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Behavioural Brain Research, 38 (1990) 145-154 Elsevier BBR01052
Anterograde and retrograde amnesia in rats with dorsal hippocampal or dorsomedial thalamic lesions Gordon Winocur Trent University, Peterborough, Ont. (Canada) (Received 5 July 1989) (Accepted 9 January 1990)
Key words: Hippocampus; Thalamus; Anterograde amnesia; Retrograde amnesia
The present research was concerned with anterograde and retrograde memory for a socially transmitted food preference in rats with lesions to the dorsal hippocampus or dorsomedial thalamus, and operated controls. In Expt. 1, food-preference training was administered postoperatively and memory was tested following various delays. Both lesioned groups acquired the preference normally, but rats with hippocampal lesions displayed a rapid rate of forgetting that indicated significant anterograde amnesia. In Expt. 2, the food preference was acquired at different times preoperatively and retrograde memory was tested postoperatively. Both lesioned groups exhibited loss of memory when training immediately preceded surgery, but only rats with hippocampal lesions displayed a temporally-graded retrograde amnesia. The results confirmed the differential effects of hippocampal and thalamic lesions on memory performance. It was suggested that memory loss following thalamic lesions was related to factors associated with original learning, whereas the pattern ofhippocampal amnesia reflected disruption at a later stage in the learning process.
INTRODUCTION
The characteristic feature of the human amnesic syndrome is a profound memory loss for events that occur subsequent to brain insult (anterograde amnesia, AA). Memory loss for premorbid events or retrograde amnesia (RA) is more variable, ranging form very little in some cases to considerable amounts that can extend back several d e c a d e s 4'6'22"28. Attempts to relate severity of RA to severity of Am 24'30, to etiologic al factors 2°, or to locus and extent of lesion 32, have generally been unsuccessful. Investigations of memory loss in braindamaged animals have confirmed that lesions to the hippocampal s y s t e m 13"36,38 o r the dorsomedial thalamus 1,36,38 produce severe AA, although the precise nature of the deficits may
differ in the two cases. Memory for preoperative events has been studied only occasionally in animal populations (e.g. refs. 23,38) and there have been no investigations of temporally-graded RA. Undoubtedly, the development of animal models of RA has been hampered by the lack of suitable paradigms. In particular, it has been difficult to devise tasks that meet two crucial conditions for testing remote memory. First, the test must assess memory for events that can be identified with a specific time period and, second, it must be possible to show that memory for the information degrades normally over a manageable test interval. The above conditions are met in a test originally developed by Galef 8'9 to study socially acquired food preferences in rats. The basic procedure involves pairing a naive subject rat (S) with a demonstrator rat (D) that has recently sampled a
Correspondence: G. Winocur, Department of Psychology, Trent University, Peterborough, Ont., Canada, K9J 7B8. 0166-4328/90/$03.50 © 1990 Elsevier Science Publishers B.V. (Biomedical Division)
146 particular food substance. By interacting with D, S acquires a preference for that food that persists at a declining rate over several days. Preliminary investigation in our lab showed that slight variations in Galef's procedure can produce food preferences that last even longer, so that the test becomes suitable for assessing more remote memories. The modified procedure was used to continue our comparison of the effects of hippocampal and thalamic lesions on memory performance. Previous studies were restricted to postoperatively acquired memories 36. In the present research, this work was extended to an assessment of retrograde memory for information acquired at various times before brain damage. EXPERIMENT1
In previous tests of postoperative learning and memory involving delayed alternation and passive avoidance tasks (Winocur, 1985), rats with dorsal hippocampal lesions performed normally when required to retain specific information for relatively brief periods of time, but were severely impaired as the length of the interval increased. Rats with dorsomedial thalamic lesions were impaired at both short and long intervals on the delayed alternation task, a task on which they also displayed poor initial learning. On the passive avoidance task, they acquired the avoidance response as well as controls and showed the same rate of forgetting over time. The overall pattern of results was similar to that observed in clinical stu d i es 11'26 and was similarly interpreted as implicating the thalamus in a fundamental encoding operation that occurs very early in the learning process. The hippocampus, on the other hand, was seen to be important for integrating recently acquired information within the existing knowledge structure, thereby contributing to the consolidation or storage of new information. By this view, in the Galef paradigm, rats with hippocampal lesions should recall postoperatively acquired food preferences as well as normal rats at short intervals but show faster forgetting as the length of the interval increases. Rats with thalamic lesions should show memory loss even
at short delays, if they are deficient in originally acquiring the food preference. Conversely, if they acquire the preference normally, little or no impairment is predicted. These predictions were tested in Expt. 1.
Me~o~ Subjects and apparatus A total of 129 male, Long-Evans rats served as Ss and an additional 20 rats of the same strain served as Ds. All rats were obtained from the Trent University Breeding Centre and were 7-10 months old at the time of the experiment. Prior to the experiment, the rats were housed individually in standard wire cages (25 × 18 x 18 cm) with food and water available at all times. Testing took place in larger cages (42 x 24 x 27 cm), divided into two equal compartments by a 1.25-cm wire mesh partition. D and S rats were placed individually in each compartment.
Surgery and histology The surgical procedure was identical to that described in previous studies (e.g. ref. 36). Rats were anaesthetized with sodium pentobarbital and positioned in a Johnson-Krieg stereotaxic instrument with the tooth bar raised to a height of 5 mm above the interaural plane. Bilateral electrolytic lesions were made by passing a 2-mA direct current through a stainless steel electrode insulated except for 0.5 mm as a tip. Stereotaxic coordinates for the hippocampal lesions were 2.2 mm posterior (P) to bregma, 1.5 and 2.5 mm lateral (L) to the midline, to a depth (D) of 3.0 mm below dura. For dorsomedial thalamic lesions, the coordinates were 1.5 P, 1.0 L, 4.5 D. Rats in the operated control groups received an incision, holes were drilled in their skulls, but no electrode was lowered. Following testing, all brain-damaged animals were deeply anaesthetized with ether and perfused intracraniaUy with physiological saline followed by 10% formol-saline solution. The brains were removed and fixed in 10~o formol-saline for 7 days. Transverse sections were subsequently made and every 5th section throughout the lesion
147 and the other containing the cinnamon-flavoured diet. After 2 h, both food cups were weighed and diet intakes calculated. (The 2-h test session was a departure from Galef and Wigrnore's procedure and was adopted because preliminary observations indicated that, during this time, S rats showed their strongest preference before sampiing, in increasing amounts, the non-preferred food. In other words, a shorter test period provided a more sensitive measure of recalled preference.) In addition to the 0 delay condition, different groups of S rats were tested at delays of 1, 2, 4, or 8 days following D - S interaction. During these delays, Ss were returned to their home cages. Once a day, they were given 20 g of rat chow in pellet form. After the delay, Ss were returned individually to the test compartment and given cinnamon- and cocoa-flavoured diets in the usual manner.
was mounted and stained with thionin. Extent of damage was determined by a comparison with the standard atlas of KOnig and Klippell TM. Procedure Rats were allowed at least 2 weeks to recover from surgery, during which time they were maintained on an ad libitum food and water diet, and handled periodically. One week before the experiment, D and S rats were placed on a 23½-h food deprivation schedule. Typically, 12 pairs of rats were studied at one time. The experimental procedure conformed closely to that described by Galef and Wigmore 9 and consisted of 5 discrete steps: (1) D and S rats were transferred in pairs from their home cage to compartments in the test cages, and allowed to become familiar with each other and the new environment. Rats were left undisturbed 2 days during which time they were fed rat chow on an ad libitum basis. (2) Food was removed from both cages for 23 h. (3) D was removed to another room and, for 60 min, fed powdered rat chow adulterated 2~o by weight with commercially prepared sifted cocoa or 1 ~o commercially ground cinnamon. (4)D was returned to its compartment beside S and the 2 rats were allowed to interact across the partition for 15 min. (5) D was removed from the cage and, in the 0 delay condition, S was offered 2 weighted food cups, 1 containing the cocoa-flavoured diet
Results and Discussion
None of the groups displayed a preference for either the cocoa or cinnamon in any of the tests. Accordingly, the data for each diet as sample were combined and are presented in Fig. 1 as the percentage sample diet of the total amount eaten by Ss at each delay period. As can be seen in Fig. 1, at 0 delay, all groups
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148 displayed an equally strong preference for the sample diet. It may be noted that, in line with preliminary observations, the groups displayed stronger preferences for the sample diet at 0 delay than typically observed by Galef in his experiments 8'9. This is probably because of procedural differences at testing. As indicated in the Methods section, in the present study the food cups were weighed after 2 h, whereas Galefmeasured preferences over a 12-h period. Although the preference decreased over time in all groups, the rate of decline was fastest in rats with hippocampal lesions. These observations were confmned by analysis of variance in which groups and days were treated as between variables. The group x day interaction was highly significant (Fs.114 = 3.04, P < 0.01) and due entirely to the smaller percentage of sample diet eaten by the hippocampal group at delays of 2, 4, and 8 days. Tukey tests indicated significant differences between the hippocampal groups and the other groups at all 3 delays (P's < 0.05). There were no differences between groups at 0 and 1 day delays, and the control and thalamic groups did not differ from each other at any time. A faster rate of forgetting by rats with hippocampal lesions was confirmed by trend analysis on the percentage eaten at each test period. These analyses indicated a significantly different trend in the hippocampal groups than in the control (F1.75 = 4.36, P < 0.05) and thalamic (F1,76 = 7.48, P < 0.01) groups. EXPERIMENT2
In Expt. 1, rats with dorsal hippocampal or dorsomedial thalamic lesions initially acquired the food preference as well as operated control rats, but the thalamic groups retained the preference better over an 8-day period. These results are consistent with previous observations 36 that rats with dorsomedial thalamic lesions are unlikely to display significant memory loss if the material is well learned. In contrast, rats with dorsal hippocampal lesions retained the information only for relatively brief periods and then showed rapid forgetting thereafter. It follows from the above pattern that if the
food preferences were well established preoperatively, the effects of dorsomedial thalamic lesions on recall would be minimal. On the other hand, if as it would appear, the hippocampus contributes to the long-term storage of newly acquired information, then preoperatively presented information that is inadequately represented, should be vulnerable to the effects of dorsal hippocampal lesions. Accordingly, by varying the time between learning and surgery, it may be possible to demonstrate temporallygraded RA in rats with dorsal hippocampal lesions. These predictions were tested in Expt. 2 using acquired food preferences as the measure of memory function. Methods
Subjects A total of 102 naive, male Long-Evans rats, approximately 6 months old, obtained from the Trent University Breeding Centre, were subjects in this experiment. Twenty rats who served as control subjects in Expt. 1 acted as Ds in Expt. 2. All rats were housed individually in wire cages and handled occasionally for 2 weeks before the experiment. Procedure All D and S rats were placed on a 23½-h fooddeprivation schedule 1 week before they were due to be transferred to the test cages. Rats were then subjected to steps 1-4 of the experimental procedure described in Expt. 1. The only difference was that, in step 4, D and S were allowed to interact for 30 min rather than the 15 min of Expt. 1. The reason for this was to establish a stronger food preference that was more likely to endure over the extended delays that applied in Expt. 2. After step 4, S rats were subjected to dorsal hippocampal, dorsomedial thalamic, or operated control surgery immediately, 2, 5, or 10 days later. S rats that were not scheduled for immediate surgery were returned to their home cages and given 20 g of food in pellet form. They were maintained on this feeding schedule until surgery. After surgery, rats were placed on ad libitum food for 5 days, followed by 23½-h food-depri-
149 and delay periods treated as between-factors revealed a significant group x day interaction (F6.9o = 8.87, P < 0.001). Further analysis with the Tukey test indicated significant group differences at the 0 delay test, where the operated control group differed from the hippocampal and thalamic groups (P's < 0.01) and at the 2-day test, where the hippocampal group differed significantly from the thalamic and operated control groups (P's < 0,01). No other group differences at the various delays were statistically significant. Comparisons within each lesion group across delay intervals yielded a number of significant differences. Operated control groups tested at 0 and 2-day intervals differed significantly from the operated control group tested at 10 days (P's < 0.05). The 0 delay thalamic group differed significantly from thalamic groups tested at the other delay intervals (P's < 0.01). Amongst the hippocampal groups, those tested at 0 and 2-day delays differed significantly from those tested at 5 and 10 days (P's < 0.05), but differences within each pair were not statistically significant. Several points can be made on the basis of the results of Expt. 2. As expected, operated control rats showed strongest memory for the most recently acquired food preferences with progressively declining performance at longer delays. In contrast, dorsal hippocampal or dorsomedial thalamic lesions abolished memory for the food preference when surgery was performed im-
vation schedule for 5 more days. Testing occurred for all rats at 10 days postsurgery. This meant that S rats, in the various groups, were tested 10, 12, 15, or 20 days after step 4 in which they interacted with the sample-fed D rats. After the experiment, brain-damaged rats were sacrificed, perfused, and their brains prepared for histological analysis in the manner described in Expt. 1. Results and Discussion
The results are presented in Fig. 2 and expressed as the percentage food sampled by each lesion group at the various delay periods. Once again, there were no significant preferences for original food and so the data for each sample diet were combined. The first thing to note in Fig. 2 is that the forgetting patterns varied between groups. The operated control groups' preference for the sample diet was strongest at 0 delay and declined progressively with longer delays. The thalamic group showed only chance recall when the food preference was established immediately before surgery, but normal recall at the other delays. The hippocampal groups were no better than chance at recalling the preference at 0 delay but showed recovery between 0 and 5 days before dropping to normal levels at the 10-day delay. An analysis of variance with lesioned groups
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Fig. 2. M e a n percentage of sample diet ingested by all groups at the various delays of Expt. 2. Bars indicate _+ 1 S.E.M.
150
mediately after the preference was established. When the delay between food preference acquisition and surgery was extended to 2 days, rats with dorsomedial thalamic lesions recovered to normal levels. Rats with dorsal hippocampal lesions did not attain normal preference levels until the delay was extended to 5 days, indicating a more gradual recovery. The results clearly indicate preoperative memory loss following dorsal hippocampal or dorsomedial thalamic lesions. The question as to whether the deficits observed in the two lesion groups reflect disruption of similar or qualitatively different mechanisms will be considered in the General Discussion. Anatomical report Photographs of typical hippocampal and thalamic lesions are presented in Fig. 3. The locus and extent of brain damage noted in the animals
of Expts. 1 and 2 were similar to that described in previous experiments using the same surgical procedures (e.g. ref. 36). Hippocampal lesions produced extensive disruption of the dorsal hippocampal formation between 3.0 and 5.0 mm anterior to the interaural plane. Varying amounts of damage were observed in the overlying cortex and corpus callosum, and the hippocampal commissure and fimbria-fornix areas were frequently affected. In a few rats, slight damage was detected in dorsal thalamic nuclei. Thalamic lesions consistently destroyed the entire dorsomedial nucleus. In all cases, the paraventricular nucleus was extensively damaged. Damage frequently extended from anterior portions of the anterior dentate gyrus and, to lesser degrees, the stria medullaris, habenular, and lateral thalamic nuclei. GENERAL DISCUSSION
Fig. 3. Photographs of cross-sections of representative hippocampal (above) and thalamic lesions.
The results of Expt. 1 demonstrate the differential effects of dorsal hippocampal and dorsomedial thalamic lesions in recalling a postoperatively acquired food preference. Rats with dorsal hippocampal lesions normally recalled the preference at relatively short delays (24 h) but not at longer delays. This pattern was similar to that displayed by hippocampal groups in other test situations (e.g. refs. 13,36). In contrast, the thalamic groups did not differ from operated controls at any delays in Expt. 1. The normal memory of rats with dorsomedial thalamic lesions may relate to the fact they were able to establish the food preference as well as other groups. In previous work, significant memory loss has been observed in rats with thalamic lesions on tasks on which they were impaired during original learning (simultaneous visual discrimination35; delayed alternation36). In contrast, in a test of passive avoidance conditioning 36, rats with thalamic lesions normally learned the avoidance response and proceeded to show excellent recall at all delay intervals. The similarities between these effects and the patterns of anterograde amnesia in patients with medial temporal lobe or diencephalic lesions have been discussed in previous r e p o r t s 26"35a.
151 Expt. 2 provided a test of retrograde memory by comparing the effects of dorsal hippocampal and dorsomedial thalamic lesions on recalling a preoperatively learned food preference. Once again a dissociation was observed between the brain-damaged groups. Although either lesion abolished memory for the food preference when acquisition immediately preceded surgery, rats with dorsomedial thalamic lesions recovered to normal levels when the interval between acquisition and surgery was extended to 2 days. In contrast, rats with dorsal hippocampal lesions did not attain normal performance levels until the interval'was extended to 5 days, indicating a more graded recovery. There were no differences between any of the groups at the longest delay period. It is important to note that the results of Expts. 1 and 2 cannot be attributed to naturally occurring preferences for either of the sample diets. In the first place, the cinnamon- and cocoaflavoured diets yielded the same results for all groups in both experiments. Second, on several test occasions in Expts. 1 and 2, rats with dorsal hippocampal or dorsomedial thalamic lesions displayed equal intake of both diets. On those occasions, it is clear that experimental procedures contributed to memory loss for the food preference. The overall pattern of results suggests that differences in anterograde or retrograde memory amongst the various groups reflect genuine differences in memory performance. The behaviour of brain-damaged groups in Expt. 2 may be compared with clinical studies of premorbid memory which, despite their variable results, indicate some interesting parallels. For example, investigations involving the classic medial-temporal lobe amnesic patient, H.M., revealed a remote memory loss that, depending on the material, can extend back several years prior to surgery ~5. Recently, Zola-Morgan etal. 39 studied retrograde memory in another amnesic patient (R.B.) with hippocampal damage. R.B. exhibited signs of memory loss for events that occurred 1-2 years before the ischemic attack that precipitated his amnesia. Although H.M. and R.B. displayed some retrograde memory loss, both patients performed well on tests of remote
memory that covered their early premorbid period. Parallels between the animal and clinical literature are very tentative at this point but it would appear that the pattern of retrograde amnesia exhibited by hippocampal groups in Expt. 2 of the present research is at least similar to that seen in amnesic patients with damage to the medial temporal lobe and, specifically, the hippocampus. In Expt. 2, rats with dorsomedial thalamic lesions failed to recall the food preference only when the learning experience immediately preceded surgery. Since both thalamic and hippocampal groups showed absolutely no recall of the food preference in the 0-day test, it is conceivable that the trauma associated with either type of brain surgery was sufficient to obliterate representations of very recent experiences. Interestingly, the patient B.Y. showed a pattern of retrograde memory loss that was very similar to that of the thalamic groups in Expt. 1. B.Y. became severely amnesic after a suspected infarct in the paramedian artery produced restricted bilateral damage to the medial thalamus. He had total amnesia for the 1 or 2 hours preceding the attack, but little measurable loss for earlier events. Other patients with relatively circumscribed thalamic lesions have been reported with profound AA but with little or no accompanying RA 25,28. On the other hand, there are reports of severe RA in patients with thalamic lesions, who do not have a history of alcoholism or Korsakoff Syndrome (see ref. 19). These apparent contradictions need to be investigated further before conclusions can be drawn regarding thalamic damage and retrograde memory loss. The results of the present research can be viewed against the continuing debate over whether amnesia following brain damage reflects a primary disruption of acquisition or retrieval processes. A simple retrieval-deficit interpretation received little support since hippocampal and thalamic groups showed some normal memory in both experiments. While it is tempting to attribute the RA of hippocampal groups in Expt. 2 to a retrieval deficit, it can be argued that temporallylimited retrograde memory loss may be part of an information processing deficit that affects the
152 organization of n e w m e m o r i e s 21,29. RA that extends back for a limited period in hippocampaldamaged subjects may be seen as another manifestation of the basic acquisition deficit that produces AA. The results of Expts. 1 and 2 clearly identified the hippocampus with a timerelated stage of the learning process and are generally in accord with this notion. Several investigators have suggested that thalamic damage interferes with new learning by disrupting the process of encoding new informationS'~l'26; but see ref. 32. Thus, material that is poorly registered early in learning is unlikely to be recalled correctly. The finding that rats with dorsomedial thalamic lesions normally acquired a socially transmitted food preference and, for the most part, displayed normal memory for that preference, supports this position. Moreover, as previously indicated, other studies have shown that animals or humans with thalamic damage are more likely to show memory loss on tasks on which they experience difficulty during original learning (e.g refs. 26,36). Finally, it is important to consider the type of memory that was affected by brain damage in the present research and how the results relate to current views on lost and preserved memories in amnesia. It is widely held that lesions to hippocampal or diencephalic regions disrupt recall of specific or episodic events, while sparing memory for information that cannot be identified with a particular context (e.g. general knowledge, skills, rules) (see reviews in refs. 16,27). If, in Galefs task, remembering a food preference depends on recalling the specific experience in which the preference was acquired, then the present results, at least with respect to the hippocampus, are generally consistent with animal and human evidence for memory dissociation in amnesia. On the other hand, the S rats may have displayed the food preference without reference to their specific encounter with the D rats. The initial learning experience may have 'primed' the Ss to favour that particular food in subsequent choice situations. If Ss initially acquired the preference by processing information related, for example, to taste and safety, that preference could be remembered later without necessarily recalling the
precise interaction with the D-rat. If, indeed, retaining an acquired food preference in the Galef task reflects non-episodic or implicit memory, the present results would suggest that amnesia following damage to hippocampal regions is not necessarily restricted to highly specific events. There is evidence that hippocampal lesions do not always produce effects on memory performance that would be predicted by commonly held views of lost and spared memory function. Several studies have shown that damage to the hippocampus in animals produces explicit and implicit memory loss (e.g. refs. 3,31,36). Other studies have shown that deficits in explicit memory produced by hippocampal damage can be reduced by task manipulations that includes, for example, providing preoperative training 38 and salient contextual cues 34. Taken together, these results suggest that memory performance in animals with hippocampal lesions depends on the demand characteristics of the task as well as the procedures used to assess memory. Similar observations have been made by investigators of human amnesia in assessing, for example, the influence of instructional set on memory for specific information in Korsakoff patients ~° or task-related variables that can affect rate of forgetting in H.M. 7 According to Moscovitch ~v'18, such evidence argues against the traditional view of independent memory systems concerned with explicit memory, on the one hand, and implicit memory, on the other. Instead, he has advocated a componentprocesses approach that emphasizes the cognitive operations required for successful performance on a particular task. By this view, memory tests that depend on similar cognitive processes will yield impairment, whether they assess explicit or implicit memory, when brain regions essential for mediating those processes are damaged. Applying this approach to the present study, the food-preference task is seen as assessing memory for a specific food preference acquired during an episodic learning experience. However, demonstrating that preference at a later time does not depend on the exclusive contribution of an explicit or implicit memory system. The preference can be maintained by recalling the learning episode, or by the more indirect influence of the
153 original experience on subsequent behaviour. The task draws on cognitive processes essential for acquiring and retrieving the preference and, as the results of Expts. 1 and 2 indicate, these processes depend on an intact hippocampus, but not necessarily on an intact thalamus. The present results point to dissociable functions between hippocampus and thalamus that have important implications for assessing anterograde and retrograde amnesia. As such, the data are consistent with a component-processes approach, although, it must be emphasized they do not permit rejection of an independent-systems model. Indeed, neither experiment was designed to address this question but the results do underscore the need to examine the issue with an aim to distinguish between those experimental conditions that are likely to lead to memory loss and those that will support residual memory function. ACKNOWLEDGEMENTS
The present research was supported by a grant from the Natural Sciences and Engineering Research Council of Canada. The help of Bennett G. Galef in developing the test paradigm for this research is greatly appreciated. The technical assistance of Bruce Osborne, Bruce Scott, John Zomer, and Doris Pereschuk is gratefully acknowledged. Thanks are also expressed to John Pinel and two anonymous reviewers for helpful comments on an earlier version of this paper. REFERENCES 1 Aggleton, J.P. and Mishkin, M., Visual recognition impairment following medial thalamic lesions in monkeys, Neuropsychologia, 21 (1983) 189-197. 2 Beracochea, D.J., Jaffard, R.J. and Jarrard, L.E., Effects of anterior or dorsomedial thalamic ibotenic lesions on learning and memory in rats, Behav. Neur. Biol., 51 (1989) 364-376. 3 Bouffard, J.-P. and Jarrard, L.E., Acquisition of a complex place task in rats with selective ibotenate lesions of hippocampal formation: combined lesions of subiculum and entorhinal cortex versus hippocampus, Behav. Neurosci., 102 (1988) 828-834. 4 Butters, N. and Albert, M.S., Processes underlying failures to recall remote events. In L. Cermak (Ed.),
Human Memory and Amnesia, Erlbaum, Hillsdale, 1982, pp. 257-275. 5 Butters, N. and Cermak, L.S., The role of cognitive factors in the memory disorder of alcoholic patients with the Korsakoff syndrome,Ann. N. Y. Acad. Sci., 233 (1974) 61-75. 6 Cermak, L.S. and O'Connor, M., The anterograde and retrograde retrieval ability of a patient with amnesia due to encephalitis, Neuropsychologia, 21 (1983) 213-234. 7 Freed, D.M. and Corkin, S., Rate of forgetting in H.M.: six-months recognition, Behav. Neurosci., 102 (1988) 823-827. 8 Galef, B.G. Jr., Utilization by Norway rats (R. norvegicus) of multiple messages concerning distant diets, J. Comp. Psychol., 97 (1983) 364-371. 9 Galef, B.G. Jr. and Wigmore, S.W., Transfer of information concerning distant food: a laboratory investigationof the 'information-centre' hypothesis, Anim. Behav., 31 (1983) 748-758. 10 Graf, P. and Schacter, D.L., Implicit and explicit memory for new associations in normal and amnesic subjects, J. Exp. Psychol.: Learn., Mem. and Cogn., 11 (1985) 501-518. 11 Huppert, F.A. and Piercy, M., Normal and abnormal forgetting in organic amnesia, Cortex, 15 (1979) 385-390. 12 Jarrard, L.E., Role of interference in retention by rats with hippocampal lesions, J. Comp. Physiol. Psychol., 89 (1975) 400-408. 13 Kesner, R.T., Correspondence between humans and animals in coding of temporal attributes: role of hippocampus and prefrontal cortex, Ann. N.Y. Acad. Sci., 444 (1985) 122-136. 14 Krnig, J.F.R. and Klippel, R.E, The Rat Brain: A Stereotaxic Atlas of the Forebrain and Lower Parts of the Brain Stem, Williams & Wilkins, Baltimore, 1963. 15 Marslen-Wilson, W.D. and Teuber, H.L., Memory for remote events in anterograde amnesia: recognition of public figures from news photographs, Neuropsychologia, 13 (1975) 353-364. 16 Moscovitch, M., Multiple dissociations of function in amnesia. In L.S. Cermak (Ed.), Human Memory and Amnesia, Erlbaum, Hillsdale, 1982, pp. 337-370. 17 Moscovitch, M., The sufficient conditions for demonstrating preserved memory in amnesia: a task analysis. In L.R. Squire and N. Butters (Eds.) Neuropsychology of Memory, Guilford, New York, 1984, pp. 104-114. 18 Moscovitch, M., Winocur, G., and McLachlan, D., Memory as assessed by recognition and reading time in normal and memory-impaired people with Alzheimer's disease and other neurological disorders, J. Exp. PsychoL : Gen., 115 (1986) 331-347. 19 Parkin, A.J., Amnesic syndrome: a lesion-specific disorder? Cortex, 20 (1984) 497-508. 20 Parkin, A.J., Memory and Amnesia, Blackwell, Oxford, 1987. 21 Rawlins, J.N.P., Associations across time: the hippocampus as a temporary memory store, Behav. Brain Sci., 8 (1985) 479-496.
154 22 Sanders, H.1. and Warrington, E.K., Memory for remote events in amnesic patients, Brain, 94 (1971) 661-668. 23 Sara, S.J., Memory deficits in rats with hippocampal or cortical lesions: retrograde effects, Behav. Neurol. Biol., 32 (1981) 504-509. 24 Shimamura, A.P. and Squire, L.R., Korsakoffs Syndrome: a study of the relation between anterograde amnesia and remote memory impairment, Behav. Neurosci., 10 (1986) 165-170. 25 Speedie, L.J. and Heilman, K.M., Amnestic disturbance following infarction of the left dorsomedial nucleus of the thalamus, Neuropsychologia, 20 (1982) 597-604. 26 Squire, L.R., Two forms of human amnesia: an analysis of forgetting, J. Neurosci., 1 (1981)635-640. 27 Squire, L.R.,Memory and Brain, Oxford University Press, New York, 1987. 28 Squire, L.R. and Cohen, N.J., Remote memory, retrograde amnesia, and the neuropsychology of memory. In L.S. Cermak (Ed.), Human Memory and Amnesia, Erlbaum, Hillsdale, 1982, pp. 275-303. 29 Squire, L.R., Cohen, N.J. and Nadel, L., The medial temporal region and memory consolidation: a new hypothesis. In H. Weingartner and E. Parker (Eds.), Memory Consolidation, Erlbaum, Hillsdale, 1984, pp. 185-210. 30 Stuss, D.T. and Guzman, D.A., Severe remote memory loss with minimal anterograde amnesia: a clinical note, Brain and Cog., 8 (1988) 21-30. 31 Van der Staay, F.J., Raaijmakers, W.G.M., Lammers, A.J.J.C. and Tonnaer, J.A.D.M., Selective fimbria lesions impair acquisition of working and reference memory in rats in a complex spatial discrimination task, Behav. Brain Res., 32 (1989) 151-161.
32 Weiskrantz, L, On issues and theories of the human amnesic syndrome. In N.M. Weinberger, J.L. McGaugh and G. Lynch (Eds.), Memory Systems q[ the Brain, Guilford, New York, 1985, pp. 380-415. 33 Winocur, G., Effects of interference on discrimination learning and recall by rats with hippocampal lesions, Physiol, Behav., 22 (1979) 339-345. 34 Winocur, G., Radial-arm maze behavior by rats with dorsal hippocampal lesions: effects of cueing, J. Comp. Physiol. Psyehol., 96 (1982) 155-169. 35 Winocur, G., Memory localization in the brain. In L.R. Squire and N. Butters (Eds.), Neuropsychology of Memoo', Guilford, New York, 1984, pp. 122-133. 35a Winocur, G., Oxbury, S., Roberts, R., Agnetti, V. and Davis, C., Amnesia in a patient with bilateral lesions to the thalamus, Neuropsychologia, 22 (1984) 123-143. 36 Winocur, G., The hippocampus and thalamus: their roles in short- and long-term memory and the effects of interference, Behav. Brain Res., 16 (1985) 135-152. 37 Zola-Morgan, S. and Squire, L.R., Amnesia in monkeys following lesions of the mediodorsal nucleus of the thalamus, Ann. Neurol., 17 (1985) 558-564. 38 Zola-Morgan, S. and Squire, L.R., Memory impairment in monkeys following lesions limited to the hippocampus, Behav. Neurosci., 100 (1986) 155-160. 39 Zola-Morgan, S., Squire, L.R. and Amaral, D., Human amnesia and the medial temporal region: enduring memory impairment following a bilateral lesion limited to the CAI field of the hippocampus, J. Neurosci., 6 (1986) 2950-2967.
Behavioural Brain Research, 38 (1990) 145-154 Elsevier BBR01052
Anterograde and retrograde amnesia in rats with dorsal hippocampal or dorsomedial thalamic lesions Gordon Winocur Trent University, Peterborough, Ont. (Canada) (Received 5 July 1989) (Accepted 9 January 1990)
Key words: Hippocampus; Thalamus; Anterograde amnesia; Retrograde amnesia
The present research was concerned with anterograde and retrograde memory for a socially transmitted food preference in rats with lesions to the dorsal hippocampus or dorsomedial thalamus, and operated controls. In Expt. 1, food-preference training was administered postoperatively and memory was tested following various delays. Both lesioned groups acquired the preference normally, but rats with hippocampal lesions displayed a rapid rate of forgetting that indicated significant anterograde amnesia. In Expt. 2, the food preference was acquired at different times preoperatively and retrograde memory was tested postoperatively. Both lesioned groups exhibited loss of memory when training immediately preceded surgery, but only rats with hippocampal lesions displayed a temporally-graded retrograde amnesia. The results confirmed the differential effects of hippocampal and thalamic lesions on memory performance. It was suggested that memory loss following thalamic lesions was related to factors associated with original learning, whereas the pattern ofhippocampal amnesia reflected disruption at a later stage in the learning process.
INTRODUCTION
The characteristic feature of the human amnesic syndrome is a profound memory loss for events that occur subsequent to brain insult (anterograde amnesia, AA). Memory loss for premorbid events or retrograde amnesia (RA) is more variable, ranging form very little in some cases to considerable amounts that can extend back several d e c a d e s 4'6'22"28. Attempts to relate severity of RA to severity of Am 24'30, to etiologic al factors 2°, or to locus and extent of lesion 32, have generally been unsuccessful. Investigations of memory loss in braindamaged animals have confirmed that lesions to the hippocampal s y s t e m 13"36,38 o r the dorsomedial thalamus 1,36,38 produce severe AA, although the precise nature of the deficits may
differ in the two cases. Memory for preoperative events has been studied only occasionally in animal populations (e.g. refs. 23,38) and there have been no investigations of temporally-graded RA. Undoubtedly, the development of animal models of RA has been hampered by the lack of suitable paradigms. In particular, it has been difficult to devise tasks that meet two crucial conditions for testing remote memory. First, the test must assess memory for events that can be identified with a specific time period and, second, it must be possible to show that memory for the information degrades normally over a manageable test interval. The above conditions are met in a test originally developed by Galef 8'9 to study socially acquired food preferences in rats. The basic procedure involves pairing a naive subject rat (S) with a demonstrator rat (D) that has recently sampled a
Correspondence: G. Winocur, Department of Psychology, Trent University, Peterborough, Ont., Canada, K9J 7B8. 0166-4328/90/$03.50 © 1990 Elsevier Science Publishers B.V. (Biomedical Division)
146 particular food substance. By interacting with D, S acquires a preference for that food that persists at a declining rate over several days. Preliminary investigation in our lab showed that slight variations in Galef's procedure can produce food preferences that last even longer, so that the test becomes suitable for assessing more remote memories. The modified procedure was used to continue our comparison of the effects of hippocampal and thalamic lesions on memory performance. Previous studies were restricted to postoperatively acquired memories 36. In the present research, this work was extended to an assessment of retrograde memory for information acquired at various times before brain damage. EXPERIMENT1
In previous tests of postoperative learning and memory involving delayed alternation and passive avoidance tasks (Winocur, 1985), rats with dorsal hippocampal lesions performed normally when required to retain specific information for relatively brief periods of time, but were severely impaired as the length of the interval increased. Rats with dorsomedial thalamic lesions were impaired at both short and long intervals on the delayed alternation task, a task on which they also displayed poor initial learning. On the passive avoidance task, they acquired the avoidance response as well as controls and showed the same rate of forgetting over time. The overall pattern of results was similar to that observed in clinical stu d i es 11'26 and was similarly interpreted as implicating the thalamus in a fundamental encoding operation that occurs very early in the learning process. The hippocampus, on the other hand, was seen to be important for integrating recently acquired information within the existing knowledge structure, thereby contributing to the consolidation or storage of new information. By this view, in the Galef paradigm, rats with hippocampal lesions should recall postoperatively acquired food preferences as well as normal rats at short intervals but show faster forgetting as the length of the interval increases. Rats with thalamic lesions should show memory loss even
at short delays, if they are deficient in originally acquiring the food preference. Conversely, if they acquire the preference normally, little or no impairment is predicted. These predictions were tested in Expt. 1.
Me~o~ Subjects and apparatus A total of 129 male, Long-Evans rats served as Ss and an additional 20 rats of the same strain served as Ds. All rats were obtained from the Trent University Breeding Centre and were 7-10 months old at the time of the experiment. Prior to the experiment, the rats were housed individually in standard wire cages (25 × 18 x 18 cm) with food and water available at all times. Testing took place in larger cages (42 x 24 x 27 cm), divided into two equal compartments by a 1.25-cm wire mesh partition. D and S rats were placed individually in each compartment.
Surgery and histology The surgical procedure was identical to that described in previous studies (e.g. ref. 36). Rats were anaesthetized with sodium pentobarbital and positioned in a Johnson-Krieg stereotaxic instrument with the tooth bar raised to a height of 5 mm above the interaural plane. Bilateral electrolytic lesions were made by passing a 2-mA direct current through a stainless steel electrode insulated except for 0.5 mm as a tip. Stereotaxic coordinates for the hippocampal lesions were 2.2 mm posterior (P) to bregma, 1.5 and 2.5 mm lateral (L) to the midline, to a depth (D) of 3.0 mm below dura. For dorsomedial thalamic lesions, the coordinates were 1.5 P, 1.0 L, 4.5 D. Rats in the operated control groups received an incision, holes were drilled in their skulls, but no electrode was lowered. Following testing, all brain-damaged animals were deeply anaesthetized with ether and perfused intracraniaUy with physiological saline followed by 10% formol-saline solution. The brains were removed and fixed in 10~o formol-saline for 7 days. Transverse sections were subsequently made and every 5th section throughout the lesion
147 and the other containing the cinnamon-flavoured diet. After 2 h, both food cups were weighed and diet intakes calculated. (The 2-h test session was a departure from Galef and Wigrnore's procedure and was adopted because preliminary observations indicated that, during this time, S rats showed their strongest preference before sampiing, in increasing amounts, the non-preferred food. In other words, a shorter test period provided a more sensitive measure of recalled preference.) In addition to the 0 delay condition, different groups of S rats were tested at delays of 1, 2, 4, or 8 days following D - S interaction. During these delays, Ss were returned to their home cages. Once a day, they were given 20 g of rat chow in pellet form. After the delay, Ss were returned individually to the test compartment and given cinnamon- and cocoa-flavoured diets in the usual manner.
was mounted and stained with thionin. Extent of damage was determined by a comparison with the standard atlas of KOnig and Klippell TM. Procedure Rats were allowed at least 2 weeks to recover from surgery, during which time they were maintained on an ad libitum food and water diet, and handled periodically. One week before the experiment, D and S rats were placed on a 23½-h food deprivation schedule. Typically, 12 pairs of rats were studied at one time. The experimental procedure conformed closely to that described by Galef and Wigmore 9 and consisted of 5 discrete steps: (1) D and S rats were transferred in pairs from their home cage to compartments in the test cages, and allowed to become familiar with each other and the new environment. Rats were left undisturbed 2 days during which time they were fed rat chow on an ad libitum basis. (2) Food was removed from both cages for 23 h. (3) D was removed to another room and, for 60 min, fed powdered rat chow adulterated 2~o by weight with commercially prepared sifted cocoa or 1 ~o commercially ground cinnamon. (4)D was returned to its compartment beside S and the 2 rats were allowed to interact across the partition for 15 min. (5) D was removed from the cage and, in the 0 delay condition, S was offered 2 weighted food cups, 1 containing the cocoa-flavoured diet
Results and Discussion
None of the groups displayed a preference for either the cocoa or cinnamon in any of the tests. Accordingly, the data for each diet as sample were combined and are presented in Fig. 1 as the percentage sample diet of the total amount eaten by Ss at each delay period. As can be seen in Fig. 1, at 0 delay, all groups
ANTEROGRADE
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148 displayed an equally strong preference for the sample diet. It may be noted that, in line with preliminary observations, the groups displayed stronger preferences for the sample diet at 0 delay than typically observed by Galef in his experiments 8'9. This is probably because of procedural differences at testing. As indicated in the Methods section, in the present study the food cups were weighed after 2 h, whereas Galefmeasured preferences over a 12-h period. Although the preference decreased over time in all groups, the rate of decline was fastest in rats with hippocampal lesions. These observations were confmned by analysis of variance in which groups and days were treated as between variables. The group x day interaction was highly significant (Fs.114 = 3.04, P < 0.01) and due entirely to the smaller percentage of sample diet eaten by the hippocampal group at delays of 2, 4, and 8 days. Tukey tests indicated significant differences between the hippocampal groups and the other groups at all 3 delays (P's < 0.05). There were no differences between groups at 0 and 1 day delays, and the control and thalamic groups did not differ from each other at any time. A faster rate of forgetting by rats with hippocampal lesions was confirmed by trend analysis on the percentage eaten at each test period. These analyses indicated a significantly different trend in the hippocampal groups than in the control (F1.75 = 4.36, P < 0.05) and thalamic (F1,76 = 7.48, P < 0.01) groups. EXPERIMENT2
In Expt. 1, rats with dorsal hippocampal or dorsomedial thalamic lesions initially acquired the food preference as well as operated control rats, but the thalamic groups retained the preference better over an 8-day period. These results are consistent with previous observations 36 that rats with dorsomedial thalamic lesions are unlikely to display significant memory loss if the material is well learned. In contrast, rats with dorsal hippocampal lesions retained the information only for relatively brief periods and then showed rapid forgetting thereafter. It follows from the above pattern that if the
food preferences were well established preoperatively, the effects of dorsomedial thalamic lesions on recall would be minimal. On the other hand, if as it would appear, the hippocampus contributes to the long-term storage of newly acquired information, then preoperatively presented information that is inadequately represented, should be vulnerable to the effects of dorsal hippocampal lesions. Accordingly, by varying the time between learning and surgery, it may be possible to demonstrate temporallygraded RA in rats with dorsal hippocampal lesions. These predictions were tested in Expt. 2 using acquired food preferences as the measure of memory function. Methods
Subjects A total of 102 naive, male Long-Evans rats, approximately 6 months old, obtained from the Trent University Breeding Centre, were subjects in this experiment. Twenty rats who served as control subjects in Expt. 1 acted as Ds in Expt. 2. All rats were housed individually in wire cages and handled occasionally for 2 weeks before the experiment. Procedure All D and S rats were placed on a 23½-h fooddeprivation schedule 1 week before they were due to be transferred to the test cages. Rats were then subjected to steps 1-4 of the experimental procedure described in Expt. 1. The only difference was that, in step 4, D and S were allowed to interact for 30 min rather than the 15 min of Expt. 1. The reason for this was to establish a stronger food preference that was more likely to endure over the extended delays that applied in Expt. 2. After step 4, S rats were subjected to dorsal hippocampal, dorsomedial thalamic, or operated control surgery immediately, 2, 5, or 10 days later. S rats that were not scheduled for immediate surgery were returned to their home cages and given 20 g of food in pellet form. They were maintained on this feeding schedule until surgery. After surgery, rats were placed on ad libitum food for 5 days, followed by 23½-h food-depri-
149 and delay periods treated as between-factors revealed a significant group x day interaction (F6.9o = 8.87, P < 0.001). Further analysis with the Tukey test indicated significant group differences at the 0 delay test, where the operated control group differed from the hippocampal and thalamic groups (P's < 0.01) and at the 2-day test, where the hippocampal group differed significantly from the thalamic and operated control groups (P's < 0,01). No other group differences at the various delays were statistically significant. Comparisons within each lesion group across delay intervals yielded a number of significant differences. Operated control groups tested at 0 and 2-day intervals differed significantly from the operated control group tested at 10 days (P's < 0.05). The 0 delay thalamic group differed significantly from thalamic groups tested at the other delay intervals (P's < 0.01). Amongst the hippocampal groups, those tested at 0 and 2-day delays differed significantly from those tested at 5 and 10 days (P's < 0.05), but differences within each pair were not statistically significant. Several points can be made on the basis of the results of Expt. 2. As expected, operated control rats showed strongest memory for the most recently acquired food preferences with progressively declining performance at longer delays. In contrast, dorsal hippocampal or dorsomedial thalamic lesions abolished memory for the food preference when surgery was performed im-
vation schedule for 5 more days. Testing occurred for all rats at 10 days postsurgery. This meant that S rats, in the various groups, were tested 10, 12, 15, or 20 days after step 4 in which they interacted with the sample-fed D rats. After the experiment, brain-damaged rats were sacrificed, perfused, and their brains prepared for histological analysis in the manner described in Expt. 1. Results and Discussion
The results are presented in Fig. 2 and expressed as the percentage food sampled by each lesion group at the various delay periods. Once again, there were no significant preferences for original food and so the data for each sample diet were combined. The first thing to note in Fig. 2 is that the forgetting patterns varied between groups. The operated control groups' preference for the sample diet was strongest at 0 delay and declined progressively with longer delays. The thalamic group showed only chance recall when the food preference was established immediately before surgery, but normal recall at the other delays. The hippocampal groups were no better than chance at recalling the preference at 0 delay but showed recovery between 0 and 5 days before dropping to normal levels at the 10-day delay. An analysis of variance with lesioned groups
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Fig. 2. M e a n percentage of sample diet ingested by all groups at the various delays of Expt. 2. Bars indicate _+ 1 S.E.M.
150
mediately after the preference was established. When the delay between food preference acquisition and surgery was extended to 2 days, rats with dorsomedial thalamic lesions recovered to normal levels. Rats with dorsal hippocampal lesions did not attain normal preference levels until the delay was extended to 5 days, indicating a more gradual recovery. The results clearly indicate preoperative memory loss following dorsal hippocampal or dorsomedial thalamic lesions. The question as to whether the deficits observed in the two lesion groups reflect disruption of similar or qualitatively different mechanisms will be considered in the General Discussion. Anatomical report Photographs of typical hippocampal and thalamic lesions are presented in Fig. 3. The locus and extent of brain damage noted in the animals
of Expts. 1 and 2 were similar to that described in previous experiments using the same surgical procedures (e.g. ref. 36). Hippocampal lesions produced extensive disruption of the dorsal hippocampal formation between 3.0 and 5.0 mm anterior to the interaural plane. Varying amounts of damage were observed in the overlying cortex and corpus callosum, and the hippocampal commissure and fimbria-fornix areas were frequently affected. In a few rats, slight damage was detected in dorsal thalamic nuclei. Thalamic lesions consistently destroyed the entire dorsomedial nucleus. In all cases, the paraventricular nucleus was extensively damaged. Damage frequently extended from anterior portions of the anterior dentate gyrus and, to lesser degrees, the stria medullaris, habenular, and lateral thalamic nuclei. GENERAL DISCUSSION
Fig. 3. Photographs of cross-sections of representative hippocampal (above) and thalamic lesions.
The results of Expt. 1 demonstrate the differential effects of dorsal hippocampal and dorsomedial thalamic lesions in recalling a postoperatively acquired food preference. Rats with dorsal hippocampal lesions normally recalled the preference at relatively short delays (24 h) but not at longer delays. This pattern was similar to that displayed by hippocampal groups in other test situations (e.g. refs. 13,36). In contrast, the thalamic groups did not differ from operated controls at any delays in Expt. 1. The normal memory of rats with dorsomedial thalamic lesions may relate to the fact they were able to establish the food preference as well as other groups. In previous work, significant memory loss has been observed in rats with thalamic lesions on tasks on which they were impaired during original learning (simultaneous visual discrimination35; delayed alternation36). In contrast, in a test of passive avoidance conditioning 36, rats with thalamic lesions normally learned the avoidance response and proceeded to show excellent recall at all delay intervals. The similarities between these effects and the patterns of anterograde amnesia in patients with medial temporal lobe or diencephalic lesions have been discussed in previous r e p o r t s 26"35a.
151 Expt. 2 provided a test of retrograde memory by comparing the effects of dorsal hippocampal and dorsomedial thalamic lesions on recalling a preoperatively learned food preference. Once again a dissociation was observed between the brain-damaged groups. Although either lesion abolished memory for the food preference when acquisition immediately preceded surgery, rats with dorsomedial thalamic lesions recovered to normal levels when the interval between acquisition and surgery was extended to 2 days. In contrast, rats with dorsal hippocampal lesions did not attain normal performance levels until the interval'was extended to 5 days, indicating a more graded recovery. There were no differences between any of the groups at the longest delay period. It is important to note that the results of Expts. 1 and 2 cannot be attributed to naturally occurring preferences for either of the sample diets. In the first place, the cinnamon- and cocoaflavoured diets yielded the same results for all groups in both experiments. Second, on several test occasions in Expts. 1 and 2, rats with dorsal hippocampal or dorsomedial thalamic lesions displayed equal intake of both diets. On those occasions, it is clear that experimental procedures contributed to memory loss for the food preference. The overall pattern of results suggests that differences in anterograde or retrograde memory amongst the various groups reflect genuine differences in memory performance. The behaviour of brain-damaged groups in Expt. 2 may be compared with clinical studies of premorbid memory which, despite their variable results, indicate some interesting parallels. For example, investigations involving the classic medial-temporal lobe amnesic patient, H.M., revealed a remote memory loss that, depending on the material, can extend back several years prior to surgery ~5. Recently, Zola-Morgan etal. 39 studied retrograde memory in another amnesic patient (R.B.) with hippocampal damage. R.B. exhibited signs of memory loss for events that occurred 1-2 years before the ischemic attack that precipitated his amnesia. Although H.M. and R.B. displayed some retrograde memory loss, both patients performed well on tests of remote
memory that covered their early premorbid period. Parallels between the animal and clinical literature are very tentative at this point but it would appear that the pattern of retrograde amnesia exhibited by hippocampal groups in Expt. 2 of the present research is at least similar to that seen in amnesic patients with damage to the medial temporal lobe and, specifically, the hippocampus. In Expt. 2, rats with dorsomedial thalamic lesions failed to recall the food preference only when the learning experience immediately preceded surgery. Since both thalamic and hippocampal groups showed absolutely no recall of the food preference in the 0-day test, it is conceivable that the trauma associated with either type of brain surgery was sufficient to obliterate representations of very recent experiences. Interestingly, the patient B.Y. showed a pattern of retrograde memory loss that was very similar to that of the thalamic groups in Expt. 1. B.Y. became severely amnesic after a suspected infarct in the paramedian artery produced restricted bilateral damage to the medial thalamus. He had total amnesia for the 1 or 2 hours preceding the attack, but little measurable loss for earlier events. Other patients with relatively circumscribed thalamic lesions have been reported with profound AA but with little or no accompanying RA 25,28. On the other hand, there are reports of severe RA in patients with thalamic lesions, who do not have a history of alcoholism or Korsakoff Syndrome (see ref. 19). These apparent contradictions need to be investigated further before conclusions can be drawn regarding thalamic damage and retrograde memory loss. The results of the present research can be viewed against the continuing debate over whether amnesia following brain damage reflects a primary disruption of acquisition or retrieval processes. A simple retrieval-deficit interpretation received little support since hippocampal and thalamic groups showed some normal memory in both experiments. While it is tempting to attribute the RA of hippocampal groups in Expt. 2 to a retrieval deficit, it can be argued that temporallylimited retrograde memory loss may be part of an information processing deficit that affects the
152 organization of n e w m e m o r i e s 21,29. RA that extends back for a limited period in hippocampaldamaged subjects may be seen as another manifestation of the basic acquisition deficit that produces AA. The results of Expts. 1 and 2 clearly identified the hippocampus with a timerelated stage of the learning process and are generally in accord with this notion. Several investigators have suggested that thalamic damage interferes with new learning by disrupting the process of encoding new informationS'~l'26; but see ref. 32. Thus, material that is poorly registered early in learning is unlikely to be recalled correctly. The finding that rats with dorsomedial thalamic lesions normally acquired a socially transmitted food preference and, for the most part, displayed normal memory for that preference, supports this position. Moreover, as previously indicated, other studies have shown that animals or humans with thalamic damage are more likely to show memory loss on tasks on which they experience difficulty during original learning (e.g refs. 26,36). Finally, it is important to consider the type of memory that was affected by brain damage in the present research and how the results relate to current views on lost and preserved memories in amnesia. It is widely held that lesions to hippocampal or diencephalic regions disrupt recall of specific or episodic events, while sparing memory for information that cannot be identified with a particular context (e.g. general knowledge, skills, rules) (see reviews in refs. 16,27). If, in Galefs task, remembering a food preference depends on recalling the specific experience in which the preference was acquired, then the present results, at least with respect to the hippocampus, are generally consistent with animal and human evidence for memory dissociation in amnesia. On the other hand, the S rats may have displayed the food preference without reference to their specific encounter with the D rats. The initial learning experience may have 'primed' the Ss to favour that particular food in subsequent choice situations. If Ss initially acquired the preference by processing information related, for example, to taste and safety, that preference could be remembered later without necessarily recalling the
precise interaction with the D-rat. If, indeed, retaining an acquired food preference in the Galef task reflects non-episodic or implicit memory, the present results would suggest that amnesia following damage to hippocampal regions is not necessarily restricted to highly specific events. There is evidence that hippocampal lesions do not always produce effects on memory performance that would be predicted by commonly held views of lost and spared memory function. Several studies have shown that damage to the hippocampus in animals produces explicit and implicit memory loss (e.g. refs. 3,31,36). Other studies have shown that deficits in explicit memory produced by hippocampal damage can be reduced by task manipulations that includes, for example, providing preoperative training 38 and salient contextual cues 34. Taken together, these results suggest that memory performance in animals with hippocampal lesions depends on the demand characteristics of the task as well as the procedures used to assess memory. Similar observations have been made by investigators of human amnesia in assessing, for example, the influence of instructional set on memory for specific information in Korsakoff patients ~° or task-related variables that can affect rate of forgetting in H.M. 7 According to Moscovitch ~v'18, such evidence argues against the traditional view of independent memory systems concerned with explicit memory, on the one hand, and implicit memory, on the other. Instead, he has advocated a componentprocesses approach that emphasizes the cognitive operations required for successful performance on a particular task. By this view, memory tests that depend on similar cognitive processes will yield impairment, whether they assess explicit or implicit memory, when brain regions essential for mediating those processes are damaged. Applying this approach to the present study, the food-preference task is seen as assessing memory for a specific food preference acquired during an episodic learning experience. However, demonstrating that preference at a later time does not depend on the exclusive contribution of an explicit or implicit memory system. The preference can be maintained by recalling the learning episode, or by the more indirect influence of the
153 original experience on subsequent behaviour. The task draws on cognitive processes essential for acquiring and retrieving the preference and, as the results of Expts. 1 and 2 indicate, these processes depend on an intact hippocampus, but not necessarily on an intact thalamus. The present results point to dissociable functions between hippocampus and thalamus that have important implications for assessing anterograde and retrograde amnesia. As such, the data are consistent with a component-processes approach, although, it must be emphasized they do not permit rejection of an independent-systems model. Indeed, neither experiment was designed to address this question but the results do underscore the need to examine the issue with an aim to distinguish between those experimental conditions that are likely to lead to memory loss and those that will support residual memory function. ACKNOWLEDGEMENTS
The present research was supported by a grant from the Natural Sciences and Engineering Research Council of Canada. The help of Bennett G. Galef in developing the test paradigm for this research is greatly appreciated. The technical assistance of Bruce Osborne, Bruce Scott, John Zomer, and Doris Pereschuk is gratefully acknowledged. Thanks are also expressed to John Pinel and two anonymous reviewers for helpful comments on an earlier version of this paper. REFERENCES 1 Aggleton, J.P. and Mishkin, M., Visual recognition impairment following medial thalamic lesions in monkeys, Neuropsychologia, 21 (1983) 189-197. 2 Beracochea, D.J., Jaffard, R.J. and Jarrard, L.E., Effects of anterior or dorsomedial thalamic ibotenic lesions on learning and memory in rats, Behav. Neur. Biol., 51 (1989) 364-376. 3 Bouffard, J.-P. and Jarrard, L.E., Acquisition of a complex place task in rats with selective ibotenate lesions of hippocampal formation: combined lesions of subiculum and entorhinal cortex versus hippocampus, Behav. Neurosci., 102 (1988) 828-834. 4 Butters, N. and Albert, M.S., Processes underlying failures to recall remote events. In L. Cermak (Ed.),
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