Journal of Physiology - Paris 97 (2003) 537–546 www.elsevier.com/locate/jphysparis

Place cells, neocortex and spatial navigation: a short review Bruno Poucet *, Pierre-Pascal Lenck-Santini, Vietminh Paz-Villagran, Etienne Save

Laboratory of Neurobiology and Cognition, LNC/CNRS, 31 Chemin Joseph-Aiguier, 13402 Marseille Cedex 20, France

Abstract Hippocampal place cells are characterized by location-specific firing, that is each cell fires in a restricted region of the envi- ronment explored by the rat. In this review, we briefly examine the sensory information used by place cells to anchor their firing fields in space and show that, among the various sensory cues that can influence place cell activity, visual and motion-related cues are the most relevant. We then explore the contribution of several cortical areas to the generation of the place cell signal with an emphasis on the role of the visual cortex and parietal cortex. Finally, we address the functional significance of place cell activity and demonstrate the existence of a clear relationship between place cell positional activity and spatial navigation performance. We conclude that place cells, together with head direction cells, provide information useful for spatially guided movements, and thus provide a unique model of how spatial information is encoded in the brain. Ó 2004 Elsevier Ltd. All rights reserved.

Keywords: ; Navigation; Place cells; Sensory systems; ; Parietal and

1. Introduction that are involved in the transmission of this informa- tion are still poorly understood. Because the entorhinal A survey of the neural substrates of spatial pro- cortex is the major area relaying the sensory informa- cessing clearly highlights the important contribution of tion to the hippocampus, one must suspect that the the hippocampus. Critical evidence for the hypothesis cortical information reaching the is that the hippocampus carries out computations in- important for place cell firing. Surprisingly, however, volved in navigation was initially provided by the only a few studies have looked at the contribution of discovery of place cells. Place cells are cells whose neocortical areas that are connected directly or indi- firing is strongly correlated with the location of a rectly to the entorhinal cortex and hippocampus to the freely moving rat in its environment [42]. Anatomi- generation of the place cell signals. The first aim of this cally, place cells are pyramidal complex-spike neurons article is to briefly review some recent studies that have that are found in the CA1 and CA3 areas of the been conducted along these lines. Even though lesion hippocampus [11]. The existence of place cells con- studies of place cell activity make up an incomplete verges with lesion evidence to suggest that the hippo- picture at this stage, they have revealed several campus might play a critical role in the processing of important aspects of the neocortical contribution to spatial information [43]. In this regard, place cells place cell spatial firing. provide a model of how such information is encoded Another important question is whether place cells are at a neural level. involved in navigation at all. Although there is volu- An important issue that immediately arises is the minous evidence from the lesion literature that removing origin of the place cell signal. Although much is known the hippocampus induces strong and permanent deficits about the sensory information that is required to shape in a wide variety of spatial tasks [43], the way hippo- the activity patterns of place cells [48], the pathways campal place cells are involved in navigation is still a matter of debate. The second aim of this review is to summarize recent experiments performed in our labo-

* ratory that deal with this point and demonstrate the Corresponding author. Tel.: +33-49-116-4469; fax: +33-49-171- 4938. existence of a clear functional relationship between place E-mail address: [email protected] (B. Poucet). cell activity and spatial navigation.

0928-4257/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.jphysparis.2004.01.011 538 B. Poucet et al. / Journal of Physiology - Paris 97 (2003) 537–546 2. Basic properties of place cells space. By inference, blind rats were aware of the object locations and were able to use motion-related informa- Place cells are characterized by stable, spatially lim- tion cues to update their own position relative to the ited ’’firing fields’’. A place cell fires rapidly when the objects, a suggestion that was confirmed by detailed rat’s head is inside its field and is usually silent elsewhere analyses of their behavior [16]. It is likely that motion- in the environment. In general, place cells fire indepen- related cues are also used by sighted rats for the ongoing dently of the direction faced by the rat: place cell dis- calculation of their position in space. One advantage of charge recorded from a rat exploring a circular arena such automatic ongoing calculation is that it puts less varies only with the rat’s location [39]. This property burden on attending to the outside environment. How- strongly suggests that the best correlate of place cells is ever, its trade-off is that it requires occasional re-cali- the animal’s location in the current environment, and bration based on external cues so as to correct for not a restricted ‘‘sensory view’’ of that environment. cumulative errors resulting from idiothetic computa- Simple manipulations of the sensory environment in tions [48]. which the rat is moving reveal that several sensory In summary, even though visual information is channels contribute in providing meaningful input to the important, several inputs from motion-related systems hippocampal place cell system. In familiar environ- and other non-visual modalities contribute to spatially ments, place cell firing relies predominantly on visual coherent place cell firing. In the absence of vision, information. In the absence of visual information, other olfactory and tactile cues provide enough information to cues, such as olfactory cues, may become important [56]. anchor the hippocampal representation in combination Another type of information previously suggested to with motion-related cues. be useful for updating place cell activity in the absence of visual cues is motion-related information [13,15,28, 40,49,58]. According to this hypothesis, hippocampal 3. Effects of neocortical damage on place cell activity place cells would update their activity by keeping track of the rat’s movements in space based on signals stem- 3.1. Entorhinal lesions ming from the vestibular and proprioceptive systems as well as from motor efference copy [28]. However, this As noted in the introduction, few studies have ad- strategy, known as path-integration [32] tends to accu- dressed the effects of cortical lesions on place cell activity mulate errors so that if no re-calibration occurs, the in spite of the strong connections that exist between the cumulative error becomes so large that any further hippocampus and the cortex (see Fig. 1 for a summary computation is inaccurate [9,13,29,31]. This is confirmed of the regions of interest). The first experiment was by the finding that, when the use of external cues is performed by Miller and Best [30] who compared the precluded, motion-related (or idiothetic) cues alone are firing patterns of place cells in normal control rats and not sufficient to support spatially stable place cell firing in rats with lesions of the entorhinal cortex (lesions of in the long term [56]. the fornix, also included in this study, are not further However, idiothetic information does contribute to discussed here as these fibers do not carry cortical sig- place cell firing as shown by our observation that blind nals). The animals were trained to run a radial maze for rats have normal firing fields [55]. In this study, place food reward while their neuronal activity was recorded. cell activity was recorded while rats blind from an early Lesions generally reduced the number of cells with age were freely moving in a cylinder arena that con- positional correlates and the firing of those cells with tained three three-dimensional objects at fixed positions clear place correlates was less robust than in normal near the wall of the apparatus. The cylinder itself was control rats. More importantly, there was a change in positioned at the center of a curtained area. The objects the type of control exerted by environmental cues over were different in size, shape and texture, so that they the firing fields following 90° rotations of the maze; all could be used as spatial landmarks likely to help rats to units from normal rats continued to fire in the same arm localize themselves in space. Blind rats had place cells very similar to those recorded from sighted rats, and, as in sighted rats [5], their firing fields depended on the Retrosplenial Parietal objects intentionally placed into the recording cylinder cortex cortex as spatial landmarks. That is, the object set exerted Hippocampus Entorhinal powerful control on firing field locations as shown by cortex the observation that rotation of the objects was followed Perirhinal Visual cortex cortex by equivalent rotation of firing fields. Thus, place cell Subiculum activity in blind rats relied on the object locations and was updated on the basis of internally generated, mo- Fig. 1. Schematic representation of major neocortical connections to tion-related cues resulting from the rat’s movements in the hippocampus. B. Poucet et al. / Journal of Physiology - Paris 97 (2003) 537–546 539 relative to the distal cues from the laboratory while only cerned with the processing of such information. As a tiny percentage of cells did so after entorhinal damage. shown in the previous section, place cell activity is not In fact, most cells (65%) recorded from rats with en- strongly altered when the rat is deprived of vision early torhinal damage lost their positional correlate. The in its life [55]. Even though the preserved properties of remaining cells (about 30%) still had firing fields but place cell firing can be explained by compensation these were observed to stay in register with the physical mechanisms such as learned sensory substitution, this arm of the maze (i.e. their location rotated with the finding suggests that vision might not be so essential maze rotation). This initial study indicates that loss of for navigation, a conclusion supported by the observa- transmission of cortical information through the en- tion that spatial performance in blind rats is not pro- torhinal cortex results in marked changes in place cell foundly impaired in water maze navigation [22]. In view activity. This information seems to concern a variety of of the relatively preserved spatial skills in blind rats, cues some of which might be related to the physical it seems therefore somewhat unexpected that ablation properties of the maze. Although informative, this study of the visual cortex induces a strong deficit in radial clearly needs to be replicated using up-to-date recording maze performance [10,26]. A direct comparison of rats methods. This would permit better documentation of with visual cortical damage and blind rats revealed a the effects of entorhinal cortex damage on several as- much stronger impairment in the brain-damaged rats pects of place cell discharge that it was impossible to [12]. This impairment suggests that the visual cortex study twenty years ago. might accomplish some central function in spatial pro- cessing. To examine this possibility, we recorded place 3.2. Perirhinal lesions cells from rats with lesions of the visual cortex [47]. The procedure was similar to that used by Save et al. [55] More recently, Muir and Bilkey [37] have addressed with blind rats (see Section 2), therefore making it the potential contribution of another cortical area, the possible to compare place cell discharge in rats with perirhinal cortex. This area appears to play a key role in visual cortex lesions and normal sighted or early blind memory [23–25], and is connected to the hippocampus rats. Thus, place cell activity was recorded while rats both directly and indirectly via the entorhinal cortex were freely moving in a cylinder with three objects near [59]. In return, the perirhinal cortex receives projections the wall of the apparatus. from the entorhinal cortex, but also from widespread Rats with visual cortex lesions were found to have neocortical areas including the frontal, parietal, tem- functional place cells whose fields were similar to the poral and occipital regions as well as the retrosplenial fields recorded from rats with an intact cortex and were cortex [1,2]. The firing characteristics of place cells were stable across time. Contrary to both normal sighted rats examined in control rats and in rats with lesions of the and early blind rats [5,55], however, place cells from rats perirhinal cortex while they were foraging in a rectan- with visual cortex lesions were shown to use three- gular environment. Perirhinal damage did not reduce dimensional objects much less efficiently for the spatial the number of cells that could be recorded nor did it anchoring of firing fields. In rats with an intact visual affect place cell firing characteristics. A major effect of cortex, rotation of the objects is followed by equivalent perirhinal damage was observed, however, when the rotation of firing fields in a vast majority of instances. same place cells were recorded after a delay of 24 h. That is, the object set exerts almost ideal control on While the firing fields of all place cells recorded from firing field locations. We found that this control is dra- control rats were similar in location across successive matically reduced in rats with visual cortex lesions: in sessions, many fields from rats with perirhinal cortex these animals, rotations of the object set only rarely lesions were found to shift position across the delay induced coherent field rotations. Thus, control rats used period. Therefore, even though the perirhinal cortex is the objects within the recording cylinder as the reference not necessary for the initial formation of firing fields in frame for anchoring their firing fields whereas rats with the hippocampus, it seems required for the maintenance visual cortex lesions used some uncontrolled, but stable of stable fields over time. This result suggests a role of cues stemming from the experimental room. Because the perirhinal cortex in the reliable identification of the their inability to use the objects was partial, however, current environment, based on the memory of cues and this effect can be best described as an alteration rather associations of cues from that environment. than a total disruption of the process that selects the spatial reference frame. A simple explanation of this 3.3. Visual cortex lesions effect is that rats with visual cortex damage may rely on non-visual distant information (such as odors or Because hippocampal place cells rely on both visual sounds) to set the reference direction for firing fields. and motion-related information to maintain stable fir- However, a more interesting possibility is that the visual ing fields (see above), we recently have started to look at cortex might be involved in the initial calibration of the the consequences of neocortical damage in areas con- spatial reference frame used by the place cell system. For 540 B. Poucet et al. / Journal of Physiology - Paris 97 (2003) 537–546 example, it might be required for selecting the visual lesions of the postsubiculum are observed to disrupt cues to use as landmarks. Interestingly, disrupted cue cue control of hippocampal firing fields (unpublished control over place cell firing fields is also observed after observations reported in [60]). lesions of the postsubiculum [60], thus raising the pos- The parietal cortex (formerly area 7 in Krieg’s ter- sibility that both the visual cortex and postsubiculum minology [19]) has reciprocal connections with the ret- work together to provide the angular reference direction rosplenial cortex and is indirectly connected to the for orienting the hippocampal spatial map. Such a hippocampus [62]. In our laboratory, we have recently function would explain the altered cue control proper- examined the effects of parietal cortex lesions on place ties of place cells as well as the spatial deficits seen after cell activity (unpublished data). Parietal-lesioned and visual cortex lesions [12,55]. control rats were allowed to forage freely for randomly scattered pellets in a recording cylinder. Three objects, similar to those used in a previous study [47], were 3.4. Retrosplenial and parietal cortex lesions placed against the wall of the cylinder to serve as land- marks in a cue-controlled environment. Contrary to Both the parietal and retrosplenial cortices are retrosplenial inactivations, parietal cortex lesions did hypothesized to contribute to the integration of visuo- not impair firing field stability in standard conditions. In spatial and motion-related cues for navigation [33,57]. addition, rotation of the object set was accompanied by These two structures receive visual afferents from sec- an equivalent rotation of firing fields, showing that ondary visual sensory cortical regions and are connected parietal rats used the objects to maintain firing field to a number of structures in the stability. The most dramatic effect of parietal cortex such as the entorhinal cortex, the subiculum and the damage was observed during the session that followed perirhinal cortex [1,64]. In addition, lesion of either the rotation test, when the objects were removed in cortical region has been shown to induce deficits in presence of the animal. In the absence of object land- spatial tasks [14,57]. Accordingly, the parietal and ret- marks, a substantial number (48%) of firing fields in rosplenial cortical areas might exert an influence over parietal-lesioned rats (15% in control rats) shifted back hippocampal place cell activity. This has been confirmed to the initial, standard, pre-rotation location (Fig. 2). In in a recent study by Cooper and Mizumori [6] who control rats, most firing fields remained stable relative examined the effects of temporarily inactivating the to the rotation session (36%) or disappeared, i.e. cells retrosplenial cortex on place cell activity in rats per- stopped firing (27%). Thus, these results suggest that forming a radial maze task. The consequences of such field stability in control rats was strongly dependent on inactivations were examined during acquisition and the objects whereas field stability in parietal-lesioned during retention of the task. In addition, for the reten- rats could be placed under the control of background tion group, the animals performed the task in light or in cues when the objects were removed. This raises the darkness. The authors found that retrosplenial inacti- possibility that the parietal cortex is involved in the vations disrupted the stability of firing fields, i.e. the processing of proximal landmarks and contributes to preferred location of firing fields shifted to unpredictable provide some stable local frame of reference to the locations of the maze, in both acquisition and retention. hippocampal place cell system. Another complementary Interestingly, these firing pattern modifications were explanation is that parietal-lesioned rats rely on back- correlated with performance deficits during acquisition ground cues because they are unable to use motion- and during retention in darkness only. This suggests that related cues to maintain firing field stability in absence cooperation between the retrosplenial cortex and the of objects. Interestingly, these results together with those place cell system is required for different stages of spatial obtained in rats with damage to the visual cortex suggest information processing, including initial integration of that the processing of visuo-spatial information along visuo-spatial and movement-related sensory cues and the occipito-parietal axis results in the calibration and the use of mnemonic visuo-spatial information in the selection of the reference frames used by the place cell absence of environmental cues [33]. Interestingly, the system to anchor stable firing fields. retrosplenial cortex is part of a large network of con- nected brain structures that includes the postsubiculum and the anterior thalamic and lateral dorsal thalamic 3.5. Commentary nuclei. All these areas contain head direction cells that fire when the rat’s head faces a specific direction inde- This short review of lesion-induced alterations of pendently of its location [3,60]. Since head direction cells the place cell signal reveals a striking parallel with the and place cells are strongly coupled [18], it is possible behavioral spatial deficits that result from damage to the that the effects of retrosplenial inactivations on hippo- corresponding cortical areas. Virtually any cortical area campal place cells were mediated by the disruption of shown to be important for performance of spatial navi- the head direction system. In support of this hypothesis, gation tasks can be demonstrated to be also important B. Poucet et al. / Journal of Physiology - Paris 97 (2003) 537–546 541

Fig. 2. Firing rate maps of two place cells recorded for five consecutive sessions. Three objects (shown as a white square, a black circle and a gray square, respectively) were placed directly into the recording cylinder (shown as a large circle) to serve as spatial landmarks. In each map, locationsin which no firing occurred during the whole session are white. The highest firing rate is coded as black, and intermediate rates are shown as light gray and dark gray from low to high. The first two sessions were conducted with the object set in a standard position. The third session was conducted with the object set rotated 90° CCW from the standard position. The rat was removed from the cylinder between each session (indicated by a vertical arrow) except between the third and fourth sessions. Before the fourth session (‘‘Removal’’), the three objects were removed from the cylinder. Thus, the rat could locate itself only based on self-motion cues combined with odors possibly remaining in the cylinder, or alternately on uncontrolled static background cues from the laboratory. The last session was conducted with the objects back to their standard positions. Cell 1 (top row) was recorded from a normal rat; its field rotated appropriately in the third session and was spatially stable after object removal. Cell 2 (bottom row) was recorded from a rat with bilateral parietal cortex damage; its field also followed the object rotation in the third session. However, it rotated back to its initial placement as soon as the objects were removed. A majority of cells from parietal rats showed this pattern, which suggests a failure to use of self- motion cues (see text for further details).

for the generation of normal place cell characteristics. alterations of place cell properties also impair per- Because spatial behavior is so easily disrupted by brain formance in place navigation tasks. For example, damage, it is often difficult, however, to determine the genetically modified mice with an impaired long-term exact nature of the processing stage that has been af- potentiation (LTP) as well as rats with a treatment- fected by the lesion. With regard to this point, consid- induced impaired LTP have abnormal place cells and ering the place cell system as a model system that, reduced performance in place navigation tasks [4,17,27, among other tasks, is a spatial information processing 34,51,52]. Thus, treatments that generate place cell module and looking at the changes in place cell dis- abnormalities seem to reliably induce abnormalities of charge provides a way of characterizing cortical contri- spatial navigation. butions in a much better defined manner. Although at Although these findings support the mapping theory, this stage it may be speculative to propose specific the weaknesses associated with lesion-type methods functions for each cortex, it appears that the effects of imply that a more direct approach is required to show damage to each cortical area on place cell discharge how the place cell signal relates to behavior in a normal match the deficits expected from known neuroanatom- animal. Probing the relationship between place cell dis- ical and behavioral data. charge and the rat’s spatial behavior requires concomi- tant recording of both events. Surprisingly, the existence of a direct relationship between place cells and naviga- 4. Relationships between place cell activity and spatial tion was only anecdotally noticed [44]. Rats were trained behavior to reach one arm of a plus-shaped maze on the basis of its location relative to a set of extra-maze cues. On a few Place cells continuously indicate the rat’s location in occasions, these cues were removed. Under these cir- the current environment. This property is the corner- cumstances, it was found that even on error trials the stone of the theory of hippocampal rat’s random choice of goal remained in register with its function [43]. This theory is further supported by the place cell firing fields, suggesting that place cell activity observation that destruction of the hippocampus dis- and spatial behavior were coupled. To explore this issue rupts the performance of rodents in a wide variety of in a more systematic way, we performed two studies spatial tasks [16,36,54]. Thus, both unit recording both of which relied on the same underlying principle: if studies and lesion work converge to indicate a central place cells provide position information useful for per- role for the hippocampus in map-based navigation. forming a spatial task, then behavioral manipulations Other evidence suggesting that place cells are the that result in the place cell information being out of essential units of the putative environmental map come register with that task should also lead to incorrect from the observation that manipulations that produce spatial behavior. 542 B. Poucet et al. / Journal of Physiology - Paris 97 (2003) 537–546 4.1. Place cell activity in a spatial memory task erroneous placements of firing fields often predicted erroneous visits to an individual arm. The contribution of place cell activity was first pro- Together, these results show that erroneous field bed in a spatial alternation task, known to depend on placements were associated with disorganized spatial the integrity of the hippocampus. Rats were trained behavior. Noticeably, the changes in firing fields con- to perform a continuous spatial alternation task in a cerned only their angular position in the maze: even Y-shaped maze in which the only available landmark though the fields were on the wrong arm relative to the was a prominent white card, positioned between two goal, their radial position relative to the maze center arms [21]. In this task, the rats had to alternate between was correct. In addition, all fields were coherent with the two arms of a Y-maze to get a food reward in the one another when several cells were simultaneously third (goal) arm (Fig. 3A). Once the rats performed well recorded. Thus, there was no evidence that cue manip- in the presence of the card (‘‘standard condition’’), place ulations resulted in the activation of a different repre- cells were recorded in several sessions after the card was sentation, as is the case when place cells are recorded in rotated or removed. These manipulations were expected several differently shaped environments [38]. Instead, the to result, on some occasions, in the angular positions of same place cell representation was active, but was firing fields shifting out of register with the positions incorrectly oriented with respect to the spatial task the seen in the standard condition. Our purpose was to rat had to accomplish. Thus, a reasonable assumption is determine if the rats’ performance was worse when fields that the observed behavioral effects were caused by the were out of register relative to their standard position. mismatch between the orientation of the hippocampal Overall, the results confirmed the existence of a representation and the learned task, rather than by the strong deterioration in performance when field positions activation of a distinct representation. were inconsistent with the learned task. First, the Interestingly, very similar findings were observed for number of correct responses was dramatically reduced head direction cells whose activity was recently dem- with rats being rewarded, on average, half as often than onstrated to correlate with spatial behavior on a radial during sessions with consistent field placements. Second, maze [7]. Head direction cells fire only when the rat is the nature of the errors was also different when fields heading at specific directions independently of its cur- were out of register with the task, with rats either rent location and are found in several brain areas (such repeating incorrect choices of an individual arm or as the postsubiculum and anterior thalamic nuclei) all of failing to follow the basic alternation rule to solve the which have extensive connections with the hippocampus task. These types of errors reflect a more complete dis- [60]. Animals implanted for record- organization than just making the most commonly ob- ings were trained to find reward on a particular arm in a served alternation (working memory) errors. Third, fixed position relative to a visible cue in the room. When

Cue card C (food)

Cue X card

?? F C

B A X X (A) Spatial alternation task (B) Place preference task (C) Principle of behavioral / unit recording studies

Fig. 3. Behavioral procedures used to probe place cell involvement in spatial performance and general principle. (A) The continuous spatial alternation task [22]. The apparatus is a Y-shaped maze with a large cue card (shown as an arc) as the single spatial landmark. The circle at the end of arm C indicates the location where the rat was rewarded with a food pellet if it had previously made a correct alternation visit to one of the other two arms A and B. (B) The place preference task [21]. The apparatus is a cylinder with a single cue card attached to the wall (shown as an arc). The rat had to enter an unmarked goal zone and stay there to trigger the release of a food reward from a dispenser situated above the cylinder. Since the released pellet could land anywhere in the cylinder, the rat had to leave the goal area to find the pellet. The small circle shows the goal location in the Far task. In the Near task, the goal area was beneath the cue card while in the Cue task, it was directly signaled by a black disk on the floor. The rat’s path to the goal is shown as a continuous line. The path away from the goal to retrieve the food pellet at location Ôx’ is shown as a dashed line. (C) The general principle of the experiments combining place cell recordings and the analysis of navigation performance is illustrated for the Far task. A schematic place cell firing field (shown as a set of concentric gray-shaded ellipses) represents the orientation of the hippocampal map. The purpose is to determine where the rat will search for the goal when a cue manipulation (here a rotation of the cue card) does not produce the expected rotation of the firing fields (i.e., of the hippocampal map). One prototypical situation in which the hippocampal map often fails to re-orient relative to the external environment is when the card is rotated in the presence of the rat. Under these circumstances, the goal location indicated by the external environment (ÔC’ for cue-referred) is distinct from the goal location indicated by the hippocampal map (ÔF’ for field-referred). The results show that rats look for the goal at the field-referred location (i.e., their choices are based on the hippocampal map) only when they have to rely on a spatial representation of the goal location (i.e., in the Far task), but not in other conditions (see text and [21] for details). B. Poucet et al. / Journal of Physiology - Paris 97 (2003) 537–546 543 the cue was rotated to another fixed position in the present, independent rotations of the disk on the cylin- room, both the animal’s choice of maze arm and the der floor. Hidden rotations were made with the rat re- head direction cell’s preferred direction shifted in con- moved from the cylinder and caused 90° firing field cert relative to the cue. However, on some infrequent rotations in a vast majority of sessions (>80%). Visible trials, the head direction cell’s preferred direction re- rotations were made while the rat was inside the cylinder mained stable relative to background cues in spite of the and, as expected [53], caused 90° field rotations only in cue rotation. In these instances, it was observed that the minority of sessions (<30%). In the latter condition, the rat’s choice also stayed stable relative to the rotated cue, failure of fields to rotate is caused by the conflict be- thus remaining in register with the head direction signal. tween motion-related and cue-related information that Overall, these findings indicate that both place cells and is generated by the visible card rotations. More impor- head direction cells play a role in guiding navigation. tantly, visible card rotations generally induced firing fields to shift out of register with the new goal location 4.2. Place cell activity in spatial and non-spatial naviga- (as defined by the rotated card location) while hidden tion tasks card rotations generally induced firing fields to stay in register with the new goal location. The cognitive map theory predicts that hippocampal In all conditions, each session started with a period integrity is more critical for place navigation than for during which the feeder was switched off, irrespective of orientation based on simpler mechanisms such as ori- the animal’s response. This partial extinction procedure enting to beacons. This hypothesis is supported by the was used to let the animals search without any feedback finding that hippocampal lesions disrupt place navigation information about the goal location and thus allowed us but not beacon navigation [35,41,45]. To address a simi- to determine where the rat ‘‘thought’’ the goal was lo- lar issue at the place cell level, we looked at performance cated (Fig. 3C). The results of the different conditions by normal animals in place and beacon navigation tasks were contrasted. A strong decrease in performance was after environmental manipulations that disturb the rela- observed in the Far condition when fields were out of tionship between the place cell representation and the register with the card-referred goal. Most rats tended to cues used to solve the problems. The theory predicts that search for the goal in the field-referred rather than card- such disturbances will disrupt performance of place referred goal location. In contrast, a modest decrease in navigation but not of beacon navigation. To test this performance was observed in the Near condition when prediction, rats were trained in several tasks that required fields were out of register with the card, with rats either map-based place navigation or simply heading searching for the goal at the card. Finally, field place- towards a strong marker stimulus [20]. ments had no effect whatsoever on performance in the We used the place preference paradigm developed by Cue condition in which the goal was directly signaled by Rossier et al. [50]. In this task, rats have to enter an a movable mark on the floor. unmarked goal designated by the experimenter as the In summary, we found that visible rotations tended to goal, which then triggers release of a food reward from a disrupt the relationship between firing fields and cues in dispenser situated above the circular arena (Fig. 3B). all tasks but impaired performance only in the spatial The rat then has to move away from the goal area to problem that required map-based navigation. Thus, it retrieve the food pellet wherever it ended up in the appears that the correct orientation of the hippocampal arena. The only spatial landmark is a salient white card map with the external stimuli is essential for efficient attached to the wall of the arena. Three distinct condi- performance in a navigational task but not in guidance tions were used with different rats. In the Far condition, or beacon navigation tasks. Noticeably, reliable place the goal was away from the wall card so that the rat had cell firing was observed in all tasks, i.e., whether or not to use a place strategy, i.e. to infer the goal location the rat had a spatial navigation task to accomplish (see from its spatial relationship with the card. In the Near also [61]). Therefore, place cells continuously provide condition, the goal was located beneath the wall card so background information as to the rat’s location, yet this that all the rat had to do was to move towards the card information appears critical only for true spatial navi- (though it could use a place strategy as well). Finally, in gation. We therefore conclude, as proposed by the the Cue condition the goal was directly signaled by a spatial theory of hippocampal function that the rodent mark (a black disk) on the floor. The mark was moved hippocampus participates in solutions of place naviga- from one session to another (thus making the wall card tion tasks but not of simpler guidance tasks. irrelevant for solving the task) so that the solution re- quired a guidance strategy. Place cells were recorded while rats performed the 5. Conclusion task. To modify relationships between visible stimuli and place cell activity, we made ‘‘hidden’’ or ‘‘visible’’ This review addressed issues about the cortical origin 90° rotations of the card on the cylinder wall and, when of the place cell firing patterns and about the functional 544 B. Poucet et al. / Journal of Physiology - Paris 97 (2003) 537–546 significance of place cell activity. As to the first of these for their contribution to some of the experimental work two issues, several cortical areas appear to subserve reported herein, Bill MacKay for checking the English, complementary functions in the generation of place cell and two anonymous reviewers for useful comments on a firing. For example, the perirhinal cortex is required for previous version. long-term stability of firing fields [37]. The retrosplenial cortex appears to be important for the initial processing of spatial cues but would also be needed for the mne- References monic use of these cues to guide navigation when they have been removed [33]. In contrast, the visual, parietal [1] R.D. Burwell, D.G. Amaral, Cortical afferents of the perirhinal, and entorhinal cortices appear to be involved in the postrhinal, and entorhinal cortices of the rat, J. Comp. Neurol. selection of cues necessary for the spatial anchoring of 398 (1998) 179–205. firing fields; the three areas seem to process separate [2] R.D. Burwell, M.P. Witter, D.G. Amaral, Perirhinal and postrh- aspects of space, with the entorhinal cortex being more inal cortices of the rat: a review of the neuroanatomical literature and comparison with findings from the monkey brain, Hippo- involved in processing distal cues [30,46], the visual and campus 5 (1995) 390–408. parietal cortices dealing with the local aspects of the [3] J. Cho, P.E. Sharp, Head direction, place, and movements environment explored by the rat [47]. Although this correlates for cells in the rat retrosplenial cortex, Behav. Neurosci. description is schematic, it has the advantage of pro- 115 (2001) 3–25. viding a framework within which more refined func- [4] Y.H. Cho, K.P. Giese, H.T. Tanila, A.J. Silva, H. Eichenbaum, Abnormal hippocampal spatial representations in aCaMKIIT286A tions can be worked out. It seems to us, however, that and CREBaD-mice, Science 279 (1998) 867–869. such refinement will require more standardized proce- [5] A. Cressant, R.U. Muller, B. Poucet, Failure of centrally placed dures for recording place cell activity among different objects to control the firing fields of hippocampal place cells, laboratories. J. Neurosci. 17 (1997) 2531–2542. With regard to the issue of the functional significance [6] B.G. Cooper, S.J.Y. Mizumori, Temporary inactivation of the retrosplenial cortex causes a transient reorganization of of place cell activity, we provided strong evidence spatial coding in the hippocampus, J. Neurosci. 21 (2001) 3986– that place cell signals are crucial when the animal 4001. needs to ‘‘know’’ its own position and the positions [7] P. Dudchenko, J.S. Taube, Correlation between head direction of other objects. An important issue, however, is whe- cell activity and spatial behavior on a radial maze, Behav. ther place cells directly guide navigation, or are just Neurosci. 111 (1997) 3–19. [8] H. Eichenbaum, T. Otto, N.J. Cohen, The hippocampus: what one component in a larger network of structures more does it do? Behav. Neur. Biol. 57 (1992) 2–36. actively involved. In the latter and more likely view, [9] A.S. Etienne, R. Maurer, V. Seguinot, in the network would probably have to include not only mammals and its interaction with visual landmarks, J. Exp. Biol. brain areas in which head direction cells were found [60], 119 (1996) 201–209. but also areas known to be involved in behavioral [10] N. Foreman, R. Stevens, Visual lesions and radial maze perfor- mance in rats, Behav. Neur. Biol. 16 (1982) 126–136. decisions in an essential way (e.g., prefrontal and pari- [11] S.E. Fox, J.B. Ranck Jr., Electrophysiological characteristics of etal cortex). hippocampal complex-spike cells and theta cells, Exp. Brain Res. Another difficulty with the correlational approach 41 (1981) 399–410. that underlies our research is that it does not reveal what [12] M.A. Goodale, R.H.I. Dale, Radial-maze performance in the rat hippocampal cell firing patterns would signal in non- following lesions of posterior neocortex, Behav. Brain Res. 3 (1981) 273–288. spatial complex tasks. Thus, it is difficult to determine [13] K.M. Gothard, W.E. Skaggs, B.L. McNaughton, Dynamics of the generality of this conclusion. In particular, it is mismatch correction in the hippocampal ensemble code for space: known that hippocampal cells have behavioral corre- interaction between path integration and environmental cues, lates in non-spatial tasks, therefore suggesting that the J. Neurosci. 16 (1996) 8027–8040. hippocampus is involved in the processing of both spa- [14] K.T. Harker, I.Q. Whishaw, Impaired spatial performance in rats with retrosplenial lesions: importance of the spatial problem and tial and non-spatial relational information [8,63]. Yet the rat strain in identifying lesion effects in a swimming pool, the specificity of the hippocampal place cell signal, as J. Neurosci. 22 (2002) 1155–1164. well as the properties of head direction cells and the [15] B. Hill, P. Best, Effects of deafness and blindness on the spatial strong coupling that seems to exist between the two correlates of hippocampal unit activity in the rat, Exp. Neurol. 74 populations of cells [18], make it very likely that an (1981) 204–217. [16] L.E. Jarrard, Selective hippocampal lesions and behavior: effects important function of this system is to process spatial of kainic acid lesions on performance of place and cue tasks, information for navigation. Behav. Neurosci. 97 (1983) 873–889. [17] C. Kentros, E. Hargreaves, R.D. Hawkins, E.R. Kandel, M. Shapiro, R.U. Muller, Abolition of long-term stability of new Acknowledgements hippocampal place cell maps by NMDA receptor blockade, Science 280 (1998) 2121–2126. [18] J.J. Knierim, H.S. Kudrimoti, B.L. McNaughton, Place cells, Support for this work was provided by the CNRS head direction cells, and the of landmark stability, and the MENRT. We thank A. Cressant and R. Muller J. Neurosci. 15 (1995) 1648–1659. B. Poucet et al. / Journal of Physiology - Paris 97 (2003) 537–546 545

[19] W.J.S. Krieg, Connections of the cerebral cortex: I. The albino [39] R.U. Muller, E.M. Bostock, J.S. Taube, J.L. Kubie, On the rat: a. topography of the cortical areas, J. Comp. Neurol. 84 directional firing properties of hippocampal place cells, J. Neuro- (1946) 221–275. sci. 14 (1994) 7235–7251. [20] P.P. Lenck-Santini, R.U. Muller, E. Save, B. Poucet, Relation- [40] J. O’Keefe, Place units in the hippocampus of the freely moving ships between place cell firing fields and navigational decisions by rat, Exp. Neurol. 51 (1976) 78–109. rats, J. Neurosci. 22 (2002) 9035–9047. [41] J. O’Keefe, D.H. Conway, On the trail of the hippocampal [21] P.P. Lenck-Santini, E. Save, B. Poucet, Evidence for a relationship engram, Physiol. Psychol. 8 (1980) 229–238. between the firing patterns of hippocampal place cells and rat’s [42] J. O’Keefe, J. Dostrovsky, The hippocampus as a spatial map. performance in a spatial memory task, Hippocampus 11 (2001) Preliminary evidence from unit activity in the freely moving rat, 377–390. Brain Res. 34 (1971) 171–175. [22] M.D. Lindner, M.A. Plone, T. Schallert, D.F. Emerich, Blind rats [43] J. O’Keefe, L. Nadel, The Hippocampus as a Cognitive Map, are not profoundly impaired in the reference memory Morris Clarendon, Oxford, 1978. water maze and cannot be clearly discriminated from rats with [44] J. O’Keefe, A. Speakman, Single unit activity in the rat hippo- cognitive deficits in the cued platform task, Cognit. Brain Res. 5 campus during a spatial memory task, Exp. Brain Res. 68 (1987) (1997) 329–333. 1–27. [23] P. Liu, D.K. Bilkey, Lesions of perirhinal cortex produce spatial [45] M.G. Packard, J.L. McGaugh, Inactivation of hippocampus and memory deficits in the radial maze, Hippocampus 8 (1998) 114– caudate nucleus with lidocaine differentially affects expression of 121. place and response learning, Neurobiol. Learn. Mem. 65 (1996) [24] P. Liu, D.K. Bilkey, Perirhinal cortex contributions to perfor- 65–72. mance in the Morris water maze, Behav. Neurosci. 112 (1998) [46] C. Parron, B. Poucet, E. Save, Entorhinal cortex lesions in rats 304–315. impair the use of distal landmarks but not of proximal landmarks [25] P. Liu, D.K. Bilkey, Excitotoxic lesions centred on perirhinal during navigation, Behav. Pharmacol. 12 (2001) S75. cortex produce delay-dependent deficits in a test of spatial mem- [47] V. Paz-Villagran, P.P. Lenck-Santini, E. Save, B. Poucet, Prop- ory, Behav. Neurosci. 112 (1998) 512–524. erties of place cell firing after damage to the visual cortex, Eur. J. [26] W.F. McDaniel, R.G. Brown, Radial maze performance following Neurosci. 16 (2002) 771–776. restricted posterior neocortical lesions, IRCS Med. Sci. 12 (1984) [48] B. Poucet, E. Save, P.P. Lenck-Santini, Sensory and memory 807–808. properties of place cells firing, Rev. Neurosci. 11 (2000) 95–111. [27] T.J. McHugh, K.I. Blum, J.Z. Tsien, S. Tonegawa, M.A. Wilson, [49] G.J. Quirk, R.U. Muller, J.L. Kubie, The firing of hippocampal Impaired hippocampal representation of space in CA1-specific place cells in the dark depends on the rat’s recent experience, NMDAR1 knockout mice, Cell 87 (1996) 1339–1349. J. Neurosci. 10 (1990) 2008–2017. [28] B.L. McNaughton, C.A. Barnes, J.L. Gerrard, K. Gothard, M.W. [50] J. Rossier, F. Schenk, Y. Kaminsky, J. Bures, The place Jung, J.J. Knierim, H. Kudrimoti, Y. Qin, W.E. Skaggs, M. preference task: a new tool for studying the relation between Suster, K.L. Weaver, Deciphering the hippocampal polyglot: the behavior and place cell activity in rats, Behav. Neurosci. 114 hippocampus as a path integration system, J. Exp. Biol. 119 (1996) (2000) 273–284. 173–185. [51] A. Rotenberg, T. Abel, R.D. Hawkins, E.R. Kandel, R.U. Muller, [29] B.L. McNaughton, L.L. Chen, E.J. Markus, ‘‘Dead reckoning’’, Parallel instabilities of long-term potentiation, place cells, and landmark learning, and the sense of direction: a neurophysiolog- learning caused by decreased protein kinase A activity, J. Neuro- ical and computational hypothesis, J. Cognit. Neurosci. 3 (1991) sci. 20 (2000) 8096–8102. 190–202. [52] A. Rotenberg, M. Mayford, R.D. Hawkins, E.R. Kandel, R.U. [30] V.M. Miller, P.J. Best, Spatial correlates of hippocampal unit Muller, Mice expressing activated CaMKII lack low frequency activity are altered by lesions of the fornix and entorhinal cortex, LTP and do not form stable place cells in the CA1 region of the Brain Res. 194 (1980) 311–323. hippocampus, Cell 87 (1996) 1351–1361. [31] H. Mittelsteadt, The role of multimodal convergence in homing by [53] A. Rotenberg, R.U. Muller, Variable place-cell coupling to a path integration, Fortschritte der Zoologie 28 (1983) 197–212. continuous viewed stimulus: evidence that the hippocampus acts [32] M.L. Mittelsteadt, H. Mittelsteadt, Homing by path integration in as a perceptual system, Phil. Trans. Roy. Soc. (London B) 352 a mammal, Naturwissenschaften 67 (1980) 566–567. (1997) 1505–1513. [33] S.J.Y. Mizumori, B.G. Cooper, S. Leutgeb, W.E. Pratt, A neural [54] E. Save, M.-C. Buhot, N. Foreman, C. Thinus-Blanc, Exploratory system analysis of adaptive navigation, Mol. Neurobiol. 21 (2001) activity and response to a spatial change in rats with hippocampal 57–82. or posterior parietal cortical lesions, Behav. Brain Res. 47 (1992) [34] R.G.M. Morris, E. Anderson, G.G. Lynch, M. Baudry, Selective 113–127. impairment of learning and blockade of long-term potentiation [55] E. Save, A. Cressant, C. Thinus-Blanc, B. Poucet, Spatial firing of by an N-methyl-D-aspartate , AP5, Nature hippocampal place cells in blind rats, J. Neurosci. 18 (1998) 1818– 319 (1986) 774–776. 1826. [35] R.G.M. Morris, J.J. Hagan, J.N.P. Rawlins, Allocentric spatial [56] E. Save, L. Nerad, B. Poucet, Contribution of multiple sensory learning by hippocampectomised rats: a further test of the ‘‘spatial information to place field stability in hippocampal place cells, mapping’’ and ‘‘working memory’’ theories of hippocampal Hippocampus 10 (2000) 64–76. function, Q, J. Exp. Psychol. B 38 (1986) 365–395. [57] E. Save, B. Poucet, Hippocampal-parietal cortical interactions in [36] R.G.M. Morris, F. Schenk, F. Tweedie, L.E. Jarrard, Ibotenate spatial cognition, Hippocampus 10 (2000) 491–499. lesions of hippocampus and/or subiculum: dissociating compo- [58] P.E. Sharp, H.T. Blair, D. Etkin, D.B. Tzanetos, Influences of nents of allocentric spatial learning, Eur. J. Neurosci. 2 (1990) vestibular and visual motion information on the spatial firing 1016–1028. patterns of hippocampal place cells, J. Neurosci. 15 (1995) 173– [37] G.M. Muir, D.K. Bilkey, Instability in the place field location of 189. hippocampal place cells after lesions centered on the perirhinal [59] C.J. Shi, M.D. Cassell, Perirhinal cortex projections to the cortex, J. Neurosci. 21 (2001) 4016–4025. amygdaloid complex and hippocampal formation in the rat, [38] R.U. Muller, J.L. Kubie, The effects of changes in the environ- J. Comp. Neurol. 406 (1999) 299–328. ment on the spatial firing of hippocampal complex-spike cells, [60] J.S. Taube, Head direction cells and the neurophysiological basis J. Neurosci. 7 (1987) 1951–1968. for a sense of direction, Prog. Neurobiol. 55 (1998) 225–256. 546 B. Poucet et al. / Journal of Physiology - Paris 97 (2003) 537–546

[61] O. Trullier, R. Shibata, A.B. Mulder, S.I. Wiener, Hippocampal [63] E.R. Wood, P.A. Dudchenko, H. Eichenbaum, The global record neuronal position selectively remains fixed to room cues only in of memory in hippocampal neuronal activity, Nature 397 (1999) rats alternating between place navigation and beacon approach 613–616. tasks, Eur. J. Neurosci. 11 (1999) 4381–4388. [64] J.M. Wyss, T. van Groen, Connections between the retrosplenial [62] M.P. Witter, Organization of the entorhinal-hippocampal system: cortex and the hippocampal formation in the rat: a review, a review of current anatomical data, Hippocampus 3 (1993) 33–44. Hippocampus 2 (1992) 1–12.