A model of grid cells involving extra hippocampal path integration, and the hippocampal loop.

In this paper, we present a model for the generation of grid cells and the emergence of place cells from multimodal input to the entorhinal cortex (EC). In this model, grid cell activity in the dorsocaudal medial entorhinal cortex (dMEC) [28] results from the operation of a long-distance path integration system located outside the hippocampal formation, presumably in retrosplenial and/or parietal cortex. If the connections between these structures and dMEC are organized as a modulo N operator, the resulting activity of dMEC neurons is a grid cell pattern. Furthermore, a robust high-resolution positional code can be built from a small set of different grid cells if the modulo factors are relatively prime. On the other hand, broad visual place cell activity in the MEC can result from the integration of visual information depending on the view-field of the visual input. The merging of entorhinal visual place cell information and grid cell information in the EC and/or in the dentate gyrus (DG) allows the building of precise and robust "place cells" (e.g., whose activity is maintained if light is suppressed for a short duration). Our model supports our previous proposition that hippocampal "place cell" activity code transitions between two successive states ("transition cells") rather than mere current locations. Furthermore, we discuss the possibility that the hippocampal loop participates in the emergence of grid cell activity but is not sufficient by itself. Finally, path integration at a short time scale (which is reset from one place to the next) would be merged in the subiculum with CA3/CA1 "transition cells" [22] to provide a robust feedback about current action to the deep layer of the entorhinal cortex in order to predict the recognition of the new animal location.

Sensory and memory properties of hippocampal place cells.

The rat hippocampus contains place cells whose firing is location-specific. These cells fire only when the rat enters a restricted region of the environment called the firing field. In this review, we examine the sensory information that is fundamental to the place cell system for producing spatial firing. While visual information takes precedence in the control of firing fields when it is available, local (olfactory and/or tactile) cues combined with motion-related cues can permit stable spatial firing. Motion-related cues are integrated by hippocampal place cells, but in the absence of external cues do not support stable firing over long periods. While firing fields are based on a variety of sensory cues, they do not strictly depend on such cues. Rather, sensory information is important for activating the representation appropriate to the current environment as reflected by the firing properties of place cell ensembles. Specific sensory channels as well as the memory properties of place cells can support ongoing firing under manipulations of the environment. These memory features raise the question of the role of the place cell system in the acquisition, storage and retrieval of spatial information. Based on the existing literature about the effects of hippocampal lesions and about the metabolic activations in spatial memory tasks, we suggest that a function of the place cell system is to automatically provide the organism with information about its current location so as to allow for the rapid acquisition of novel information.

Spatial navigation and hippocampal place cell firing: the problem of goal encoding.

Place cells are hippocampal neurons whose discharge is strongly related to a rat's location in the environment. The existence of such cells, combined with the reliable impairments seen in spatial tasks after hippocampal damage, has led to the proposal that place cells form part of an integrated neural system dedicated to spatial navigation. This hypothesis is supported by the strong relationships between place cell activity and spatial problem solving, which indicate that the place cell representation must be both functional and in register with the surroundings for the animal to perform correctly in spatial tasks. The place cell system nevertheless requires other essential elements to be competent, such as a component that specifies the overall goal of the animal and computes the path required to take the rat from its current location to the goal. Here, we propose a model of the neural network responsible for spatial navigation that includes goal coding and path selection. In this model, the hippocampal formation allows for place recognition, and stores the set of places that can be accessed from each position in the environment. The prefrontal cortex is responsible for encoding goal location and for route planning. The nucleus accumbens translates paths in neural space into appropriate locomotor activity that moves the animal towards the goal in real space. The complete model assumes that the hippocampal output to nucleus accumbens and prefrontal cortex provides information for generating solutions to spatial problems. In support of this model, we finally present preliminary evidence that the goal representation necessary for path planning might be encoded in the prelimbic/infralimbic region of the medial prefrontal cortex.

Effects of lesions of the associative parietal cortex on the acquisition and use of spatial memory in egocentric and allocentric navigation tasks in the rat.

It has been hypothesized that the rat associative parietal cortex (APC) is involved in the association between visuospatial and locomotion-generated (kinesthetic) information. To study the kinesthetic component, APC-lesioned and control rats were trained in total darkness to reach a submerged platform in the Morris water maze. In the egocentric task, the relative position of the starting point and the platform was constant all over training. Parietal rats have been found impaired in acquisition and to a less extent in retention of this task. In the allocentric task, rats were then trained in the standard version of the navigation task. A mild deficit was observed in acquisition of this task because the APC-lesioned rats displayed longer escape latencies but control-like search patterns. These results suggest that the APC is involved in the coding of kinesthetic information that plays an important role in place navigation.

Dissociation of the effects of bilateral lesions of the dorsal hippocampus and parietal cortex on path integration in the rat.

Rodents are able to rely on self-motion (idiothetic) cues and navigate toward a reference place by path integration. The authors tested the effects of dorsal hippocampal and parietal lesions in a homing task to dissociate the respective roles of the hippocampus and the parietal cortex in path integration. Hippocampal rats exhibited a strong deficit in learning the basic task. Parietal rats displayed a performance impairment as a function of the complexity of their outward paths when the food was placed at varying locations. These results suggest that the parietal cortex plays a specific role in path integration and in the processing of idiothetic information, whereas the hippocampus is involved in the calibration of space used by the path integration system.

Object exploration and reactions to spatial and nonspatial changes in hooded rats following damage to parietal cortex or hippocampal formation.

Hooded rats with bilateral lesions of the anterior part of the hippocampal formation (HIP), anterior region of the posterior parietal cortex (APC), or posterior region of the posterior parietal cortex (PPC) were compared with controls for their exploration of 5 objects in an open field, habituation of locomotion and object investigation, and response to spatial and nonspatial change. First, all groups displayed habituation of both locomotor and exploratory activity. Second, controls selectively reexplored displaced objects, and APC-lesioned rats reexplored all objects, whereas PPC- and HIP-lesioned rats failed to react to the spatial change. Third, a novel object induced reexploration in all groups. The results are consistent with the roles of the HIP and PPC in spatial information processing. Moreover, the APC and PPC are involved in attentional effortful processing and visuospatial information processing necessary for spatial representation, respectively.

Visually guided locomotion, distractibility, and the missing-stimulus effect in hooded rats with unilateral or bilateral lesions of parietal cortex.

When hooded rats with bilateral lesions of Krieg's area 7 (parietal cortex) were trained to locomote toward visual targets in a runway, they ran less accurately than did controls, although unilaterals ran accurately. When flashing lights were presented unexpectedly during their run, bilateral parietals were less disrupted than were controls, but they failed to show total neglect. Unilateral paritals turned toward distracters on either side but turned preferentially toward distracters contralateral to the intact hemisphere, particularly when distracters occurred bilaterally and simultaneously. Effects due to the omission of expected distracters were similar in parietals and controls. Rat parietal cortex is not essential for the redirection of attention to stimuli notable for their unexpected presence or absence, but parietal cortex may resolve interhemispheric competition. The results suggest a homology between parietal cortex in rat and primate.

Involvement of the hippocampus and associative parietal cortex in the use of proximal and distal landmarks for navigation.

Rats with dorsal hippocampus or associative parietal cortex (APC) lesions and sham-operated controls were trained on variants of the Morris water maze navigation task. In the 'proximal landmark condition', the rats had to localize the hidden platform solely on the basis of three salient object landmarks placed directly in the swimming pool. In the 'distal landmark condition', rats could rely only on distal landmarks (room cues) to locate the platform. In the 'beacon condition', the platform location was signaled by a salient cue directly attached to it. Rats with hippocampal lesions were impaired in the distal and to a less extent in the proximal landmark condition whereas rats with parietal lesions were impaired only in the proximal landmark condition. None of the lesioned groups was impaired in the beacon condition. These results suggest that the processing of information related to proximal, distal landmarks or associated beacon are mediated by different neural systems. The hippocampus would contribute to both proximal and distal landmark processing whereas the APC would be involved in the processing of proximal landmarks only. Navigation relying on a cued-platform would not require participation of the hippocampus nor the APC. Assuming that the processing of proximal landmarks heavily depends on the integration of visuospatial and idiothetic information, these results are consistent with the hypothesis that the APC plays a role in the combination of multiple sensory information and contributes to the formation of an allocentric spatial representation.

Re-evaluation of the spatial memory deficits induced by hippocampal short lasting inactivation reveals the need for cortical co-operation.

Evidence has accumulated that the rat hippocampus plays a central role in spatial memory. In complement to lesion studies, reversible lidocaïne-induced inactivations have been used to investigate the time-course of the memory processes mediated by the hippocampus. A number of studies suggest that, in some conditions, the hippocampus is not necessary for online acquisition of spatial information. To test this hypothesis, we examined the effects of bilateral lidocaïne-induced inactivations of the dorsal hippocampus in the acquisition of new spatial information. After initial learning of a place navigation task in the water maze, rats were tested for acquisition of a new platform location and received injections of lidocaïne in the hippocampus prior to each daily four-trial block. The training blocks were separated by a 24-h period allowing the hippocampus to recover from inactivation. The results show that lidocaïne-injected rats were able to learn the new platform location like controls. Inactivations, however, was found to induce a within-block learning impairment. This suggests that the hippocampus can perform off-line processing and that another structure is able to handle spatial information during hippocampal inactivations. Parietal-lesioned rats that received an injection of lidocaïne were still able to learn the new platform location suggesting that the parietal cortex does not sustain this role. Overall, our results suggest that the hippocampus is not necessary for all stages of memory formation and co-operates with other brain, possibly cortical, structures which remain to be determined.

Posterior parietal cortex lesions severely disrupt spatial learning in DBA mice characterized by a genetic hippocampal dysfunction.

C57BL/6 (C57) and DBA/2 (DBA) inbred mice with posterior parietal cortex or sham lesions were tested in a radial eight-arm maze task with all the paths baited. In the high learner C57 strain, parietal lesions produced a limited impairment of performance without affecting maze-running strategies while the same lesions were found to affect more severely performance in the poor learner DBA strain. Because (1) the processing of spatial information has been found to depend on the conjunctive participation of the hippocampus and the posterior parietal cortex, and (2) DBA mice represent a genetic model of hippocampal dysfunction, the fact that parietal lesions impair spatial performance more severely in the DBA strain suggests that the contribution of the posterior parietal cortex to spatial learning depends on the degree of functionality of the hippocampus.

Exploratory activity and response to a spatial change in rats with hippocampal or posterior parietal cortical lesions.

Rats with bilateral lesions of posterior parietal cortex (PPC: Krieg's Area 7) or dorsal hippocampus (HIP) were compared with controls for their response to environmental change. In the first experiment, following subjects' exploration of a relatively homogeneous open-field environment, a stimulus-rat was introduced at a particular location beneath the glass floor. All groups selectively explored the location of the stimulus-rat, but only the control and PPC groups displayed habituation. On removal of the stimulus-rat, only the control group selectively re-explored the place where the stimulus-rat had been. A second experiment, similar to the first, used additional prominent visual cues beneath the floor. When the cues were spatially separate from the location of the stimulus-rat (Dissociated object condition), the same results were obtained as in the first experiment. When the additional cues were positioned close to the stimulus-rat location (Associated object condition), habituation occurred in all groups including the hippocampal group, and again the removal of the stimulus-rat resulted in a selective re-exploration of its former location in the control group only. However, a selective preference for staying at the stimulus-rat's previous location was found in PPC animals as in controls. Hippocampal rats failed to investigate the location of the missing stimulus in all conditions. The results confirm the role played by the hippocampus in spatial memory and suggest that the posterior parietal cortex is involved in the cognitive-demanding aspects of spatial encoding, particularly in environments that are poorly visually differentiated.

Effects of parietal cortex lesions on spatial problem solving in the rat.

The Maier 3-table task was used to examine spatial representations in rats with lesions of the parietal cortex. Some animals had anteriorly placed lesions, some posteriorly placed in cortical areas, sometimes regarded as 'parietal' in earlier studies. After 5 days of familiarization, animals were given 18 days of testing on the standard Maier task. Both parietal groups were initially impaired, but reached the same level of performance as controls by the end of the test period. Learning occurred both within and between sessions for the anterior group, but only between sessions for the posterior group. There was no major functional differentiation apparent on this task between the two 'parietal' areas. Rate of exploration increased in both parietal groups across test sessions as task performance improved. It is argued that the change in exploratory activity across sessions in parietal groups may reflect the adoption of a compensatory strategy which improved performance, but that improvement could also have been due to neural changes, as structures, such as the frontal cortex or hippocampus, assume some functions normally mediated by the parietal area.

Effortful information processing in a spontaneous spatial situation by rats with medial prefrontal lesions.

Previous research has suggested that the rat prefrontal cortex might play a role in spatial information processing and in divided attention. More recent work showed that the effect of prefrontal lesions is more important when the task involves response selection in complex situations. The first aim of the present study was to test the effect of lesions of the prelimbic area of the rat prefrontal cortex in spatial exploration, a situation involving the processing of spatial and non-spatial information, but requiring no response selection. The second aim was to manipulate the degree of cognitive effort required by the task. The latter effect was tested by manipulating the number of items to explore. Rats explored either a simple (3 objects) or a complex (6 objects) situation. We reasoned that acquiring spatial information so as to react adequately to spatial or non spatial changes involved more effortful processing in the complex situation than in the simpler one. The results suggest that the medial prefrontal cortex is not crucially involved in effortful processing when the task requires no response selection.

The differences shown by C57BL/6 and DBA/2 inbred mice in detecting spatial novelty are subserved by a different hippocampal and parietal cortex interplay.

Inbred C57BL/6 (C57) and DBA/2 (DBA) mice with hippocampus, posterior parietal cortex or sham lesions were placed in an open-field containing five objects and their reactivity to the displacement (spatial novelty) or the substitution (object novelty) of some of these objects was examined. C57 mice reacted to spatial novelty by exploring more the displaced than the non-displaced objects while DBA mice did not show any consistent reaction. In the highly reactive C57 strain, the peak of exploratory responses directed towards the displaced objects was completely abolished by hippocampal and posterior parietal cortex lesions. In the non-reactive DBA strain, hippocampal lesions induced an aspecific decreased interest towards the two categories of objects while posterior parietal cortex lesions did not produce any behavioral modification. The high reactivity of C57 mice to spatial change appears to be subserved by the conjunctive participation of the hippocampus and the posterior parietal cortex. Conversely, the deficit shown by DBA mice in that situation seems to be related to: (i) a poorly functional hippocampus; and (ii) the non-involvement of the posterior parietal cortes. The present data suggest that the participation of the posterior parietal cortes to the detection of spatial novelty may depend on the degree of functionality of the hippocampus.

Different effects of yohimbine and idazoxan in the light-dark choice procedure.

In a light-dark choice situation, the alpha(2) adrenoceptor antagonists yohimbine and idazoxan had different effects: idazoxan decreased time spent in the fit box, but yohimbine did not. The effects of idazoxan were not blocked by the alpha(2) adrenoceptor agonist clonidine. The benzodiazepine receptor antagonist Ro 15-1788 itself decreased time spent in the lit box, but in the presence of Ro 15-1788, idazoxan did not cause any further reduction.

Anxiogenic-like effects of yohimbine and idazoxan in two behavioral situations in mice.

In a light-dark choice situation, the alpha-2 adrenoceptor antagonist idazoxan shows anxiogenic-like effects, which cannot be blocked by the alpha-2 adrenoceptor agonist clonidine, or by the benzodiazepine receptor antagonist Ro 15-1788. In a conditioned conflict situation, both idazoxan and the alpha-2-adrenoceptor yohimbine show anxiogenic-like effects; the effect of idazoxan could not be blocked by clonidine or Ro 15-1788. These data suggest that systems other than alpha-2 adrenoceptors or benzodiazepine receptors must be found to explain these anxiogenic-like properties.

The hippocampo-cortical loop: spatio-temporal learning and goal-oriented planning in navigation.

We present a neural network model where the spatial and temporal components of a task are merged and learned in the hippocampus as chains of associations between sensory events. The prefrontal cortex integrates this information to build a cognitive map representing the environment. The cognitive map can be used after latent learning to select optimal actions to fulfill the goals of the animal. A simulation of the architecture is made and applied to learning and solving tasks that involve both spatial and temporal knowledge. We show how this model can be used to solve the continuous place navigation task, where a rat has to navigate to an unmarked goal and wait for 2 seconds without moving to receive a reward. The results emphasize the role of the hippocampus for both spatial and timing prediction, and the prefrontal cortex in the learning of goals related to the task.

Stability and variability of place cell activity during behavior: functional implications for dynamic coding of spatial information.

In addition to their discharge strongly related to a rat's location in the environment, hippocampal place cells have recently been discovered to carry other more subtle signals. For instance, place cells exhibit overdispersion, i.e., a tendency to have highly variable firing rates across successive passes in the firing field, which may reflect the processing of different classes of cues. In addition, the place cell population tends to fire synchronously during specific phases of place navigation, presumably signaling the animal's arrival at the goal location, or to be reactivated during either sleep or wakefulness following exposure to a new environment, a process thought to be important for memory consolidation. Although these various phenomena are expressed at different timescales, it is very likely that they can occur at the same time during an animal's exposure to a spatial environment. The advantage of such simultaneous processing is that it permits the organism both to be aware of its own location in the environment, and to attend to other environmental features and to store multiple experiences. However its pitfall is that it may result in noisy signals that are difficult to decipher by output structures. Therefore the question is asked of how the information carried by each process can be disentangled. We provide some examples from recent research work showing that this problem is far from being trivial and we propose an explanatory framework in which place cell activity at different timescales could be viewed as a series of dynamic attractors nested within each other.

Oxidative stress and prevention of the adaptive response to chronic iron overload in the brain of young adult rats exposed to a 150 kilohertz electromagnetic field.

Iron surcharge may induce an oxidative stress-based decline in several neurological functions. In addition, electromagnetic fields (EMF) of frequencies up to about 100 kHz, emitted by electric/electronic devices, have been suggested to enhance free radical production through an iron dependent pathway. The purpose of this study was therefore to determine a possible relationship between iron status, exposure to EMF, and brain oxidative stress in young adult rats. Samples were micro-dissected from prefrontal cortex, hippocampus, striatum, and cerebellum after chronic saline or iron overload (IO) as well as after chronic sham exposure or exposure to a 150 kHz EMF or after combining EMF exposure with IO. The brain samples were used to monitor oxidative stress-induced lipid peroxidation and activity of the antioxidant enzymes superoxide dismutase and catalase. While IO did not induce any oxidative stress in young adult rats, it stimulated antioxidant defenses in the cerebellum and prefrontal cortex in particular. On the contrary, EMF exposure stimulated lipid peroxidation mainly in the cerebellum, without affecting antioxidant defenses. When EMF was coapplied with IO, lipid peroxidation was further increased as compared to EMF alone while the increase in antioxidant defenses triggered by the sole IO was abolished. These data suggest that EMF exposure may be harmful in young adults by impairing the antioxidant defenses directed at preventing iron-induced oxidative stress.

Spatial discrimination of visually similar environments by hippocampal place cells in the presence of remote recalibrating landmarks.

Place cells in the rat hippocampus commonly show place-related firing activity in the animal's current environment. Here, we evaluated the capability of the place cell system to discriminate visually identical environments. Place cell activity was first recorded while rats moved freely in a cylinder divided into three connected sectors. Two sectors were visually identical whereas the third sector was made distinctive by the addition of visual and tactile cues. When in a given sector, the rats could not perceive the cues present in the other two sectors. Most cells had distinctive place fields in each sector, including the two identical sectors. To rule out the influence of non-controlled cues, rotations of the cylinder (+/- 120 degrees) were conducted. When successful, cylinder rotations resulted in equivalent field rotation for all cells. These results suggest that the place cell system is able to form a specific spatial representation for all sectors, so that the rat knows, at any time, in which sector it is currently located. Presumably, such discrimination relies on angular path integration in which the computational errors stemming from self-motion cues would be corrected by environmental landmarks provided by the distinctive sector.