《认知神经科学》课程教学资源（参考文献）[Squire, L. R.（1992）] Memory and the hippocampus_a synthesis from findings with rats, monkeys, and humans.pdf_P6-P10

200 A 100 r 90 0 80 1 > S. 70 I so 50 LARRY R. SQUIRE NMTS-1 B I00r 90 80 70 60 50 NMTS-2 A=3 15 60 10nwi Delay (s) 15 60 10min Delay (s) Figure 3. Performance on the delayed-nonmatching-to-sample (NMTS) task by normal monkeys (N), monkeys with lesions of the amygdala (A), monkeys with damage to the hippocampal formation (H*), monkeys with conjoint lesions of the hippocampal formation and the amygdala (H*A), monkeys with large medial temporal lobe resections (H*A+ ), and monkeys with lesions of the hippocampal formation and the perirhinal cortex adjacent to the amygdala (H**). The numbers in the figure show the number of animals in each group. Performance was tested approximately 1 month after surgery (NMTS-1) and then again 1 to 2 years after surgery (NMTS-2). The performance curve for the H*+ group in the left panel may underestimate the memory deficit, because one animal in this group required a remedial procedure in which the sample object was always presented twice instead of once. The WA* group was tested only once. (From "The Medial Temporal Lobe Memory System" by L. R. Squire and S. Zola-Morgan, 1991, Science, 253, p. 1382. Copyright 1991 by the American Association for the Advancement of Science. Reprinted by permission.) bilateral carotid occlusion together with pharmacologically induced hypotension. Monkeys prepared in this way had cell loss restricted mainly to the CA1 field of the hippocampus and to somatostatin-containing cells in the dentate gyrus. Only minor, occasional histological damage could be detected in other brain regions. Monkeys with this lesion (ISC) also had impaired memory, although the impairment was less severe overall than the impairment associated with surgical lesions of the hippocampal formation (the H+ lesion). Specifically, on the delayed nonmatching to sample task monkeys with ischemic lesions were impaired to about the same degree as monkeys with H + lesions. However, on two other tasks (object discrimination and eight-pair concurrent discrimination), monkeys in the ISC group performed better (p = .06) than monkeys with H* lesions. It has also been possible to compare monkeys with ISC lesions to monkeys with selective lesions of the hippocampus, which were produced using stereotaxic coordinates established by MR imaging (the H lesion). The H lesion damaged the hippocampus, dentate gyrus, and subiculum, but spared the underlying cortex (Alvarez-Royo, Glower, Zola-Morgan, & Squire, 1991; Glower, Alvarez-Royo, Zola-Morgan, & Squire, 1991). Monkeys with the H lesion performed similarly to monkeys with ISC lesions across all the tasks and significantly better than JH* monkeys on two of the tasks. The findings for ISC lesions, taken together with the findings for H and H* lesions, show that even incomplete damage to the hippocampus is sufficient to produce detectable memory impairment in monkeys, just as it can in humans (patient R. B.). It has been difficult to rule out entirely the possibility that some additional ischemic damage affecting memory functions did occur in patient R. B. and that this damage was not detected in histological analysis. The results with ischemic monkeys are able to illuminate this issue to some extent. Specifically, if significant additional damage had occurred in the ISC monkeys in areas important for memory function, one would expect the memory impairment to have approximated more closely or even to have exceeded the memory impairment associated with surgical lesions of the hippocampal formation. However, the ISC lesion produced less severe memory impairment overall than the H+ surgical lesion and about the same level of impairment as H surgical lesions. Accordingly, it is implausible that the ischemic animals (and by analogy the ischemic patient R. B.) had widespread pathological change affecting memory that was not subsequently detected by histological examination. The pathology in the ischemic animals must involve less tissue in structures related to memory function than is involved in the № lesion itself. Although the H* lesion produces a considerable degree of memory impairment, the level of the deficit is unmistakably greater after a larger bilateral medial temporal lobe removal (the H+A + lesion; Mishkin, 1978; Zola-Morgan & Squire, 1985;

MEMORY AND THE HIPPOCAMPUS 201 Zola-Morgan et al., 1989a). The finding that H*A+ lesions produce more severe memory impairment than H*" lesions (Figure 3) implies that some of the damage produced by the tPA"1 " lesion, which is not included in the H+ lesion, are important for memory functions. Herein lies the explanation for why H. M. is more amnesic than other amnesic study patients, including R. B. H. M. sustained an H+A + lesion, but R. B. sustained a lesion involving only a portion of the hippocampus. Considerable effort has been directed toward identifying which structures are damaged in the EPA"1 " lesion but not in the H* lesion. The early evidence on this point seemed to point to the amygdala (Mishkin, 1978; Murray & Mishkin, 1985; Saunders, Murray, & Mishkin, 1984). However, all these early studies were based on surgical groups in which the amygdala was removed together with underlying cortex. At the same time, the cytoarchitectonics and connectivity of the underlying cortex were incompletely understood, and there was little basis for supposing that it should contribute to memory function. The underlying cortex was only incidentally involved in these surgical procedures, not a target of study. An early hint that the underlying cortex might play a role in memory came from behavioral studies of monkeys in which anteroventral temporal cortex was reversibly cooled (Horel & Pytko, 1982). When surgical lesions of this area were produced, the most affected animal had a lesion that involved perirhinal cortex (Horel, Pytko-Joiner, Voytko, & Salsbury, 1987). The possibility of studying this cortical region improved considerably when the territory of the perirhinal cortex was denned by modern neuroanatomical methods, and its connectivity with the hippocampal formation was established (Insausti, Amaral, & Cowan, 1987). The entorhinal cortex was already known to be the source of the major afferent projection to the hippocampus and dentate gyms. The important newer finding was that the adjacent perirhinal and parahippocampal gyrus provide nearly two thirds of the cortical input to the entorhinal cortex. Perirhinal and parahippocampal cortex are therefore essential for the normal exchange of information between the neocortex and the hippocampal formation. With these anatomical facts in mind, we reexamined a group of H*A+ monkeys (Zola-Morgan, Squire, & Mishkin, 1982) that had been prepared with the standard surgical approach to the amygdala. Substantial damage to perirhinal cortex had occurred in all the animals (see Zola-Morgan, Squire, Amaral, & Suzuki, 1989). On the basis of this observation, it seems plausible that damage to perirhinal cortex adjacent to the amygdala would also have occurred during the similar surgical approach used to make more limited lesions directed at the amygdala itself or the amygdalofugal pathway (Bachevalier, Saunders, & Mishkin, 1985; Mishkin, 1978). In short, it appears that the lesions in the earlier studies that were intended to test the role of the amygdala had damaged cortex in addition to the amygdala that on anatomical grounds might be expected to have a role in memory function. It thus became important to determine experimentally the separate contributions to memory impairment of amygdala damage and damage to underlying cortex. To evaluate the effect of amygdala damage itself on memory, we developed a surgical procedure involving bilateral stereotaxic lesions, which damaged virtually all the components of the amygdaloid complex but spared adjacent cortex (the A lesion). Monkeys with the A lesion performed normally on four memory tasks (delayed nonmatching to sample, retention of object discriminations, concurrent discrimination, and delayed response (Zola-Morgan, Squire, & Amaral, 1989b). In contrast, monkeys with H+ or H*A+ lesions were impaired on all four tasks. We also evaluated monkeys who had bilateral lesions of the hippocampal formation (H*) made conjointly with circumscribed lesions of the amygdaloid complex (the H"A lesion). The H*A monkeys were also impaired on the four memory tasks, but their impairment was no greater than after H* lesions. Thus, amygdala damage alone did not impair memory; nor did it exacerbate the memory impairment associated with damage to the hippocampal formation (Figure 3). These findings suggested that more severe memory impairment observed after H*A+ lesions might be attributable to damage to the cortical regions that surround the amygdala. This possibility was tested directly in two different ways. First, monkeys were prepared with H*" lesions that were brought forward to include the anterior entorhinal cortex and much of the perirhinal cortex (the H1 " 1 " lesion). The intention in this group was to reproduce as much of the H+A+ lesion as possible but to leave the amygdala intact. On delayed nonmatching to sample, the impairment associated with H*4 ' lesions was nearly as severe as that following H"A+ lesions (Figure 3) and significantly more severe than the impairment following either H*" or H*A lesions (Squire & Zola-Morgan, 1991). Thus, lesions of the cortex surrounding the amygdala, but not lesions of the amygdala itself, exacerbated memory impairment in monkeys following lesions of the hippocampal formation. The H4 " 1 " monkeys were also as impaired as №A+ monkeys on a second task: object-discrimination learning. The second test of the idea that the cortical regions surrounding the amygdala are important for memory was motivated by current understanding of the anatomical connections of the hippocampus and adjacent cortex (Figure 2). In particular, as described earlier, perirhinal and parahippocampal cortex are major routes by which information is exchanged between the neocortex and the hippocampal formation. Accordingly, monkeys were prepared with bilateral lesions limited to the perirhinal cortex and parahippocampal gyrus (PRPH) that spared the hippocampus, the amygdala, and the entorhinal cortex (Zola-Morgan, Squire, Amaral, & Suzuki, 1989). The white matter underlying perirhinal cortex was also transected in an attempt to remove other cortical input to entorhinal cortex. These monkeys were severely impaired on the three memory tasks they were given (delayed nonmatching to sample, object discrimination, and concurrent discrimination). In general, the impairment following PRPH lesions was similar to that observed following tfA+ lesions and H1 " 1 " lesions. Histological analysis showed that, as intended, damage had occurred not only to the perirhinal and parahippocampal cortex but also to projections to the entorhinal cortex from orbitofrontal cortex, superior temporal gyrus, insula, and cingulate gyrus. It is unlikely that the severe memory deficit after either PRPH lesions or H^ lesions resulted from indirect effects of these lesions on the function of the amygdala. This possibility merits consideration because perirhinal cortex does originate direct projections to the amygdala (Amaral, 1987; Van Hoesen

202 LARRY R. SQUIRE 1981). However, there are two difficulties with the idea that damage to these projections contributed to the memory impairment. First, removal of the amygdala itself had no effect on memory. Second, quantitative studies of emotional behavior have been carried out with the same operated groups that were given memory tests. The finding was that either partial or complete damage to the amygdala caused readily detectable changes in emotional behavior as evidenced by an abnormal tendency to approach or touch stimulus objects (Zola-Morgan, Squire, Alvarez-Royo, & Clower, 1991). Yet, monkeys with PRPH lesions exhibited normal emotional behavior. Indeed a double dissociation was found. Among six operated groups, the groups of monkeys with amygdala damage exhibited abnormal emotional behavior. Unless there was also hippocampal damage, memory was unaffected. Conversely, all operated groups with damage to the hippocampus or its associated cortex exhibited memory impairment. However, unless the amygdala was also damaged, emotional behavior was normal. The findings from PRPH lesions and H++ lesions, taken together with the finding of intact memory after circumscribed amygdala damage, strongly suggest that the severe memory impairment associated with large medial temporal lobe lesions (tTA* lesions) results from damage to the hippocampal formation and adjacent anatomically related cortex, not from conjoint damage to the hippocampus and amygdala. One important implication of these studies with monkeys is that the cortex adjacent to the hippocampus is not simply a conduit for funneling information from neocortex to the hippocampus. This conclusion follows from the finding that the PRPH lesion and the H4 " 1 " lesion produced a more severe memory impairment than the IF lesion and also from the finding that the H+ lesion produced a more severe impairment than the H lesion. Thus, it appears that information from neocortex need not reach the hippocampus itself for some memory storage to occur (Figure 4). The cortical structures adjacent to the hippocampus (entorhinal, perirhinal, and parahippocampal cortex) appear to participate with the hippocampus in a common memory function. This idea explains why memory impairment can be increased by lesions in structures adjacent to the hippocampus. These cortical structures in the medial temporal lobe are sites of convergent projections from widespread unimodal and polymodal association areas in neocortex, and these connections are reciprocal (Amaral, 1987; Van Hoesen, 1982). The entorhinal cortex itself (which projects directly to hippocampus) receives direct cortical input from a limited number of cortical areas. The perirhinal and parahippocampal cortices (and the other cortical regions that project to entorhinal cortex) receive information from and send information to a much broader extent of neocortex. Thus, the system as a whole is likely to be privy to much of the processing that occurs in neocortex. In summary, the findings from work with monkeys emphasize the importance for memory functions of the hippocampal formation and the surrounding cortex of the medial temporal lobe. Other recent work in monkeys and humans is consistent with this proposal (Friedman & Goldman-Rakic, 1988; George, Horel, Cirillo, 1989; Squire, Ojemann, Miezin, Petersen, Videen, & Raichle, in press; Van Hoesen & Damasio, 1987). It seems likely that the medial temporal lobe memory system influences memory primarily through its reciprocal projections with widespread areas of neocortex. In separate studies, damage to the major efferent system of the hippocampal formation, the fornix, and damage to the major diencephalic target of the fornix, the mammillary nuclei, had only mild effects on memory using the same tasks (Aggleton & Mishkin, 1985; Bachevalier et al., 1985; Zola-Morgan et al., 1989a). These latter findings do not describe the severity of memory impairment in any absolute sense, but they make the important point that the impairment after fornix section or mammillary nuclei lesions is less severe than after damage to the hippocampal formation. Another region of the brain that when damaged produces amnesia is the medial thalamus. Medial thalamic lesions in the monkey produce severe memory impairment (Aggleton & Mishkin, 1983). It is not yet entirely clear which thalamic nuclei must be damaged to cause amnesia (for a review, see Zola-Morgan & Squire, in press). The areas most often linked to memory functions are the medial dorsal nucleus, the anterior nucleus, the internal medullary lamina, and the mammillothalamic UNIMODAL AND POLYMODAL ASSOCIATIONAL AREAS FRONTAL LOBE TEMPORAL LOBE PARIETAL LOBE Figure 4. Schematic representation of the connectivity of the perirhinal and the parahippocampal cortices in the monkey brain. The width of the arrows corresponds to the relative proportion of cortical inputs arising from the areas indicated. EC - eatorhinal cortex; DC = dentate gyrus; SUB = subicular complex; CA3 and CA1 are fields of the hippocanpus proper. (From "Memory: Organization of Brain Systems and Cognition" by L. R. Squire, & Zo1» Mocgin, C B. Cave, F. Haist, G. Musen, and W Suzuki, 1990, Cold Spring Harbor Symposium on Quantitative Biology, 55, p. 1019. Copyright 1990 by Cold Spring Harbor Laboratory. Reprinted by permission.)

MEMORY AND THE HIPPOCAMPUS 203 tract (Aggleton & Mishkin, 1983; Graff-Radford, Tranel, Van Hoesen, & Brandt, 1990; Squire, Amaral, Zola-Morgan, Kritchevsky, & Press, 1989; Victor, Adams, & Collins, 1989; von Cramon, Rebel, & Schuri, 1985). Most of these thalamic regions have anatomical connections to either the hippocampal formation or the perirhinal cortex. It is also unclear to what extent diencephalic and medial temporal lobe pathology in humans and monkeys might produce different patterns of memory impairment (for two points of view, see Parkin, 1984; Victor et al, 1989). Although one would expect that these brain regions make different contributions to normal memory, each region may belong to a tightly linked functional system such that damage to any component causes rather similar kinds of impairment. Memory Impairment in Rats During the past several years, many points of contact have developed between work with rats and work with humans and nonhuman primates. In the rat, hippocampal lesions or lesions of related structures (fornix or entorhinal cortex) impair performance on a wide variety of memory tasks. These include spatial memory tasks, odor-discrimination learning, timing tasks, and discrimination tasks that require learning relationships between stimuli. One major focus of this work has been to characterize the kind of learning and memory that is impaired (see next section). Another focus has been to compare the effects of hippocampal lesions with the effects of lesions in adjacent structures. Studies directed at this second objective have obtained two important findings. The first pertains to the roles of the hippocampus and the amygdala in memory. The second pertains to the separate contributions of the structures and connections within the hippocampal formation. First, at least seven examples can be identified where hippocampal lesions or lesions of anatomically related structures produce an effect on memory, but amygdala lesions produce no impairment (Table 3). In addition, three studies have found that adding an amygdala lesion to a lesion of the hippocampal system did not increase the deficit beyond what was observed following the hippocampal lesion alone (Aggleton, Hunt, & Rawlins, 1986, Experiment 2; Eichenbaum, Pagan, & Cohen, 1986; Sutherland & McDonald, 1990). One important feature of the studies with rats is that amygdala lesions were typically produced stereotaxically. This procedure makes it possible to produce amygdala lesions without damaging cortical areas surrounding the amygdala. An apparent exception to this pattern of findings is a report that conjoint lesions of amygdala and hippocampus impaired performance on a task of object recognition, whereas separate lesions of hippocampus or amygdala had no effect, even when animals had to retain information up to delays of 60 s (Aggieton, Blindt, & Rawlins, 1989). This task was a modified version of the visual delayed nonmatching-to-sample task used with monkeys. Rats were rewarded for choosing the arm of a Y maze that differed visually from the starting arm. Multiple, removable arms were used so that on each trial rats saw one arm identical to the starting arm and a second arm that differed from the starting arm along several dimensions. Although one might expect from studies of monkeys that performance on such a task should be measurably impaired by hippocampal lesions alone (Mahut et al., 1982; Mishkin, 1978; Zola-Morgan et al, 1989a), rats with hippocampal lesions performed this task normally. Because hippocampal lesions alone did not disrupt performance on this task, it is difficult to interpret the impairment that occurred with larger lesions. One possibility, which has scarcely been explored, is that rats might approach some variants of the delayed nonmatching-to-sample task with a different strategy than nonhuman primates. For example, Sutherland and Rudy (1989) pointed out that this task could in principle be solved by two fundamentally different strategies (also see the note to Table 2 for the importance of strategy differences in how monkeys and humans accomplish pattern-discrimination learning). In any case, there is no evidence that amygdala lesions in rats impair performance on tasks that are also impaired by hippocampal lesions. The findings in rats are therefore in agreement with the findings from monkeys, namely that the hippocampus and related structures participate in a particular kind of memory function and that the amygdala is not part of this functional system. Indeed, work in both monkeys and rats suggests that the amygdala is important for other functions, including the acquisition of conditioned fear and the establishment of affective significance for neutral stimuli, as expressed, for example, by the development of conditioned responses that are directed toward conditioned stimuli (Davis, 1986; Gaffan & Harrison, Table 3 Effects of Lesions of the Hippocampal System or the Amygdala on Memory Tasks in the Rat Task Hippocampus Amygdala Reference Water maze Odor discrimination Timing of events Learning cue relationships Spatial alternation Nonspatial alternation Radial maze Sutherland & McDonald, 1990 Eichenbaum, Pagan, & Cohen, 1986' Olton, Meek, & Church, 1987' Sutherland, McDonald, Hill, & Rudy 1989 Aggleton, Hunt, & Rawlins, 1986; Aggleton, Blindt, & Rawlins, 1989 Raffaele & Olton, 1988" Becker, Walker, & Olton, 1980* Note. Plus sign indicates impairment; minus sign indicates no impairment. • These lesions damaged the fornix rather than the hippocampus itself

204 LARRY R. SQUIRE 1987; Gallagher, Graham, & Holland, 1990; Kesner, in press; LeDoux, 1987; Nachman & Ashe, 1974; Sutherland & McDonald, 1990). It is possible, too, that the amygdala has a more general role in forming associations between stimuli, for example, in making associations across modalities (Murray & Mishkin, 1985). However, when these ideas are based on amygdala lesions prepared by a direct surgical approach, the contribution of underlying cortical regions included in the amygdala lesions needs to be evaluated. The second important and anatomically relevant finding to emerge from work with rats is that the deficit associated with restricted hippocampal lesions can be increased by additional damage to anatomically related structures and fiber tracts such as the subiculum or the alveus (Jarrard, 1986; Morris, Schenk, Tweedie, & Jarrard, 1990). These findings are in agreement with the findings from monkeys that different levels of impairment can be produced depending on the extent of damage within the medial temporal lobe (e.g., the H+ lesion vs. the H++ lesion). As described earlier, the same is also true in humans (e.g., patient R. B. vs. H. M.). Multiple Memory Systems Progress in identifying the structures and connections that make up the medial temporal lobe memory system has been paralleled by gains in understanding how this system participates in memory functions. An important step in this achievement was the insight that the hippocampal formation is important for only a particular kind of memory. The implication was that memory is not a single entity but consists of multiple processes or systems. Converging evidence about the selective role of the hippocampal formation in memory is now available from rats, monkeys, and humans. It took time for the idea of multiple memory systems to become firmly established. In 1962, the severely impaired amnesic patient H. M. was reported to be capable of day-to-day improvement in a hand-eye coordination skill, despite having no memory for the practice sessions (Milner, 1962). Nevertheless, subsequent discussions of memory in general and amnesia in particular tended to set aside motor skill learning and to focus on the unitary nature of the rest of memory. Amnesia was considered to impair memory globally, with the recognition that an exception should be made for motor skills. Findings of unexpectedly good learning by amnesic patients on tasks not requiring motor skills were also reported many years ago. Specifically, patients performed well when the retention test provided partial information (e.g., fragments) about previously presented pictures or words (Milner, Corkin, & Teuber, 1968; Warrington & Weiskrantz, 1968, 1970, 1974, 1978). However, there were two reasons why these reports, and others that followed, did not lead to the idea of multiple memory systems. First, although the performance of amnesic patients was sometimes good, or at least better than might have been expected, it was often below normal levels. Accordingly, the data were open to a proportionality interpretation, namely, that some tasks are simply easier than other tasks or provide more sensitive measures of memory. It could therefore be argued that certain task conditions simpJy improve performance in normal subjects and amnesic patients alike. Second, even when amnesic patients appeared to perform normally, the data could be interpreted as evidence that amnesia is a retrieval deficit that can be reversed when the appropriate tasks are selected (Warrington & Weiskrantz, 1970; Weiskrantz, 1978). Subsequently, it was discovered that motor skills are just one example of a broader category of skill learning that is intact in amnesic patients (Cohen, 1984; Cohen & Squire, 1980; Squire, 1982). At the same time, the success of partial information at the time of retrieval in eliciting recall in amnesic patients came to be better understood (e.g., word stems like inc or mot— as cues for recently studied words). It turned out that only one kind of instruction yields normal performance (complete the stem to form the first word that comes to mind; Graf, Squire, & Mandler, 1984). With conventional memory instructions (use the stem as a cue to recall a recently presented word), normal subjects maintain their advantage over amnesic patients (Graf et al., 1984; Squire, Wetzel, & Slater, 1978). Intact performance by amnesic patients on such tasks, when indirect instructions are used, is now understood as an example of word priming, and a large body of work has accumulated with both normal subjects and amnesic patients in support of the idea that priming reflects a different kind of memory than the kind that is tapped in conventional memory experiments (Shimamura, 1986; Tulving & Schacter, 1990). The emergence of the idea that memory consists of different systems (Cohen, 1984; Moscovitch, 1982; Schacter, 1987; Squire, 1982; Tulving, 1985; Weiskrantz, 1987; Wickelgren, 1979) was influenced greatly by work with amnesic patients. In addition, experimental work with normal subjects was influential (for reviews, see Hintzman, 1990; Polster, Nadel, & Schacter, 1991; Richardson-Klavehn, & Bjork, 1988). Distinctions between kinds of memory can be found in earlier writings that reflect the traditions of developmental psychology (Bruner, 1969; memory with record and memory without record), psychology (Bergson, 1911; memory and habit), philosophy (Ryle, 1949; knowing how and knowing that), and artificial intelligence (Winograd, 1975; Winston, 1977; declarative and procedural). The tradition of work with amnesic patients explains why the idea of multiple memory systems led naturally to a consideration of what kind of memory depends on the integrity of the brain structures, including hippocampus, that are damaged in amnesia. In addition, the idea that the hippocampus might be involved in only one kind of memory appeared independently in the animal literature, on the basis of the selective effects of limbic lesions (Gaftan, 1974; Hirsch, 1974; O'Keefe & Nadel, 1978; Olton et al., 1979). The sections that follow suggest that the findings from humans and experimental animals, including rats and monkeys, are now in substantial agreement about the kind of memory that depends specifically on the hippocampus and related structures. This kind of memory has been termed declarative (Cohen & Squire, 1980) in the sense that one can bring to mind or declare the content of this kind of memory (for its earlier use in psychology, see Anderson, 1976). The term declarative was derived from work with human subjects and has been difficult to apply usefully to experimental animals. The problem is not that declarative memory seems to imply an ability to declare one's knowledge verbally. Indeed, declarative memory includes mem-