BEHAVIORALAND NEURALBIOLOGY57, 2--36 (1992)

REVIEW The Hippocampus

What Does It Do? 1

HOWARD EICHENBAUM AND TIM OTTO

Department of Psychology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599 AND

NEAL J. COHEN Beckman Institute and Department of Psychology, University of Illinois at Urbana-Champaign, Champaign, Illinois 61820

It seems like a simple and straightforward question, "What does it do?" It is the kind of question that colleagues who work on a different issue within neuroscience might ask about the hippocampus, and for which they might justifiably expect an equally straightforward answer. To those who actually devote their research efforts to understanding hippocampal function, however, the answer is anything but straightforward. The simplest answer to the question, "What does the hippocampus do?" is "Memory." That the hippocampus, together with associated medial temporal-lobe structures (collectively, the hippocampal system), plays a critical role in memory has been known with certainty ever since Scoville and Milner's (1957) report of profound amnesia in the patient H.M. following bilateral surgical resection of hippocampal system structures. However, from the very first report of this patient, it was clear that the hippocampal system cannot play a crucial role in all aspects or types of memory, and that it cannot support any aspect or type of memory by itself. Subsequent work with H.M. and other amnesic patients has served to underline such a conclusion. Moreover, despite the important insights derived 1 Preparation of this manuscript was supported in part by NIH Grant NS26402, NIA Grant AG09973, ONR Grant N0014-91-J1881 and NSF Grants BNS-8721157 and BNS-8810095 to H.E. Please address correspondence and reprint requests to Dr. H. Eichenbaum, Department of Psychology, University of North Carolina, CB 3270 Davie Hall, Chapel Hill, NC 27599. Fax: (919) 962-2537.

0163-1047/92 $3.00 Copyright © 1992 by AcademicPress, Inc. All rights of reproduction in any form reserved.

from intensive neuropsychological studies of H.M. (e.g., see Milner et al., 1968; Corkin, 1984) as well as of other amnesic patients (e.g., see Squire, 1987; Parkin, 1987; Mayes, 1988 for major reviews), such work cannot by itself provide a truly comprehensive account about the functional role of the hippocampus in memory. Studies aimed at an understanding of memory not only in humans but in animals as well, and across a wide range of neurobiological analyses, will be required in order to answer each of the several, more focused questions concerning the basic function of the hippocampus that have been posed in the field. Four such focused questions that are the targets of the present review are: (1) What is the f u n d a m e n t a l nature of memory supported by the hippocampal system, and is it the same kind of memory in humans as in various animal species? (2) What is the contribution of the hippocampus itself versus that of other closely connected brain structures usually damaged along with the hippocampus in amnesic subjects? (3) How is information encoded by the activity of hippocampal neurons in carrying out that structure's role in memory processing? (4) Does the hippocampus actually store memories and, if so, what are the storage rules and mechanisms? Readers familiar with research on the hippocampus will recognize that each of the above questions represents an active research agenda, and in each area there has been significant recent progress. However, these agendas are pursued largely as separate themes; only rarely has there been systematic efforts to integrate the

WHAT THE HIPPOCAMPUSDOES findings across the different agendas. The account offered here is an attempt at just such an integration.

Do We Need Another Theory of Hippocampal Function? Much of our own collaborative research effort to t:his end has focused specifically on the question of the kind of memory with which the hippocampus is critically involved across species. Starting initially with a goal of providing some resolution to apparent discrepancies between the basic phenomena of human and animal amnesias and between various theoretical positions about hippocampal function across species, we have sought to characterize the fundamental properties of hippocampal-dependent versus hippocampal-independent memory in a way that has cross-species validity. It is important to note that the following treatment is not yet another theory about the functional role of the hippocampal system, but rather an elaboration of one existing theory (based on the procedural-declarative memory distinction) that permits it to be extended to account for other properties or aspects of hippocampal function emphasized in alternative theories. We believe that many of the competing alternative theories successfully, if not always completely, account for the data set they address. However, a truly comprehensive view of the functional role, and of the properties and mechanisms, of the hippocampus has remained out of reach because, we believe, the alternative accounts have considered only a limited domain of the empirical data that bear on hippocampal function. Our strategy has been to seek common threads among existing theories and their respective supporting data. As will be described in detail below, the conclusion derived from this effort is that an existing theory that has been very fruitful in accounting for the data on human amnesia--the view that the hippocampal system mediates declarative memory (Cohen and Squire, 1980; Cohen, 1981, 1984; also see Squire and Cohen, 1984; Squire, 1987; Squire et al., 1989)--can be extended to account for the diata across species and across research agendas. In the following sections of this paper we first outline our elaborated view of hippocampal involveraent in the declarative memory system and describe how this view accounts for the characteristics of amnesia in humans, nonhuman primates, and rodents. We then review the progress in the field regarding each of the remaining three specific ques-

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tions posed above, considering the implications for each of these questions of the theory of hippocampal memory we offer. For each, the goal is to integrate the findings and ideas across levels of neurobiological analysis and across various species. HIPPOCAMPUS, DECLARATIVE MEMORY, AND AMNESIA IN HUMANS AND ANIMALS We have proposed that the hippocampus and related structures (the hippocampal system) are critical for a declarative memory system that is to be distinguished from a hippocampal-independent procedural memory system (Cohen, 1981, 1984, 1985; Cohen & Eichenbaum, 1991; Cohen & Squire, 1980; Eichenbaum et al., 1986a, 1988, 1989a, 1991). Declarative memory is responsible for the accumulation of facts and data derived from learning experiences. This system stores the outcomes of processing by the (neocortical sensory and limbic) modules that feed the hippocampal system. As described by Cohen (1984), declarative memory is represented in such a way as to permit the processing and storage of comparisons among learning events and among the items within learning events. Elaborating this idea, the critical property of declarative memory that permits this is the encoding of memories in terms of the relations among multiple items and events. Thus the nature of declarative representation is fundamentally relational, and can be envisioned as a multidimensional network of memories--a memory "space"--entailing a highly interconnected network with connections among informational elements characterizing possible relations (Eichenbaum et al., 1991). A consequence of the relational nature of declarative representation, and a second defining property of declarative memory, is that the stored representations are promiscuously accessible to, and can therefore be activated by, the brain's various processing modules; and they can be expressed independent of the circumstances in which the information was initially acquired (Cohen, 1984). We have suggested that a central property of relational networks is that activation of a subset of informational nodes leads to activation of other informational elements, including both those previously activated at the same time during the learning experience and those only indirectly connected with the activated node, revealing all manner of relations among the stored items. In this way, declarative memories can be activated by all manner of external sensory or even purely internal inputs, regardless

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of the current context. This in turn gives rise to the final critical property of declarative memory, namely representational flexibilitymthe ability of declarative memories to be manipulated and used flexibly to guide performance under an enormous range of testing conditions, including those differing significantly from the circumstances of original learning. Thus, declarative memory is to be considered as inherently generative, conferring the ability to construct novel responses in new situations (Eichenbaum et al., 1991). By contrast, procedural memory as instantiated in brain systems operating independently of the hippocampal system is fundamentally dedicated and inflexible. Storage of procedural memory resides within and remains inextricably tied to the processing modules that were engaged during initial learning. This type of memory involves not the storage of outcomes of processing events, but rather a tuning and modification of the processors engaged during the processing events (Cohen, 1984). Thus, procedural memories are fundamentally individual representations, mediating the tuning of processors or biasing of responses in reaction to individual processing events, as well as the learned significance of individual stimuli, stored independently from procedural memories of other stimuli, associations, or processing events. As a result, procedural memory can be revealed only in the restrictive range of stimuli and context in which it was originally acquired. This type of representation is therefore inflexible, in that it is accessible only to the processing modules that were engaged during learning, and only when they are again engaged; it cannot be manipulated or used in novel circumstances. The representations therefore can be expressed or otherwise exert their influence only during a repetition of the original learning event or other circumstances that reinstantiate the original processing elements. Having outlined the fundamental distinction between procedural and declarative memory systems, we turn now to describing how this view accounts for the pattern of sparing and loss of memory function in h u m a n and animal amnesias following damage to the hippocampal system. Before we do so, however, we must raise two issues about the relationship of the theory to behavioral performance data. First, few if any real-world learning and memory performances are mediated exclusively by either declarative or procedural memory; rather, the two systems ordinarily operate together to support the great majority of behavioral performances. Indeed, so seamlessly do the two systems usually operate together that it has required extensive research on

the behavioral consequences of selective damage to the declarative system in order to infer the two systems' separate contributions to memory. What this means is that we have to move into the laboratory to provide adequate tests of the theory, using carefully designed tasks that depend critically on only one (either one) of the two memory systems. Even in the laboratory, however, simple tests of the theory are difficult. It is often the case that procedural and declarative memory systems can each drive performance on a given task. Indeed, other accounts distinguishing the hippocampal-dependent and hippocampal-independent memory systems have also suggested that either system is capable of mediating most learning tasks, thereby seriously complicating our ability to dissociate them experimentally (e.g., Mishkin & Petri, 1984). Furthermore, we argue that the representational demands of a given task--the extent to which it favors or requires declarative versus procedural m e m o r y m depends critically upon how a subject views the task and what learning strategy is then chosen. In the terminology of the theory, there are any number of situations in which learning can be adequately demonstrated by either engaging processors that have been tuned, biased, or primed by their previous experience, making them more optimally adapted (faster and less error prone) to the situation at hand, or, alternatively, gaining access to and flexibly using the stored outcomes of previous processing events to guide performance in a cognitively mediated way. Accordingly, an empirical result showing either impaired or spared learning in subjects with hippocampal system damage on any particular memory task cannot, by itself, provide a definitive test of the procedural-declarative theory--it must first be ascertained which learning strategies were adopted and hence whether declarative memory or procedural memory was invoked. As such an admonition would suggest, results with many categories of task should be decidedly mixed, sometimes showing impairment and sometimes showing sparing after hippocampal-system damage, depending upon the specific variant of the task that was used and the representational demands it presented. As it turns out, this is indeed the case, as is illustrated below.

So, How Can the Theory Be Tested? The most fruitful approach to testing the theory involves a two-phase assessment. First, one should employ a set of variants of a given behavioral paradigm; these variants should differ systematically

WHAT THE HIPPOCAMPUSDOES iLn that each is likely to confer an advantage to one system or the other, based on the properties outlined above or on other operating properties that differentiate the declarative and procedural systems. However, this assessment by itself cannot provide definitive results because it is not possible in ad'vance to guarantee that each task variate has in :Fact conferred a significant advantage to the appropriate memory system. Thus, second, one must employ some form of "probe" testing that requires subjects to apply the acquired memories to solve novel :problems; such probe tests should be designed to assess the qualitative nature of the memory representation, demonstrating either its flexibility, the critical property associated with declarative representation, or its inflexibility, as defines procedural :representations. Examples of the successful application of this approach are given below. A second issue about the relationship of the theory •to behavioral performance is that, in addition to ,differences in the nature of the representations sup:ported by procedural versus declarative memory-,differences that we take to be fundamental to the :proposed distinction--there are other differences of importance between these two memory systems in terms of their operating characteristics. As will be ,discussed in more detail below, the systems differ in terms of the incremental strength of the memory "trace" produced by exposure to each to-be-remembered item and in the persistence (decay rate) of such traces. The declarative system is apparently capable of adding full-fledged memories (i.e., making relatively large-scale changes) to relational networks after but a single exposure, with such memories persisting for long durations (hours, days, or more). This conforms with our description of declarative memory as storing the outcomes of processing events, with those memories that are being woven into an existing organization of items in memory space. The ability to retrieve or gain access to any given declarative memory, it should be noted, depends in large measure on the strength and number of its connections to other items in relational networks. This can be significantly increased, thereby increasing the functional persistence of the memory, with repeated exposures to the same item. In most common learning tasks, procedural representations are acquired as relatively small, incremental tunings, biasings, or primings of various processors. The persistence of each individual change can be potentially quite substantial, depending upon the degree to which the tunings, biasings, or primings produced in the same processor by subsequent processing events "pushes" the system in a similar di-

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rection. If, however, subsequent processing events tend to bias the system in competing directions, tuning it toward optimization for different stimulus items, then the persistence of the original trace will be quite temporary. Also, in a few specialized adaptive learning situations, e.g., the acquisition of flavor aversions or conditioned emotional responses, robust procedural learning can occur in a single trial. The biases or tuning of the system that occur here are not likely to be overwritten by immediately subsequent experiences and will show strong persistence. Thus strength and persistence characteristics by themselves cannot always distinguish the two memory systems. Indeed, as will be described below, whether the performance of the two systems differ with regard to strength and persistence characteristics varies across paradigms depending on idiosyncratic properties of the category of learning materials and the species tested. In any particular type of learning, only the two-phase assessment outlined above can provide conclusive evidence about which system, if either, prevails. We take the fundamental distinction between declarative and procedural memory systems to be in terms of the representations they support--declarative memory supporting relational representations capable of being used flexibly in novel situations and procedural memory supporting inflexible individual representations--and thus find the most useful evaluations of the distinction to include manipulations of the representational demands. However, because quantitative differences in the memory strength and persistence characteristics can also help distinguish these systems, they can be exploited to some extent in experimentally dissociating hippocampal-dependent and hippocampalindependent memory. McClelland and Rumelhart's (1986) connectionist model of memory and amnesia is interesting in this light: They offered the "limited increment hypothesis" of amnesia, in which it was proposed that damage to the hippocampal system reduced or limited the increments to memory that could be produced in response to a learning event. They argued that this would markedly disable the ability to add new facts to memory on the basis of a learning event, because this would require large changes of or increments to memory networks; but it would not harm the ability to gradually and incrementally shape performance in accordance with multiple experiences, because this would require only modest changes or tunings of existing memory. This view is easily interpreted (or reinterpreted) in terms of the operating characteristics of declarative and procedural memory, respectively.

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It turns out that work on humans, monkeys, and rats has differed with regard to which aspect of the distinction between procedural and declarative memory has been tapped by the experimental manipulations. Recent work on h u m a n amnesia has focused primarily on the flexibility of memory in normal controls versus amnesic patients; most of the recent work on amnesia in monkeys has focused on the issues of strength and persistence differences; and most of the work on amnesia in rats has focused on relational versus individual representations. In all three literatures, however, the difference between normal and amnesic memory abilities, and between impaired and spared memory performances in amnesic subjects, can be explained in terms of the distinction between declarative and procedural memory. We turn now to a brief discussion of each of these three literatures. Human Amnesia

Early work with H.M. stressed the pervasiveness and global nature of his impairment. After removal of most of the hippocampal formation and its associated medial temporal lobe structures (the amygdala and most of the hippocampus and parahippocampal cortical areas), this patient had a profound impairment in new learning causing "forgetting of the events of daily life as quickly as they occur" (Scoville & Milner, 1957). He demonstrated impairment in nearly every learning and memory test that could be devised for him, including recall or recognition of "words, digits, paragraphs, faces, names, maze routes, spatial layouts, geometric shapes, nonsense patterns, nonsense syllables, clicks, tunes, tones, public and personal events, and more" (Cohen, 1984). Memory was impaired regardless of the form of the to-be-remembered materials and regardless of the modality of their presentation. This is why the work with H.M. sent such a clear message that the hippocampus is critical for memory. Yet, even the initial report of H.M. (Scoville & Milner, 1957) indicated that the hippocampus was important to only certain aspects of memory. He still had intact perceptual, cognitive, linguistic, and motor capacities: He could comprehend and respond appropriately to objects in the world; read, write, and engage in reasonable conversations; reason and think; solve crossword puzzles and watch television. H.M. also showed normal retention of much of the remote autobiographical memories he had acquired years before the surgery, i.e., of his childhood experiences. Thus, he had intact access to represen-

tations of remote memory. H.M. further demonstrated an intact primary- or immediate-memory capacity, permitting him to retain the series of digits comprising a telephone number, and recite the list in order, if tested immediately. However, once he was distracted, H.M. rapidly forgot the numbers, and even the experience of having heard the numbers, thereby revealing an inability to establish or maintain new, retrievable long-term memories. What about within the domain of new learning and the storage of new long-term memories? More recent work with amnesic patients has shown conclusively that only certain aspects of new learning or of long-term memory are impaired. This work has indicated a set of preserved learning and memory capacities that help to separate forms of hippocampal-independent and hippocampal-dependent memory representation. Thus, despite the profound impairment shown by H.M. and other amnesic patients in explicitly remembering their learning experiences, these patients are able to take advantage of these same learning experiences implicitly in their performances. They are intact in acquiring and expressing new motor, perceptual, and cognitive skills; they can exhibit normal sensory adaptations; and they have normal "priming" of perceptual and lexical stimuli (for reviews of the set of preserved capacities, see Cohen, 1984; Schacter, 1987; Shimamura, 1986; Squire, 1987; Tulving & Schacter, 1990). For example, having been exposed to some words or line drawings during an initial study phase, amnesic patients show the same facilitation of performance for, biasing of performance toward, or priming of those previously studied items, when the subsequent test requires identification, naming, fragment completion, or categorization of a set of stimuli that includes the previously studied ones. Such priming effects occur despite the patients' impaired recall or recognition of the repeated materials and impaired recollection of the experiences responsible for the priming (e.g., Graf, Squire, & Mandler, 1984; Warrington & Weiskrantz, 1970; and many others cited in the above reviews). Likewise, patients asked to read mirror-reversed text across multiple trials show a normal acquisition and retention of skill, getting better with practice, despite being unable to explicitly remember the actual words or even the learning experiences (Cohen & Squire, 1980; Martone et al., 1984). One important point to make is that impairment or sparing can be observed with the very same learning materials, depending upon exactly what the subject is instructed to do or chooses to do with the materials. This is exactly the case for the prim-

WHAT THE HIPPOCAMPUSDOES ing effects discussed just above. Consider the Graf et al. (1984) study, involving the use of two different performance tasks to test "retention" of words whose initial three letters also formed the initial stem of several other words but were not on the study list (e.g., the to-be-presented words might include motel and cyclone, words whose initial three letters also ibrm the stems of mother and cycle). Subjects were presented with a list of such words to study and were then tested for memory with the three-letter stems (e.g., mot and cyc). The findings were that when subjects were tested in a cued recall condition-i.e., when their instructions were to use the word stems as cues to help them recall the items that had been on the list---amnesic patients' performances were markedly impaired; but when the same subjects receiving the same study items and the same stems were tested in a word completion condition i.e., when their instructions were simply to report "the first word that comes to mind" that completes each stem, the patients performed as well as normal subjects. These results can be restated as fbllows: Amnesic patients were impaired on verbal list learning when given a novel test that encouraged active searching for representations and comparing and matching them to prompts ("Which word from the list began with this word stem?"), but they could access the same words unconsciously or implicitly, by taking advantage of the tuning or biasing of the word recognition processes engaged during initial learning, when now asked to reengage those processes when prompted by the same word stems ("What is the first word that comes to mind that begins with this word stem?"). The spared and impaired memory performances in amnesia can be understood within the procedural-declarative account, by considering the representational demands of the tasks with respect to the representational properties of the two proposed memory systems, just as we have done in the Graf et al. example above. The examples of performance in which amnesic patients are profoundly impaired, especially the explicit remembering tasks of recall and recognition memory, depend critically upon the active searching and comparing mechanisms of the declarative system, supported by its fundamentally relational representation; whereas the demonstrations of spared learning in h u m a n amnesia involve the reactivation at test time of identical neural mechanisms engaged during the original experience. In some formal tests of memory, such as paired associate learning, demands for relational representation and/or representational flexibility--and

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hence declarative memory--are immediately evident. However, in other formal and many everyday situations in which impairment is observed, these fundamental properties of declarative memory are evident only after more detailed consideration of the processing events associated with normal memory performance. One illustrative example, perhaps, is the recall of autobiographical memories ("What did you have for breakfast this morning?"). The typical answer generated involves conscious reflection upon the morning's events leading to the identification of the particular representations that define which food was eaten, and ultimately producing an explicit oral description of those foods. Such a memory search engages neural processing devices (primarily linguistic ones) that are quite distinct from those visual, olfactory, gustatory, and motor processes engaged during the breakfast event, and serves as a prime example of the fundamentally promiscuous nature of the processing events required for the everyday verbal recall of facts and events. That amnesic patients would be impaired on such tasks, then, is understood quite directly within the procedural-declarative framework. Similarly, the inability of amnesic patients to recollect their previous training experiences, or to have awareness of the linkage of their preserved priming or skill learning effects to specific previous training experiences, results from the same absence of hippocampal-mediated flexible representations. Stated most generally, deficits are observed in the conscious recollection of and verbal reflection upon stored memories because such performances have the same demand as explicit remembering tasks for comparing and contrasting items, supported by relational representation, and for the expression of memory by neural processing systems distinct from those used in the learning experience, supported by representational flexibility, both properties exclusively of declarative memory. Conversely, in each of those situations of spared learning that involves the biasing of performance toward, or priming of, previously studied items, the engagement of processing mechanisms identical to those activated during initial exposure is evident. A particularly good example illustrating the capacities of the spared procedural representation under conditions that reengage the relevant processing modules is an unusual method for assessing simple picture recognition. Thus, although memory for pictoral scenes is impaired in h u m a n amnesics under conventional recognition testing conditions where the patients require many times the normal expo, sure to obtain reasonable performance levels (Hu-

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EICHENBAUM, OTTO, AND COHEN

100%

HippocampalIndependent Immediate

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FIG. 1. Idealized strength and persistence characteristics for a single exposure to a visual object in monkeys. LTM, long-term memory.

bert & Piercy, 1979; Squire, 1981), they demonstrate strikingly good retention without requiring any extra exposure when the retrieval conditions gradually replicate the original perceptual identification process (Milner et al., 1968; Warrington & Weiskrantz, 1968; for further discussion, see Eichenbaum & Cohen, 1988). Furthermore, in those experiments where performance on such tasks has been tested under conditions where even superficial aspects of the stimuli are altered (e.g., the font of printed verbal cues), recognition falls dramatically in amnesic subjects. This "inflexibility" of such spared memory representations, here considered a fundamental property of individual representations, has also been stressed in other accounts of amnesia in humans (see Schacter and Tulving's discussion of hyperspecificity [Schacter, 1985; Tulving & Schacter, 1990]).

The Nonhuman Primate Model of Amnesia Significant success has been achieved in developing a nonhuman primate model of h u m a n amnesia, using a specific, carefully selected set of behavioral tests (e.g., Gaffan, 1974; Mishkin et al., 1984; Squire et al., 1988; Zola-Morgan & Squire, 1985). The set of tasks largely involves three-dimensional objects as memory cues. In one type of task, called delayed nonmatch to sample, subjects are exposed to an object once and then, after a delay, asked to recognize the object by indicating the unfamiliar in a two-choice presentation display. A second type of task is based on the object discrimination paradigm in which one or more pairs of objects is presented repeatedly at a predetermined interval, with the same object(s) always considered to be "pos-

itive"; responses to this (these) object(s) are always rewarded. A third type of task involves motor skill learning across multiple trials, entailing manipulation of a lifesaver candy along a bent rod. On this set of tasks, h u m a n amnesic patients and monkeys with hippocampal system damage perform comparably: Both are intact in acquiring individual object discriminations and both show spared acquisition of motor learning; both are impaired on delayed nonmatching to sample, acquisition of concurrent object discrimination, and delayed retention of object discriminations. In addition, retention of object discriminations learned well before, but not just before, hippocampal damage is spared in monkeys, similar to the sparing of memories acquired remotely before the onset of amnesia in humans (Zola-Morgan & Squire, 1990). These data are fully consistent with the procedural-declarative distinction outlined above. For acquisition of motor skill and individual object discriminations, in which learning is manifested as a gradual improvement across trials on the same performance measure in response to the same stimulus presentations, successful performance could be accomplished by gradual tuning, biasing, or priming of the relevant perceptual operations and motor programs through repeated experience. This is exactly the set of conditions for which the hippocampalindependent procedural memory system is sufficient. Zola-Morgan and Squire (1990) have offered precisely this interpretation of these data. By contrast, the delayed nonmatch to sample task and delayed retention or concurrent learning of object discriminations encourages the noting, storing, and utilizing of relationships among stimuli presented at different times in different locations. This strategy requires the use of the relational representation we propose as characterizing declarative memory, and hence would be expected to be impaired following hippocampal system damage. Note, however, that the specific pattern of sparing and loss on the object memory and object discrimination learning tasks owes much to the selection of testing intervals that take advantage of differences between hippocampal-dependent and hippocampal-independent systems in the strength and persistence of object-cued memories (Gaffan, 1974; Mishkin et al., 1984), and thus says more about these characteristics of declarative memory than the qualitative nature of declarative representation (but for two exceptions discussed below). Three properties seem critical here: First, both intact and amnesic monkeys can make use of hippocampal-independent immediate or short-term memory to

WHAT THE HIPPOCAMPUSDOES support performance in short-delay conditions (see Fig. 1). Hippocampal amnesia spares such performance across species. Second, the hippocampal-dependent memory system also develops a strong representation of these 3D objects lasting for up to :hours after only a single exposure. This is profoundly impaired in amnesic monkeys. The hippocampal-independent system, preserved in amnesia, develops only a weak representation after a single ,exposure to these 3D objects, although its maintenance can outlast that for the hippocampal-dependent trace in these paradigms (see Fig. 1). Third, both :forms of memory show enhancement of strength by repetitions given within their survival time, although the benefit shown by the hippocampal-independent procedural system is only gradually incremental. These increments are reflected both in terms of performance level and persistence. These memory strength and persistence characteristics permit us to understand the specific pattern of sparing and impairment observed in monkeys with hippocampal damage: They show normal performance at delays supported by immediate or shortterm memory; impairment in performance at delays :for which the maintenance of hippocampal-dependent memory would confer an advantage; and no impairment in performance when the objects are repeated at delays longer than the period effectively bridged by hippocampally mediated representation. :Let us consider the empirical findings. In various •tests of delayed (non)matching, amnesic monkeys and intact monkeys perform comparably in remembering novel objects across delays of several seconds; but, lacking a hippocampally mediated memory that :persists for many minutes or hours, amnesic mon:keys show impaired performance for the longer delay conditions. Likewise, on concurrent object-discrimination learning with massed practice, amnesic :monkeys, with no hippocampal-mediated capacity :for maintenance of object memory between repeated ,exposures to cues spaced at a few minutes (well within the persistence characteristics of that system), show impaired acquisition compared to normal :monkeys. Furthermore, even a small amount of '.massed practice on single object discriminations results in strengthening of hippocampal-dependent memory, extending its duration to the periods required for success in delayed testing; amnesic mon]keys, with only a gradually incrementing hippocampal-independent memory, are impaired. Finally, 'when very long delays (24 h) are inserted between repetitions of cues in spaced concurrent-object discrimination learning, i.e., when practice is spaced too far apart for the advantage usually conferred

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by the hippocampal system in memory maintenance to be applicable, amnesic monkeys perform as well as normal animals. It should be noted that the magnitude of differences in the strength and persistence of hippocampal-dependent versus hippocampal-independent memory is likely to vary significantly across learning materials and across species. Thus, within monkeys, these differences may be much smaller in discrimination learning involving two-dimensional patterns than in discrimination learning involving three-dimensional objects; for object discrimination learning, these differences may be much larger for humans than for monkeys (see Squire et al., 1988). In rats, the persistence of memories for single exposures to colors, local environmental cues, odors, and spatial positions differs for the hippocampaldependent and hippocampal-independent systems (for references see below), whereas persistence of memories for single exposures to 3D objects may not (Rothblat & Kromer, 1991). In addition, the degree of preoperative training may be an important factor even in tests of recent memory (e.g., Bachevalier et al., 1985; Barnes, 1988). The bulk of the data on the effects of hippocampalsystem damage on object recognition and discrimination learning in monkeys is well explained by differences in strength and persistence of declarative and procedural representations, as discussed in this section. However, there are at least two other lines of work that have explored the nature of hippocampal-dependent and hippocampal-independent memory representation in monkeys, more akin to the work in h u m a n amnesia discussed earlier in this paper. In a series of studies, Gaffan and colleagues (Gaffan & Harrison, 1989; Murray et al., 1989) have shown that object discrimination in monkeys with hippocampal system damage can be either impaired or spared depending on whether or not successful performance demands processing complex configurations of objects and background cues. Monkeys with hippocampal system damage performed as well as normal subjects when the reward assignments of objects were contingent on the place in the test room where the cues were presented, but were severely impaired when object reward assignments depended on the configuration of the cues within backgrounds composed of the same stimuli. In the other line of work, the nature of the memory representation supporting a version of object discrimination learning was explored. Monkeys with hippocampal-system damage were initially intact in object-pairs discrimination learning; in a later probe test, however, their memory was markedly impaired when the

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same objects were presented individually, as opposed to the pairings used in the original study context (Saunders & Weiskrantz, 1989), suggesting that the normal a n i m a l s - b u t not the amnesic ani m a l s - h a d access to the sort of relational representations we propose as characteristic of declarative memory. The "inflexibility" of the hippocampalindependent representations to which amnesic monkeys are restricted was stressed in Saunders and Weiskrantz's (1989) account of these findings as well as in Mishkin et al.'s (1984) account of amnesia in monkeys. These findings, and the interpretations offered, find a comfortable fit within our characterization of declarative and procedural memory systems offered above as an account of h u m a n amnesia, and also closely parallel our work with rodents, described next.

Rodent Models of Amnesia The work on rodent models of amnesia has for some time now been explicitly addressed at understanding the contents and nature of hippocampal memory representation through studies of impaired versus spared learning capacities following hippocampal system damage. Unfortunately, however, this literature is not easily compared to that on h u m a n amnesia (or the work on monkeys), and there remains a disturbing lack of consensus even within the rodent amnesia literature. Thus, there has been any number of differing and competing characterizations offered to distinguish between hippocampal-mediated and nonhippocampal-dependent memory systems, respectively: "place learning" versus "taxon learning" (O'Keefe & Nadel, 1978; O'Keefe & Nadel, 1991); "contextual encoding" versus "learning along the performance line" (Hirsh 1974), learning of "external context attributes" versus acquiring "rules" (Kesner, 1984), "confignral association" versus "simple association" (Sutherland & Rudy, 1989), "working memory" versus "reference memory" (Olton et al., 1979), and "representational memory" versus "dispositional memory" (Thomas & Gash, 1986). The lack of consensus seems apparent to even casual inspection. It is difficult, for example, to see what might be common between such different (and prominent) characterizations of the amnesic deficit as an impairment in place learning (entailing the ability to construct, maintain, and make use of spatial representations or "maps" in memory) and an impairment in working memory (involving the storage of information that is relevant only for the current trial); the former implicates memory for a particular

kind of information or content, whereas the latter implicates memory for information from a particular timeframe or temporal context regardless of its actual content. Yet, upon more careful inspection, two themes seem to emerge from among these theories, suggesting some fundamental properties of hippocampal memory that are compromised in rodent amnesia. Importantly, from the point of view of attempting to synthesize the rodent amnesia work with work on h u m a n and primate amnesia, these two themes are well captured by and explainable within the procedural-declarative framework. One theme can be seen by starting with the place learning or cognitive mapping view of hippocampal function in rodents. This view can be understood to emphasize the role of the hippocampal system in memory for spatial relations among environmental cues; animals with damage to this system must use "taxons" to guide their performance in the absence of internally represented "cognitive maps" of the environment. If we broaden this view, from the claim that hippocampal representation is for specifically spatial relations, to the position that hippocampus is crucial for representing configurations among perceptually independent cues, both spatial and nonspatial relations alike (see Cohen & Eichenbaum, 1991), then the place learning or cognitive mapping theory can be synthesized with accounts that propose a critical role for the hippocampal system in the creation of configural cues from cue elements (Sutherland & Rudy, 1989; Sutherland et al., 1989) or in learning dependent on conditional or contextual cues (Hirsh, 1974; Winocur & Olds, 1978). The second theme can be seen by considering the proposals focusing on hippocampal participation in comparisons of items in the current perceptual domain to representations stored earlier. Gray made this notion explicit in his account of the hippocampus as a "comparator" (Gray, 1979; see also Gabriel et al., 1980) and this view has been tied to the maintenance characteristics of hippocampal involvement (Gray & Rawlins, 1986). Furthermore, a comparator operation would seem to be implicit in accounts of hippocampal system participation in recognition (Gaffan, 1974) and working memory (Olton et al., 1979), two paradigms in which events are temporally tagged so that stimuli presented later can be matched to their representations in choice decisions. Attempting to synthesize these two themes, hippocampal system function as critical for learning configurations and as critical for temporal tagging

WHAT THE HIPPOCAMPUSDOES and matching, we arrive at the common requirement for comparison and manipulation of representations according to significant relationships among perceptually independent stimuli presented either at the same time (configuration learning) or sequentially (temporal tagging). Animals with hippocampal system damage are impaired on tasks involving either of these two types of fundamentally :relational processing. Conversely, what characterizes each view of the learning capacities spared in animals with hippocampal system damage is the :intact ability to process stimuli individually, as opposed to relationally, and to learn the significance of individual stimuli, without reference to other :items in memory. This distinction between relational and individual representation, offered as a characterization of hippocampal-mediated versus nonhippocampal-dependent memory in rats, is a ,critical aspect of the declarative-procedural account offered at the outset of this paper. As such, it thus permits the bridging of human, primate, and rodent amnesias, and it goes a considerable distance toward accomplishing the goal we articulated at the outset of characterizing the fundamental properties of hippocampal and nonhippocampal memory systems in a way that is applicable to a variety of animal species. The utility of characterizing the rodent amnesia data in terms of relational versus individual representation, and the connection of this account to the declarative versus procedural distinction, is illustrated with a few examples of our collaborative 'work in rats, described next.

The hippocampal system and relational representation. To assess the importance of relational representation to the hippocampal system's involvement in learning, we focused on the capacity of intact rats versus rats with disconnection of the hippocampal system via fornix transection (FX) in 'variations of odor discrimination and place learning paradigms. We selectively manipulated the demand for relational processing by developing variates of these paradigms that used identical olfactory or distal visual cues (for odor discrimination and place learning tasks, respectively) but emphasized or hindered comparison between those cues (Eichenbaum et al., 1988, 1990). In experiments on odor discrimination learning we either presented odor cues simultaneously and in close spatial juxtapo,~ition, requiring a response selection between equivalent left/right choices; or we presented odors successively across trials, hindering stimulus comparison and requiring only completing or dis-

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continuing the stimulus sampling behavior, thus eliminating the response choice. Consistent with predictions from the relational representation hypothesis, FX rats were severely and persistently impaired on a series of simultaneous odor discrimination problems that differentially encouraged a relational representation (Fig. 2A, left). In striking contrast, FX rats were equivalent or even superior to normal rats in acquiring the same series of discrimination problems under the conditions of the successive discrimination task, for which individual representations were encouraged (Fig. 2B, left; see also Eichenbaum et al., 1986a; Otto et al., 1991a; Staubli et al., 1984). In a parallel assessment of relational representation in place learning, we employed the Morris water maze paradigm in which, over successive trials, rats progressively require less search time to find an escape location identified only by distal visual cues (Eichenbaum et al., 1990). We found that when different starting points were used on successive trials, encouraging rats to represent the place of escape by comparisons among the positions of extramaze stimuli and the starting position across trials, FX rats were severely and persistently impaired (Fig. 2A, right). In contrast, when we eliminated the need to compare views across different starting positions by releasing the rat from the same starting position on each trial (the "constant start" condition) thereby encouraging performance to be guided by the acquisition of an individual association between a particular place (defined by the same extramaze stimuli), FX rats learned nearly as rapidly as intact rats (Fig. 2B, right). Furthermore, it was confirmed that both normal and FX rats identified the place of escape by the extramaze cues rather than solely by the approach trajectory by applying a "transfer" test developed by Morris (1984) to assess the strength of the place-memory representation revealed in a tendency to search near the site of an absent platform. Thus, with identical nonspatial (olfactory) or spatial stimulus materials, learning in rats with hippocampal system damage was observed to be impaired or spared, depending the demand for relational processing.

The hippocampal system and representational flexibility. To assess the importance of mnemonic flexibility in the memory representation of normal rats and rats with hippocampal system damage, a series of follow-up experiments were pursued, using both the odor discrimination and place learning paradigms. These "probe" tests revealed that, even when FX rats succeeded in learning odor discrimination

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EICHENBAUM, OTTO, AND COHEN

ODOR

simultaneous

A

PLACE LEARNING

DISCRIMINATION

variable

discrimination

500

start

70 60

400

50 FX

300

40 uJ 30

200

20 100 10. 0 2 PROB_EM

successive

3

2-6

• 400

O

300