. In several cases the corpus callosum was damaged. Parietal and occipital lesions were approximately the same size, and were smaller than frontal lesions. The average size of the lesions was 7-S mm”, range 2-3 mm wide by 3-4 mm long. Parietal lesions typically extended through the corpus callosum. In only one case was there damage to the hippocampus, and this animal showed no abnormal choice or circling tendencies. The lesions generally fell at the intersection of Krieg areas 1, 2, 3, and 7. The occipital lesions extended down to the corpus callosum, and there appeared to be no damage to the callosum. The lesions centered on Krieg area 17. Figure 6 illustrates the damage in Hippocampal and Cortical Control groups. In most of the former, the ventral portion of the hippocampus was not damaged, comparable to the hippocampal lesions performed in other laboratories. Hippocampal and cortical control lesions alike were generally larger than the lesions of the first experiment. In both cases (and especially in several hippocampal lesions) there was considerable damage to the cortical visual areas. However, there was no clear indication that the bias was a function of lesion size, and the first experiment showed no sign of bias as a result of damage to visual cortex. Discussion
It is likely that the choice bias produced by unilateral lesions of the hippocampus and frontal cortex reflect an impairment of motor rather than sensory systems. Whatever might have been the sensory impairments produced by the parietal and occipital lesions of the first experiment, or by the parietotemporal lesion of the second experiment, there was no evidence of a choice bias as a consequence of that damage. Various observations indicate that the area of the frontal cortex involved in the lesion in the first experiment serves for motor control. Using morphological criteria, this region has been shown to contain a large population of pyramidal cells (14)) and lesions of it result in extensive degeneration in the pyramidal tract (13. 16). M ovement of the head and forelimb has been reported with electrical stimulation of this region (15), and Peterson (24) has found that unilateral lesions near this area can produce a shift of hand preference.
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FIG. 6. Maximum and minimum damage is shown in the upper diagrams for each of the groups, and total extent of damage is shown in the lower diagrams. A. Hippocampal. B. Cortical control. For both groups the cross sections were taken at de Groot coordinates A 3.4 mm and A 2.6 mm.
Laterality of motor control has been reported with damage to frontal cortex in monkeys. Kennard and Ectors (8) found that monkeys with unilateral lesions to the rostra1 bank of the arcuate sulcus (the frontal eyefields) circled to the ipsilateral side, and tended to disregard objects appearing in the contralateral visual field. Denny-Brown and Chambers (3) reported that monkeys with lesions of the posterior half of the parietal lobe would not reach out and grasp objects approaching from that side, and termed the deficit an “attention heminopia.” If, in addition to the parietal lesion, precentral pyramidal fields were removed, there was a tendency to turn the head toward the side of the lesion. The monkey’s head and eyes appeared to be attracted to that side.
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The behavioral effects of lesions to the orbitofrontal cortex in higher animals may be especially relevant. It seems clear that the orbitofrontal region has some role in motor control, since stimulation of it has been shown to inhibit monosynaptic and polysynaptic somatomotor (7, 12, 27) and autonomic reflexes (7). Several investigators have observed deficits after orbitofrontal lesions which are similar to the deficits produced by hippocampal lesions. For example, Teitelbaum (28) directly compared the effects of both lesions in cats and found an impairment of tactile discrimination reversal, while there was no indication of a disability in original learning with either lesion. Warren, Warren and Akert (31) studied the behavior of cats with orbitofrontal lesions, found deficits in alternation learning, and found that these animals had difficulty in learning to inhibit response tendencies. These deficits are like those which characterize the “hippocampal syndrome.” The results of the present study also suggest that the hippocampus performs functions similar to those performed by frontal cortex, and therefore complement the studies of the orbitofrontal area. However, the issue of homology of function across species must be considered. One defining feature of orbitofrontal cortex is that it receives a projection from the mediodorsal nucleus of the thalamus (26). The area of the cortex in the rat which receives a mediodorsal projection, lies on the dorsal lip of the rhinal sulcus and along the medial wall of the frontal pole (16), and in only two instances did the lesions of the present study include any damage to this region. Generally the area damaged in the present study corresponds to premotor cortex in carnivores and primates. Since Allen (1) found that lesions in premotor cortex or in the presylvian SU~CUS of the dog produced losses in conditioned responses similar to the losses produced by orbitofrontal lesion, one might argue that damage to any of the motor control systems may produce a similar behavioral impairment. It is not likely that the choice bias observed in the present study reflects impairment of an “attentional device.” Although a perceptual imbalance certainly could produce biased choices in the T maze, it would not produce a compulsive circling of the animals toward the side of the lesion. However, in the fina analysis a rapprochement between theories of attentional gating and motor control may be in order. Teuber (29) surveyed many studies of behavioral impairment in rodents, carnivores, subhuman primates, and man after damage to the frontal lobes. He has concluded that the common element in each behavior dysfunction is a lack of sensorymotor coordination, and that the function of the frontal systems is to signal the sensory systems of impending motor activity. If the hippocampus performs operations similar to these frontal systems, perhaps it also serves to coordinate sensory processing with the animal’s ongoing behavior.
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