- Email: [email protected]
Is the rodent hippocampus just for ‘place’?
187
Is the rodent hippocampus just for ‘place’? Howard
Eichenbaum
The prominent view that the rodent hippocampus
is
dedicated to spatial memory has been challenged recently by observations that both limit the nature of hippocampal spatial representation and extend its scope beyond literal space. These findings reveal that the rodent hippocampus mediates memory representations on the basis of non-spatial, as well as spatial, relations among items in memory, and supports access to these memories in a variety of situations. Therefore, the defining features of hippocampal representation in rodents, as in humans, lie not in the modality of the information processed, but in the organization of the information that supports a capacity for flexible memory expression.
Address Center for Behavioral Neuroscience, State University of New York at Stony Brook, Stony Brook, New York 11794-2575, USA e-mail: [email protected] Current Opinion in Neurobiology 1996, 6:187-l
95
0 Current Biology Ltd ISSN 0959-4388
Introduction In humans, damage to the hippocampal region results in an amnesia for all modalities of information, including, but not limited to, spatial information [l]. This impairment is characterized as a deficit in declarative memory: that is, the memory for everyday facts and events that is subject to conscious recollection and verbal or other explicit means of expression. Several experimental models of amnesia have been reported in rats, but none that closely parallels the phenomena of declarative memory loss in humans. The most prominent rodent model of hippocampal function is O’Keefe and Nadel’s 1978 theory [Z] of the hippocampus as mediating cognitive maps or neural representations of physical space. Their account of hippocampal function is driven mainly by a convergence of two lines of evidence: first, neuropsychological findings that indicate that damage to the hippocampal region results in a severe impairment in spatial learning, and second, the discovery of hippocampal ‘place cells’, which are neurons that fire in association with a rat’s place in the environment, independent of any particular stimulus or ongoing behavior. Much research has confirmed that the hippocampus is critical to spatial learning and memory, but recent studies have indicated limitations to its role in spatial processing, as well as its ability to process information outside ‘literal space’, even in rodents. The evidence for a broader domain of rodent hippocampal memory function, in line with that observed in humans, is the focus of this review.
Exceptions to critical hippocampal involvement in spatial memory Several recent reports have documented exceptions to the deficit in spatial learning customarily observed following hippocampal damage, and these findings offer clues about the nature of spatial information processing by the hippocampus. For example, rats with fornix lesions are typically impaired in the conventional radial arm maze task, where animals must actively visit each of several maze arms only once per trial. McDonald and White [3], however, found that memory based on distal spatial cues was fully intact following fornix lesions in a variant of this task, where rats adopted a preference for an arm in which they were confined and food was available. Notably, active exploration of the entire maze before training interfered with later preference conditioning, and fornix lesions eliminated the interference [4*,5**]. These findings suggest that place learning on the radial maze can be supported by extrahippocampal as well as hippocampal circuits. Moreover, hippocampal-dependent spatial memory can be distinguished by the extent of information integrated through active exploration. Relevant to this point are recent findings on contextual fear conditioning, a form of learning that involves the acquisition of fearful responses to a ‘place’ associated with shock. The training sometimes also involves a phasic auditory cue that signals the impending shock. When only brief exposure to the context was provided before shock, hippocampal lesions blocked acquisition of fear to the context, regardless of whether the shock was signaled by a tone cue [6,71. Even when rats were given substantial pre-exposure to the environment, contextual conditioning was found to be sensitive to fornix damage if the tone signal was included [8-l. In contrast, no contextual conditioning was observed in the latter study when the phasic cue was omitted. Taken together, these results suggest that whether or not this sort of ‘place’ learning relies on hippocampal function depends on a combination of how extensively the animal explores the context, and the presence of a ‘foreground’ signal that serves to define the environment as a ‘background’ context. Recent studies on spatial learning, using the Morris water maze task, also suggest that active exploration plays a critical role in hippocampal spatial processing. In the conventional, hippocampal-dependent version of the water maze task, rats are required to begin each trial at the circumference of the circular maze and then swim to a distant, hidden, escape platform. However, Whishaw ef al. [9*] found that rats with hippocampal lesions could still succeed if they were trained (shaped) gradually: that is, initially placing the rat directly on the platform, then placing it next to the platform, then placing it farther away
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it swim to the visible platform, and eventually placing it at the circumference of the maze and making it swim to a submerged platform, as in the conventional task. My colleagues and I [lo] also showed that rats with hippocampal damage can learn the water maze through a successive ‘shaping’ protocol. In addition, we found that, whereas normal rats can apply their success in learning one swim route to locate accurately other escape sites from novel starting points, rats with hippocampal damage are unable to navigate in such a flexible way. Thus, success in learning the water maze can be achieved without hippocampal processing using a highly restricted training protocol that limits active exploration. A major limitation of the non-hippocampal representation, however, is its inability to support flexible expression, such as navigation along novel routes.
and making
These recent observations, based on findings from three prominent spatial memory tasks, indicate that multiple brain systems can support allocentric spatial memory performance [4*,5**,10]. They also suggest two general characteristics of hippocampal-dependent spatial representations. First, hippocampal representations involve extended integration of spatial and foreground/background features of the environment acquired through active exploration. Second, hippocampal representations can support flexible memory expression by guiding navigation in novel test situations. As I will argue below, non-spatial learning that emphasizes integration of multiple stimulus elements and flexible memory expression also depends on hippocampal function. Furthermore, these properties offer links between cognitive mapping, as conceived by O’Keefe and Nadel [Z], and declarative memory dependent on the hippocampus in humans [ 11,121.
Extension of hippocampal non-spatial memory
involvement
to
O’Keefe and Nadel [Z] dismissed observed deficits in non-spatial learning following hippocampal damage as inconsistent. Although no comprehensive accounting of the large range of findings remains (for a review, see [ll]), new data suggest several properties that distinguish hippocampal-dependent from hippocampal-independent representations in non-spatial memory across the spectrum from simple conditioning to complex learning paradigms. For example, variations in the timing of events in experimental protocols can be sufficient to determine whether or not damage in the hippocampal region affects learning or memory in otherwise identical tasks. Thus, in tests of simple object discrimination learning by rats with hippocampal damage, the imposition of an extended memory interval can distinguish intact acquisition across short inter-trial intervals from impaired long-term retention during re-training of the same task [13]. Even more impressively, in studies of classical eyelid conditioning [14], or its consolidation [ 15.1, in rabbits with hippocampal lesions, the addition of a few hundred milliseconds to the duration of a ‘trace’ interval separating conditioned
stimulus (CS) offset and unconditioned stimulus (US) onset determines whether memory is severely impaired or totally spared. Obviously, a demand for spatial processing is not apparent in any of these variants of simple discrimination or conditioning. Research on complex forms of non-spatial learning have also yielded a mixture of findings that cannot be explained according to the cognitive mapping view. For example, several studies have shown that rats with hippocampal damage are impaired for a variety of non-spatial ‘working memory’ tasks that have in common the requirement for non-repetition of a previous response to maze arms that are distinguished by individual cues [16-181. Yet, several ’ examples of spared non-spatial working memory following hippocampal damage have been reported [ 19-221. Rawlins and colleagues [23,24,25”] recently investigated these contradictory findings and showed that the critical factor is simply the size of the maze arms and accompanying cues, such that impairment is observed when the memory cues involve enclosures large enough for the rat to traverse. Consistent with a spatial view of hippocampal function, these findings might be interpreted as suggesting that a deficit is observed when rats perceive the stimuli as ‘places’. At the same time, cognitive mapping is not required for solving this task, and would serve no advantage, because the spatial relationships among the enclosures change constantly within the larger environment [.2.P]. Conflicting results have also accumulated from studies on conditional discrimination tasks, situations in which the reward contingencies of non-spatial cues depend on the particular combinations in which they are presented [11,26]. The results for several different tasks (e.g. ‘transverse patterning’ [27*], ‘transwitching’ [28] and ‘negative patterning’ [26]) are mixed, and it is not yet known precisely what variable accounts for critical dependence on hippocampal function in any of them. It is clear, however, that subtle variations of the stimulus presentation sequence and response measure can affect the performance of both normal rats and those with hippocampal damage [26,29-311. Together with other studies reviewed above, these findings suggest that, as in the case of spatial memory, multiple memory systems support different forms of representation across a wide range of non-spatial tasks, including discrimination, classical conditioning, working memory, and conditional learning. We have a long way to go in understanding what role the hippocampus plays in all of these situations. Nevertheless, for each, it is the nature of the representational demands, and not whether or not the task is ‘spatial’, that determines critical hippocampal involvement.
Different components of the hippocampal region may subserve distinct memory functions An additional problem in sorting out contradictory findings regarding deficits in spatial and non-spatial learning follow-
The hippocampus and ‘place’ memory Eichenbaum
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Flaure 1 The hippocampus and its role in memory for social transmission of food preferences. (a) This paired associate learning is tested on a task comprising three phases. In Phase I, a ‘demonstrator’ rat is given a distinctively scented food, and then, in Phase II, is presented to a ‘subject’ rat for a brief period of social interaction. During this experience, the subject associates two odors carried on the demonstrator’s breath, the distinctive food odor and carbon disulfide (CS$, a natural constituent of rats’ breath [851. In Phase Ill, memory for the food odor (minus CS2) is tested by presenting subjects with the same food and another distinctively scented food, either immediately or after a 24 h delay. (b) Normal (sham lesion) rats show a strong selection preference for the trained food odor in both tests. (Error bars indicate standard error.) Similar to the pattern of impairment in human amnesic patients, rats with selective hippocampal (including subiculum) damage show intact short-term memory, but completely forget the association within 24 hours. Adapted from [42-l.
‘Natural’ odor guided, paired associate learning (a) Phase I Demonstrator
cr,”
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(b) Trained odor selection (%)
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) 1996 Current Opinion in Neurobology
ing hippocampal damage in rodents may lie in differences among studies in the locus and extent of damage within the hippocampal region [29]. For example, with regard to spatial learning, it has been argued that damage to the dorsal hippocampus may produce substantially greater deficits than lesions of the ventral hippocampus ([32]; see also [33]). With regard to non-spatial learning, distinctions between procedures in producing hippocampal lesions, resulting in differences in localization of damage within the hippocampal formation, can produce different results in the acquisition of a configural discrimination [30].
Furthermore, several recent studies have reported that damage to cortical regions surrounding the hippocampus produces behavioral deficits different to those produced by damage to the hippocampus itself [21,29,34-36,37’]. On the basis of his applications of selective lesion techniques to examining several learning and memory paradigms, Jarrard ([29]; see also [37’]) has suggested that parahippocampal cortical areas may be critical to non-spatial memory, whereas spatial functions may be restricted to the hippocampus itself. We [38*] have extended this view, arguing that the parahippocampal cortical region
Cognitive neuroscience
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Figure 2
(c) Test for transitivity
(a) Odor-paired associates
0.25 0.15 0.05 -0.05 -0.15 -0.25
(b) Learning-paired associates Errors to criterion
(d) Test for symmetry Preference index
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Training set Q 1996 Current ODinion m Neurobioloav
The hippocampus and its role in odor-paired associate learning, and flexible memory expression. (a) Paired associate training and probe tests. Each training and testing trial consists of two phases. In the sample phase, the rat is presented with a cup containing a scented mixture of sand and ground rat chow with a buried reward. In the choice phase, two scented items are presented. Both choice items involve odors that are different from the sample odor, and the correct choice depends on the identity of the sample odor. Initially, rats are trained on two sets of paired associates with overlapping elements. Subsequently, two types of probes are presented to test for flexible access to these memory representations. In the probe for transitivity, rats are presented with trials comprising a sample odor from set 1 and unbaited choice odors from set 2. Transitivity is indexed by preferential digging in the choice cup that is associated only indirectly with the sample. In the test for symmetry, trials on set 2 are re-presented, but now the sample and choice items are reversed: that is, the former sample items are now the choices and vice versa. (b) Hippocampal lesions did not block the acquisition of odor-paired associates. Errors to criterion refers to the number of errors the animal made before reaching a performance criterion of 11 correct out of 14 consecutive trials. (c) Controls showed strong transitivity across the sets, with a preference index (for methods, see [43”1) corresponding approximately to 2:l in favor of choice items indirectly associated with the presented sample; see (a). In contrast, rats with hippocampal damage were severely impaired in that they showed no evidence of transitivity. (d) Controls had a preference index corresponding approximately to 3:l in favor of the symmetrical association; see (a). In contrast, rats with hippocampal damage, again, were severely impaired, showing no significant capacity for symmetry. Error bars in parts (b-d) indicate standard error. Adapted from [43**1.
mediates the convergence and persistent storage of single item representations, whereas the hippocampus processes both spatial and non-spatial relationships among these items. Alternatively, the observed dissociations between the effects of different lesions within the hippocampal region can also be explained by differences in the overall extent of damage or disconnection [39,40*].
Towards a reconciliation of views about hippocampal memory function in rodents Contradictions in the findings on hippocampal function in rodents might be resolved if the cognitive mapping notion
were expanded beyond spatial memory per se, guided by the two properties previously argued to distinguish hippocampal from non-hippocampal representations in spatial learning: the integration of multiple relationships among items in memory, and the flexible expression of memories in novel situations [11,38*,41]. Conclusive support for such a general hippocampal function in ‘relational representation’ would necessarily focus on experiments that examine the role of the hippocampus in learning non-spatial relationships among stimulus items, and that incorporate measures of flexible memory expression in accordance with those relationships. In
The hippocampus and ‘place’ memory
given the controversy surrounding potential functional differences between distinct areas within the hippocampal region (see above), compelling evidence concerning the hippocampus itself would require the use of highly selective lesions. addition,
Such data are now at hand, coming from novel behavioral paradigms that exploit natural situations in which rats learn specific stimulus-stimulus associations and use their memory flexibly. Bunsey and I [42*] have demonstrated that cell loss restricted to the hippocampus and subiculum does not affect acquisition but blocks long-term retention of a naturally acquired association between odors (Figure 1). A central component of our experimental paradigm was that learning involved mere exposure to stimulus pairings in a social situation, whereas memory was expressed in quite a different situation to guide food selection. In addition, Bunsey and I [43**] have recently used a more formal testing paradigm to examine learning and flexible expression of stimulus associations in rats with cell loss entirely selective to the hippocampus itself. These rats successfully acquired sets of odor-paired associates, consistent with previous reports that non-hippocampal systems can mediate some form of stimulus-stimulus association [44-46]. The same rats failed, however, when challenged to identify indirect relations between the items, specifically transitive relations between neverpaired items that shared a common association and
Eichenbaum
symmetrical relations for stimulus pairings presented in reversed order (Figure 2). These recent findings provide compelling evidence that hippocampal function is not limited to an encoding of literal space, but rather extends to map-like representations that can organize all kinds of memories for flexible expression.
Hippocampal ‘place’ cells encode much more than spatial location Can the data on place cells also be reconciled with the broader view that the hippocampal region is involved in the representation of non-spatial as well as spatial relations among items in memory? A number of studies have emerged showing that rodent hippocampal neurons encode goal-directed behavioral actions [47-501 and temporal [47,51-53,54”,55], as well as positional [48,53,54”,55] relationships among relevant non-spatial cues in animals performing various non-spatial learning and memory tasks. Thus, in a broad range of situations explicitly designed to study hippocampal cellular activity during learning, both spatial and non-spatial information are prominently represented, and these encodings primarily reflect relationships or conjunctions among cues and behavioral responses. In addition, recent findings related to place cells, such as the data from lesion experiments, have raised qualifications regarding the role of the hippocampus in spatial coding, as well as its role in coding information beyond
Figure 3
cell 1
Dell 2
Cell 3
Cell 4
call 5
(a) Random searoh
(b) Directed search
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.;
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Changes in hippocampal cell spatial firing patterns in a rat performing two different tasks within the same apparatus. Five cells were recorded simultaneously. (a) Initial recordings (‘random search’) were taken as the rat searched for rewards dropped randomly onto a open circular platform. (b) During later recordings within the same session (‘directed search’), rewards were dropped in sequence at four specific loci near the edge of the platform. Cells 1, 2, 4 and 5 changed their spatial representations dramatically between the two tasks. Cell 2 had a place field only in the directed search task, whereas cell 4 lost one of its place fields in this task. The place field of cell 3 was relatively unchanged between the two tasks. Figure reproduced, with permission, from [59*‘1.
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Figure 4 Hippocampal cell firing patterns in rats performing a non-spatial working memory task (a) Each maze arm contained a unique visual-tactile cue: numbered l-4 in (b) below. Their spatial configurations varied randomly across the trial sequence. Trials were presented in sets such that, within each set, rewards were provided only the first time the rat traversed an arm containing that cue. Thus, the rat was required to remember specific cues, without regard to their spatial locations, and visit each cue only once per trial set. After data collection, the firing rate associated with the rat’s location on the maze arms across many trials was sorted according to each cue and to the location in which it appeared (see arrows). (b) Each of the three rows indicates significant increases in firing by an example cell associated with each of the four cues and the north, south, east and west locations. The relative position of an animal on an arm was also considered in the analysis by subdividing each arm into four segments. Some cells increased firing only associated with a particular cue. The example ‘cue cell’ always fired in a mid-segment of the arm with cue 4, regardless of the spatial location of that arm (although firing associated with this cue did not reach significance in the north location). Other cells increased firing significantly only associated with a particular location. The example ‘place cell’ fired only in the initial segment of the east arm, regardless of the cue on that arm (although it also increased firing significantly on the initial segment of the south arm with cue 1). Most cells fired associated with the conjunction of a particular cue and a particular location. The example ‘cue x place cell’ fired only in the mid-segments of the north arm when it was covered with cue 3. Adapted from [64**].
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the representation of space. O’Keefe [56] characterized place cells as neurons that fire in response to the animal’s location, independent of any particular sensory cue or the animal’s direction or ongoing behavior. Indeed, hippocampal cells can reflect the same spatial signal even when all critical visual cues are removed [57], as well as in the dark [SO,%]. However, an unexpected observation in several recent studies is that manipulations of specific cues or other task parameters within a constant environment can have dramatic effects on the spatial firing patterns of place cells [59**,60-621.
in an open field task where it chases randomly dropped food pellets [63]. In contrast, place cells are strongly ‘directional’ when rats run in and out of arms in the radial maze [50,59”,63]. Even the same place cells that are non-directional when rats perform the pellet-chasing task become directional when the rat performs on the radial maze [59”,63]. Moreover, the spatial firing patterns of many place cells change entirely, even in the same environment, when the task is switched from random pellet chasing to one that encourages stereotyped directed movements [.59”] (Figure 3).
Recent studies on ‘directionality’ in place cells provide compelling demonstrations of this point. Place cells show no difference in firing associated with the rat’s heading
These observations confirm Wiener and colleagues’ [48] suggestion that place cell directionality is a reflection of the behavioral significance of directional movements that
I
The hippocampus and ‘place’ memory Eichenbaum
are inherent in some tasks (the radial maze) and absent in others (random pellet chasing). Moreover, these findings reinforce the conclusion that conditions other than the spatial stimuli that define a place can determine how an environment is encoded. The combined results indicate that ‘place’ itself is only part of the hippocampal spatial representation. One of the strongest lines of evidence in favor of the spatial coding view has been that a predominance of hippocampal cells fire in association with spatial location as rats explore open fields. This finding, however, is virtually always made in experimental protocols where distal spatial cues are emphasized while local non-spatial cues are both minimized and made irrelevant. To examine the extent of spatial and non-spatial coding in a situation that does not overly emphasize spatial cues, Young and colleagues [64**] recorded from hippocampal cells in rats performing a radial maze task where working memory performance was guided by specific visual and tactile cues on the maze arms, and where minimal spatial cues were made irrelevant. In this situation, an equivalent number of hippocampal cells independently encoded either the non-spatial cues or maze locations, as well as other aspects of performance (Figure 4). Nonetheless, the majority of cells encoded conjunctions of non-spatial and spatial information. It appears, therefore, that when spatial and non-spatial cues are both available, hippocampal cells encode both types of information, and the overall hippocampal representation reflects both spatial and non-spatial relationships among cues and associated behavioral actions. Combining these findings with those from recordings in rats performing a delayed matching task [54”] and searching for rewards in an open field environment [59**], it seems appropriate to conclude that hippocampal representations involve all manner of relationships among cues and actions relevant to the task at hand. This characterization of hippocampal coding is entirely consistent with the findings from the lesion studies discussed above.
Conclusions O’Keefe and Nadel’s proposal [Z] concerning the hippocampus as a cognitive map provides a framework for thinking about hippocampal function in terms of mapping relationships among significant cues. Yet, recent evidence from both neuropsychological and electrophysiological studies requires that the notion of cognitive mapping be better qualified and extended to the organization of memories according to non-spatial, as well as spatial, dimensions. We are still far from a full understanding of the nature of hippocampal-dependent memory representations, but the findings reviewed here point in specific and potentially
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fruitful directions. Hippocampal memory organizations are established through active exploration and integration of relationships among items to be remembered, and are characterized by access to memories through a variety of routes and forms of behavioral expression. These qualities of hippocampal function bring the findings on rodents in line with those from studies on human amnesia, suggesting that spatial memory in rodents, as well as conscious recollection and explicit memory expression in humans, are prime examples of a fundamental declarative memory function mediated across species by the hippocampus [ll].
Acknowledgements Work discussed in this review was supported by National Institute of Mental Health grants MH52090 and MH51570, National Institute on Aging grant AG09973, Office of Naval Research grant NOO0149410131, and the Human Frontiers Science Program.
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Rothblat LA, Kromer LF: Object recognition memory in the rat: the role of the hippocampus. Behav Brain Res 1991, 42:25-32.
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Rawline JNP, Lyford GL, Seferiades A, Deacon RMJ, Cassaday HJ: Critical determinants of nonspatial working memory deficits in rats with conventional lesions of the hlppocempus or fornix. Behav Neurosci 1993, 107:236-249.
24.
Yee BK, Rawlins JNP: The effects of hippocampal formation
ablation or fimbria-fornix section on performance of a nonspatial radial arm maze task by rats. J Neurosci 1994, 14~3766-3774. 25. ..
Nadel L: The role of the hippocampus in declarative memory: a comment on Zola-Morgan, Squire, and Ramus (1994). Hippocampus 1995, 5:232-234. .-1 This paper IS a cnttque ot Lola-Morgan et ab’e 1391 summary of the effects or hippocampal damage in monkeys. Taken together, the paper and the rebuttal [40*1 cover several issues about hippocampal function in non-spatial memory that are relevant to rodents as well. 38. .
Eichenbaum H, Otto T, Cohen NJ: Two functional components of the hippocsmpal memory system. Brain Behav Sci 1994, 17:449-518. This paper, including the accompanying commentaries, review the evidence regarding a potential distinction between the functional roles of the hippocampus and the parahippocampal region. It is argued that the hippocampus itself mediates the organization of items according to spatial or nonspatial relationships (as discussed elsewhere in this review). In contrast, the parahippocampal cortical region is viewed as being critical to the convergence of multimodal inputs from association cortical areas and the interrnediate term storage of single simple or configural representations. 39.
Cassaday HJ, Rawline JNP: Fomix-fimbria
section and working
Zola-Morgan S, Squire LR, Ramue SJ: Severity of memory impairment in monkeys as a function of locus and extent of
memory deficits in rats: stimulus complexity and stimulus size.
damage within the medial temporal lobe memory system.
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The hippocempus
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Zola-Morgan S, Squire LR, Rsmus SJ: The role of the hippocampus in declarative memory: a reply to Nadel. Hippocampus 1995, 5:235-239. In this rebuttal to Nadel 137.1, the authors review findings in rodents and monkeys that indicate a role for the hippocampus itself in non-spatial memory. Expanding on their summary paper [39], the authors argue that differences in the observance or magnitude of deficit on spatial and non-spatial tasks may be attributable to the amount of damage within the hippocsrnpal region rather than to the locus of that damage within the region.
Deadwyler SA, Bunn T, Hampson RE: Hippocampal ensemble activity during spatial delayed-nonmatch-to-sample performance in rats. J Neurosci 1996, 16:354-372. Statistical (canonical discriminant) analyses of multiple hippocsmpsl neurons in rats performing a delayed matching to sample task revealed that small neural ensembles encode the loci of stimuli and responses, the task phase in which these occur, and the accuracy of the memory response. The findings also showed that hippocampal ensemble activity predicts two types of memory errors, those due to miscoding and those due to forgetting.
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Quirk GJ. Muller RU. Kubie JL: The firing of hiooocampal olace cells in the dark depends on the rat’sieceni experi&cel J Neurosci 1990, 10:2008-2017.
Eichenbaum H, Otto T, Cohen NJ: The hippocampus does it do? Behav Neuraal Bioll992, 57:2-36.
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Bunsey M, Eichenbaum H: Selective damage to the hippocampal region blocks long term retention of a natural and nonspatial stimulus-stimulus association. Hippocampus 1995, 5:546-556. A previous study [66] reported deficits in acquisition and consolidation of a socially transmitted odor association following non-selective hippocampal lesions. Here, it was found that highly selective neurotoxic cell loss localized to hippocampal subfields resulted in the same severe impairment in long-term memory (Figure I). Short-term memory wss spared, indicating that sensory, motivational and behavioral aspects of performance were all intact. This naturally occurring and rapidly acquired associative memory has no spatial component, providing a serious challenge to the notion that the hippccampus itself is dedicated to spatial memory. 42. .
Bunsey M, Eichenbaum H: Conservation of hippccampal memory function in rats and humans. Nature 1996. 379~255-257. This study showed that rats can form an integrated, ‘map-like’ representation of odor stimuli. Rats can link associations between items not experienced directly together, and can generate appropriate inferential responses from these representations (Figure 2). Moreover, these capacities critically depend on the hippocampus itself. These observations extend the scope of cognitive mapping [67] to connect with properties that characterize declsrative memory in animals 112,681 and humans [691.
43. ..
54. ..
place cells. frog
Markus EJ, Qin Y-L, Leonard B, Sksggs WE, McNaughton BL, Barnes CA: Interactions between location and task affect the spatial and directlonal firlng of hlppocampal neurons. J Neurosci 1995, 15:7079-7094. The directionality of place cells is not attributable to the complexity of available spatial cues on either an open field or radial maze, but rather to whether or not the task encourages spatially directed movement patterns. Moreover, the finding that merely a change in the demand for spatially directed movements results in new spatial mappings indicates that the hippocampus encodes specific ‘situations’ and not merely the ‘place’ that the rat occupies. 59. ..
60.
Knierim JJ, Kudrimoti HS, McNaughton BL: Place cells, head direction cells, and the learning of landmark stability. J Neurosci 1995, 15:1648-l 659.
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Eichenbaum H, Bunsey M: On the binding of associations in memory: clues from studies on the role of the hlppocampal region in paired-associate learning. Curr Directions Psycho/ Sci 1995, 4:19-23.
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Sharp PE, Blair HT, Etkin D, Tzsnetos DB: Influences of vestibular and visual motion information on the spatial firing patterns of hippocampal place cells. J Neurosci 1995, 15:173-l 89.
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Cho YH, Kesner RP: Relational object association learning In rats with hippocampal lesions. Behav Brain Res 67:91-98.
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Gothard KM, SkaQgs WE, Moore KM, McNaughton BM: Binding of hippocsmpal CA1 neural activity to multiple reference frames in a landmark based navigation task. J Neurosci 1996, 16:823-835.
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Muller RU, Bostock E, Taube JS, Kubie JL: On the directional firing properties of hippocampel place cells. J Neurosci 1994, 1417235-7251.
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Young BJ, Fox GD, Eichenbaum H: Correlates of hippocampal complex-spike cell activity in rats performing a nonspatial radial maze task. J Neurosci 1994, 14:6553-6563. In wntrast with most recording studies using the radial maze (e.g. [57,59**,60,63]), this study minimized spatial cues while emphasizing nonspatial cues and requiring rats to use the non-spatial cues in a working memory task. The result was a major shift towards coding of non-spatial stimuli as well as spatial cues. These findings indicate that the hippocampal code changes to reflect different kinds of information depending on their importance in task performance.
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Wiener SI, Paul CA, Eichenbaum H: Spatial and behavioral correlates of hippocampal neuronal activity. J Neurosci 1969, 912737-2763.
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Is the rodent hippocampus just for ‘place’? Howard
Eichenbaum
The prominent view that the rodent hippocampus
is
dedicated to spatial memory has been challenged recently by observations that both limit the nature of hippocampal spatial representation and extend its scope beyond literal space. These findings reveal that the rodent hippocampus mediates memory representations on the basis of non-spatial, as well as spatial, relations among items in memory, and supports access to these memories in a variety of situations. Therefore, the defining features of hippocampal representation in rodents, as in humans, lie not in the modality of the information processed, but in the organization of the information that supports a capacity for flexible memory expression.
Address Center for Behavioral Neuroscience, State University of New York at Stony Brook, Stony Brook, New York 11794-2575, USA e-mail: [email protected] Current Opinion in Neurobiology 1996, 6:187-l
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Introduction In humans, damage to the hippocampal region results in an amnesia for all modalities of information, including, but not limited to, spatial information [l]. This impairment is characterized as a deficit in declarative memory: that is, the memory for everyday facts and events that is subject to conscious recollection and verbal or other explicit means of expression. Several experimental models of amnesia have been reported in rats, but none that closely parallels the phenomena of declarative memory loss in humans. The most prominent rodent model of hippocampal function is O’Keefe and Nadel’s 1978 theory [Z] of the hippocampus as mediating cognitive maps or neural representations of physical space. Their account of hippocampal function is driven mainly by a convergence of two lines of evidence: first, neuropsychological findings that indicate that damage to the hippocampal region results in a severe impairment in spatial learning, and second, the discovery of hippocampal ‘place cells’, which are neurons that fire in association with a rat’s place in the environment, independent of any particular stimulus or ongoing behavior. Much research has confirmed that the hippocampus is critical to spatial learning and memory, but recent studies have indicated limitations to its role in spatial processing, as well as its ability to process information outside ‘literal space’, even in rodents. The evidence for a broader domain of rodent hippocampal memory function, in line with that observed in humans, is the focus of this review.
Exceptions to critical hippocampal involvement in spatial memory Several recent reports have documented exceptions to the deficit in spatial learning customarily observed following hippocampal damage, and these findings offer clues about the nature of spatial information processing by the hippocampus. For example, rats with fornix lesions are typically impaired in the conventional radial arm maze task, where animals must actively visit each of several maze arms only once per trial. McDonald and White [3], however, found that memory based on distal spatial cues was fully intact following fornix lesions in a variant of this task, where rats adopted a preference for an arm in which they were confined and food was available. Notably, active exploration of the entire maze before training interfered with later preference conditioning, and fornix lesions eliminated the interference [4*,5**]. These findings suggest that place learning on the radial maze can be supported by extrahippocampal as well as hippocampal circuits. Moreover, hippocampal-dependent spatial memory can be distinguished by the extent of information integrated through active exploration. Relevant to this point are recent findings on contextual fear conditioning, a form of learning that involves the acquisition of fearful responses to a ‘place’ associated with shock. The training sometimes also involves a phasic auditory cue that signals the impending shock. When only brief exposure to the context was provided before shock, hippocampal lesions blocked acquisition of fear to the context, regardless of whether the shock was signaled by a tone cue [6,71. Even when rats were given substantial pre-exposure to the environment, contextual conditioning was found to be sensitive to fornix damage if the tone signal was included [8-l. In contrast, no contextual conditioning was observed in the latter study when the phasic cue was omitted. Taken together, these results suggest that whether or not this sort of ‘place’ learning relies on hippocampal function depends on a combination of how extensively the animal explores the context, and the presence of a ‘foreground’ signal that serves to define the environment as a ‘background’ context. Recent studies on spatial learning, using the Morris water maze task, also suggest that active exploration plays a critical role in hippocampal spatial processing. In the conventional, hippocampal-dependent version of the water maze task, rats are required to begin each trial at the circumference of the circular maze and then swim to a distant, hidden, escape platform. However, Whishaw ef al. [9*] found that rats with hippocampal lesions could still succeed if they were trained (shaped) gradually: that is, initially placing the rat directly on the platform, then placing it next to the platform, then placing it farther away
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it swim to the visible platform, and eventually placing it at the circumference of the maze and making it swim to a submerged platform, as in the conventional task. My colleagues and I [lo] also showed that rats with hippocampal damage can learn the water maze through a successive ‘shaping’ protocol. In addition, we found that, whereas normal rats can apply their success in learning one swim route to locate accurately other escape sites from novel starting points, rats with hippocampal damage are unable to navigate in such a flexible way. Thus, success in learning the water maze can be achieved without hippocampal processing using a highly restricted training protocol that limits active exploration. A major limitation of the non-hippocampal representation, however, is its inability to support flexible expression, such as navigation along novel routes.
and making
These recent observations, based on findings from three prominent spatial memory tasks, indicate that multiple brain systems can support allocentric spatial memory performance [4*,5**,10]. They also suggest two general characteristics of hippocampal-dependent spatial representations. First, hippocampal representations involve extended integration of spatial and foreground/background features of the environment acquired through active exploration. Second, hippocampal representations can support flexible memory expression by guiding navigation in novel test situations. As I will argue below, non-spatial learning that emphasizes integration of multiple stimulus elements and flexible memory expression also depends on hippocampal function. Furthermore, these properties offer links between cognitive mapping, as conceived by O’Keefe and Nadel [Z], and declarative memory dependent on the hippocampus in humans [ 11,121.
Extension of hippocampal non-spatial memory
involvement
to
O’Keefe and Nadel [Z] dismissed observed deficits in non-spatial learning following hippocampal damage as inconsistent. Although no comprehensive accounting of the large range of findings remains (for a review, see [ll]), new data suggest several properties that distinguish hippocampal-dependent from hippocampal-independent representations in non-spatial memory across the spectrum from simple conditioning to complex learning paradigms. For example, variations in the timing of events in experimental protocols can be sufficient to determine whether or not damage in the hippocampal region affects learning or memory in otherwise identical tasks. Thus, in tests of simple object discrimination learning by rats with hippocampal damage, the imposition of an extended memory interval can distinguish intact acquisition across short inter-trial intervals from impaired long-term retention during re-training of the same task [13]. Even more impressively, in studies of classical eyelid conditioning [14], or its consolidation [ 15.1, in rabbits with hippocampal lesions, the addition of a few hundred milliseconds to the duration of a ‘trace’ interval separating conditioned
stimulus (CS) offset and unconditioned stimulus (US) onset determines whether memory is severely impaired or totally spared. Obviously, a demand for spatial processing is not apparent in any of these variants of simple discrimination or conditioning. Research on complex forms of non-spatial learning have also yielded a mixture of findings that cannot be explained according to the cognitive mapping view. For example, several studies have shown that rats with hippocampal damage are impaired for a variety of non-spatial ‘working memory’ tasks that have in common the requirement for non-repetition of a previous response to maze arms that are distinguished by individual cues [16-181. Yet, several ’ examples of spared non-spatial working memory following hippocampal damage have been reported [ 19-221. Rawlins and colleagues [23,24,25”] recently investigated these contradictory findings and showed that the critical factor is simply the size of the maze arms and accompanying cues, such that impairment is observed when the memory cues involve enclosures large enough for the rat to traverse. Consistent with a spatial view of hippocampal function, these findings might be interpreted as suggesting that a deficit is observed when rats perceive the stimuli as ‘places’. At the same time, cognitive mapping is not required for solving this task, and would serve no advantage, because the spatial relationships among the enclosures change constantly within the larger environment [.2.P]. Conflicting results have also accumulated from studies on conditional discrimination tasks, situations in which the reward contingencies of non-spatial cues depend on the particular combinations in which they are presented [11,26]. The results for several different tasks (e.g. ‘transverse patterning’ [27*], ‘transwitching’ [28] and ‘negative patterning’ [26]) are mixed, and it is not yet known precisely what variable accounts for critical dependence on hippocampal function in any of them. It is clear, however, that subtle variations of the stimulus presentation sequence and response measure can affect the performance of both normal rats and those with hippocampal damage [26,29-311. Together with other studies reviewed above, these findings suggest that, as in the case of spatial memory, multiple memory systems support different forms of representation across a wide range of non-spatial tasks, including discrimination, classical conditioning, working memory, and conditional learning. We have a long way to go in understanding what role the hippocampus plays in all of these situations. Nevertheless, for each, it is the nature of the representational demands, and not whether or not the task is ‘spatial’, that determines critical hippocampal involvement.
Different components of the hippocampal region may subserve distinct memory functions An additional problem in sorting out contradictory findings regarding deficits in spatial and non-spatial learning follow-
The hippocampus and ‘place’ memory Eichenbaum
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Flaure 1 The hippocampus and its role in memory for social transmission of food preferences. (a) This paired associate learning is tested on a task comprising three phases. In Phase I, a ‘demonstrator’ rat is given a distinctively scented food, and then, in Phase II, is presented to a ‘subject’ rat for a brief period of social interaction. During this experience, the subject associates two odors carried on the demonstrator’s breath, the distinctive food odor and carbon disulfide (CS$, a natural constituent of rats’ breath [851. In Phase Ill, memory for the food odor (minus CS2) is tested by presenting subjects with the same food and another distinctively scented food, either immediately or after a 24 h delay. (b) Normal (sham lesion) rats show a strong selection preference for the trained food odor in both tests. (Error bars indicate standard error.) Similar to the pattern of impairment in human amnesic patients, rats with selective hippocampal (including subiculum) damage show intact short-term memory, but completely forget the association within 24 hours. Adapted from [42-l.
‘Natural’ odor guided, paired associate learning (a) Phase I Demonstrator
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ing hippocampal damage in rodents may lie in differences among studies in the locus and extent of damage within the hippocampal region [29]. For example, with regard to spatial learning, it has been argued that damage to the dorsal hippocampus may produce substantially greater deficits than lesions of the ventral hippocampus ([32]; see also [33]). With regard to non-spatial learning, distinctions between procedures in producing hippocampal lesions, resulting in differences in localization of damage within the hippocampal formation, can produce different results in the acquisition of a configural discrimination [30].
Furthermore, several recent studies have reported that damage to cortical regions surrounding the hippocampus produces behavioral deficits different to those produced by damage to the hippocampus itself [21,29,34-36,37’]. On the basis of his applications of selective lesion techniques to examining several learning and memory paradigms, Jarrard ([29]; see also [37’]) has suggested that parahippocampal cortical areas may be critical to non-spatial memory, whereas spatial functions may be restricted to the hippocampus itself. We [38*] have extended this view, arguing that the parahippocampal cortical region
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Figure 2
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The hippocampus and its role in odor-paired associate learning, and flexible memory expression. (a) Paired associate training and probe tests. Each training and testing trial consists of two phases. In the sample phase, the rat is presented with a cup containing a scented mixture of sand and ground rat chow with a buried reward. In the choice phase, two scented items are presented. Both choice items involve odors that are different from the sample odor, and the correct choice depends on the identity of the sample odor. Initially, rats are trained on two sets of paired associates with overlapping elements. Subsequently, two types of probes are presented to test for flexible access to these memory representations. In the probe for transitivity, rats are presented with trials comprising a sample odor from set 1 and unbaited choice odors from set 2. Transitivity is indexed by preferential digging in the choice cup that is associated only indirectly with the sample. In the test for symmetry, trials on set 2 are re-presented, but now the sample and choice items are reversed: that is, the former sample items are now the choices and vice versa. (b) Hippocampal lesions did not block the acquisition of odor-paired associates. Errors to criterion refers to the number of errors the animal made before reaching a performance criterion of 11 correct out of 14 consecutive trials. (c) Controls showed strong transitivity across the sets, with a preference index (for methods, see [43”1) corresponding approximately to 2:l in favor of choice items indirectly associated with the presented sample; see (a). In contrast, rats with hippocampal damage were severely impaired in that they showed no evidence of transitivity. (d) Controls had a preference index corresponding approximately to 3:l in favor of the symmetrical association; see (a). In contrast, rats with hippocampal damage, again, were severely impaired, showing no significant capacity for symmetry. Error bars in parts (b-d) indicate standard error. Adapted from [43**1.
mediates the convergence and persistent storage of single item representations, whereas the hippocampus processes both spatial and non-spatial relationships among these items. Alternatively, the observed dissociations between the effects of different lesions within the hippocampal region can also be explained by differences in the overall extent of damage or disconnection [39,40*].
Towards a reconciliation of views about hippocampal memory function in rodents Contradictions in the findings on hippocampal function in rodents might be resolved if the cognitive mapping notion
were expanded beyond spatial memory per se, guided by the two properties previously argued to distinguish hippocampal from non-hippocampal representations in spatial learning: the integration of multiple relationships among items in memory, and the flexible expression of memories in novel situations [11,38*,41]. Conclusive support for such a general hippocampal function in ‘relational representation’ would necessarily focus on experiments that examine the role of the hippocampus in learning non-spatial relationships among stimulus items, and that incorporate measures of flexible memory expression in accordance with those relationships. In
The hippocampus and ‘place’ memory
given the controversy surrounding potential functional differences between distinct areas within the hippocampal region (see above), compelling evidence concerning the hippocampus itself would require the use of highly selective lesions. addition,
Such data are now at hand, coming from novel behavioral paradigms that exploit natural situations in which rats learn specific stimulus-stimulus associations and use their memory flexibly. Bunsey and I [42*] have demonstrated that cell loss restricted to the hippocampus and subiculum does not affect acquisition but blocks long-term retention of a naturally acquired association between odors (Figure 1). A central component of our experimental paradigm was that learning involved mere exposure to stimulus pairings in a social situation, whereas memory was expressed in quite a different situation to guide food selection. In addition, Bunsey and I [43**] have recently used a more formal testing paradigm to examine learning and flexible expression of stimulus associations in rats with cell loss entirely selective to the hippocampus itself. These rats successfully acquired sets of odor-paired associates, consistent with previous reports that non-hippocampal systems can mediate some form of stimulus-stimulus association [44-46]. The same rats failed, however, when challenged to identify indirect relations between the items, specifically transitive relations between neverpaired items that shared a common association and
Eichenbaum
symmetrical relations for stimulus pairings presented in reversed order (Figure 2). These recent findings provide compelling evidence that hippocampal function is not limited to an encoding of literal space, but rather extends to map-like representations that can organize all kinds of memories for flexible expression.
Hippocampal ‘place’ cells encode much more than spatial location Can the data on place cells also be reconciled with the broader view that the hippocampal region is involved in the representation of non-spatial as well as spatial relations among items in memory? A number of studies have emerged showing that rodent hippocampal neurons encode goal-directed behavioral actions [47-501 and temporal [47,51-53,54”,55], as well as positional [48,53,54”,55] relationships among relevant non-spatial cues in animals performing various non-spatial learning and memory tasks. Thus, in a broad range of situations explicitly designed to study hippocampal cellular activity during learning, both spatial and non-spatial information are prominently represented, and these encodings primarily reflect relationships or conjunctions among cues and behavioral responses. In addition, recent findings related to place cells, such as the data from lesion experiments, have raised qualifications regarding the role of the hippocampus in spatial coding, as well as its role in coding information beyond
Figure 3
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Changes in hippocampal cell spatial firing patterns in a rat performing two different tasks within the same apparatus. Five cells were recorded simultaneously. (a) Initial recordings (‘random search’) were taken as the rat searched for rewards dropped randomly onto a open circular platform. (b) During later recordings within the same session (‘directed search’), rewards were dropped in sequence at four specific loci near the edge of the platform. Cells 1, 2, 4 and 5 changed their spatial representations dramatically between the two tasks. Cell 2 had a place field only in the directed search task, whereas cell 4 lost one of its place fields in this task. The place field of cell 3 was relatively unchanged between the two tasks. Figure reproduced, with permission, from [59*‘1.
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Figure 4 Hippocampal cell firing patterns in rats performing a non-spatial working memory task (a) Each maze arm contained a unique visual-tactile cue: numbered l-4 in (b) below. Their spatial configurations varied randomly across the trial sequence. Trials were presented in sets such that, within each set, rewards were provided only the first time the rat traversed an arm containing that cue. Thus, the rat was required to remember specific cues, without regard to their spatial locations, and visit each cue only once per trial set. After data collection, the firing rate associated with the rat’s location on the maze arms across many trials was sorted according to each cue and to the location in which it appeared (see arrows). (b) Each of the three rows indicates significant increases in firing by an example cell associated with each of the four cues and the north, south, east and west locations. The relative position of an animal on an arm was also considered in the analysis by subdividing each arm into four segments. Some cells increased firing only associated with a particular cue. The example ‘cue cell’ always fired in a mid-segment of the arm with cue 4, regardless of the spatial location of that arm (although firing associated with this cue did not reach significance in the north location). Other cells increased firing significantly only associated with a particular location. The example ‘place cell’ fired only in the initial segment of the east arm, regardless of the cue on that arm (although it also increased firing significantly on the initial segment of the south arm with cue 1). Most cells fired associated with the conjunction of a particular cue and a particular location. The example ‘cue x place cell’ fired only in the mid-segments of the north arm when it was covered with cue 3. Adapted from [64**].
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the representation of space. O’Keefe [56] characterized place cells as neurons that fire in response to the animal’s location, independent of any particular sensory cue or the animal’s direction or ongoing behavior. Indeed, hippocampal cells can reflect the same spatial signal even when all critical visual cues are removed [57], as well as in the dark [SO,%]. However, an unexpected observation in several recent studies is that manipulations of specific cues or other task parameters within a constant environment can have dramatic effects on the spatial firing patterns of place cells [59**,60-621.
in an open field task where it chases randomly dropped food pellets [63]. In contrast, place cells are strongly ‘directional’ when rats run in and out of arms in the radial maze [50,59”,63]. Even the same place cells that are non-directional when rats perform the pellet-chasing task become directional when the rat performs on the radial maze [59”,63]. Moreover, the spatial firing patterns of many place cells change entirely, even in the same environment, when the task is switched from random pellet chasing to one that encourages stereotyped directed movements [.59”] (Figure 3).
Recent studies on ‘directionality’ in place cells provide compelling demonstrations of this point. Place cells show no difference in firing associated with the rat’s heading
These observations confirm Wiener and colleagues’ [48] suggestion that place cell directionality is a reflection of the behavioral significance of directional movements that
I
The hippocampus and ‘place’ memory Eichenbaum
are inherent in some tasks (the radial maze) and absent in others (random pellet chasing). Moreover, these findings reinforce the conclusion that conditions other than the spatial stimuli that define a place can determine how an environment is encoded. The combined results indicate that ‘place’ itself is only part of the hippocampal spatial representation. One of the strongest lines of evidence in favor of the spatial coding view has been that a predominance of hippocampal cells fire in association with spatial location as rats explore open fields. This finding, however, is virtually always made in experimental protocols where distal spatial cues are emphasized while local non-spatial cues are both minimized and made irrelevant. To examine the extent of spatial and non-spatial coding in a situation that does not overly emphasize spatial cues, Young and colleagues [64**] recorded from hippocampal cells in rats performing a radial maze task where working memory performance was guided by specific visual and tactile cues on the maze arms, and where minimal spatial cues were made irrelevant. In this situation, an equivalent number of hippocampal cells independently encoded either the non-spatial cues or maze locations, as well as other aspects of performance (Figure 4). Nonetheless, the majority of cells encoded conjunctions of non-spatial and spatial information. It appears, therefore, that when spatial and non-spatial cues are both available, hippocampal cells encode both types of information, and the overall hippocampal representation reflects both spatial and non-spatial relationships among cues and associated behavioral actions. Combining these findings with those from recordings in rats performing a delayed matching task [54”] and searching for rewards in an open field environment [59**], it seems appropriate to conclude that hippocampal representations involve all manner of relationships among cues and actions relevant to the task at hand. This characterization of hippocampal coding is entirely consistent with the findings from the lesion studies discussed above.
Conclusions O’Keefe and Nadel’s proposal [Z] concerning the hippocampus as a cognitive map provides a framework for thinking about hippocampal function in terms of mapping relationships among significant cues. Yet, recent evidence from both neuropsychological and electrophysiological studies requires that the notion of cognitive mapping be better qualified and extended to the organization of memories according to non-spatial, as well as spatial, dimensions. We are still far from a full understanding of the nature of hippocampal-dependent memory representations, but the findings reviewed here point in specific and potentially
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fruitful directions. Hippocampal memory organizations are established through active exploration and integration of relationships among items to be remembered, and are characterized by access to memories through a variety of routes and forms of behavioral expression. These qualities of hippocampal function bring the findings on rodents in line with those from studies on human amnesia, suggesting that spatial memory in rodents, as well as conscious recollection and explicit memory expression in humans, are prime examples of a fundamental declarative memory function mediated across species by the hippocampus [ll].
Acknowledgements Work discussed in this review was supported by National Institute of Mental Health grants MH52090 and MH51570, National Institute on Aging grant AG09973, Office of Naval Research grant NOO0149410131, and the Human Frontiers Science Program.
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