Hippocampal LTP modulation and glutamatergic receptors following vestibular loss.

Vestibular dysfunction strongly impairs hippocampus-dependent spatial memory performance and place cell function. However, the hippocampal encoding of vestibular information at the synaptic level, remains sparsely explored and controversial. We investigated changes in in vivo long-term potentiation (LTP) and NMDA glutamate receptor (NMDAr) density and distribution after bilateral vestibular lesions (BVL) in adult rats. At day 30 (D30) post-BVL, the LTP of the population spike recorded in the dentate gyrus (DG) was higher in BVL rats, for the entire 3 h of LTP recording, while no difference was observed in the fEPSP slope. However, there was an increase in EPSP-spike (E-S) potentiation in lesioned rats. NMDArs were upregulated at D7 and D30 predominantly within the DG and CA1. At D30, we observed a higher NMDAr density in the left hippocampus. NMDArs were overexpressed on both neurons and non-neuronal cells, suggesting a decrease of the entorhinal glutamatergic inputs to the hippocampus following BVL. The EPSP-spike (E-S) potentiation increase was consistent with the dorsal hippocampus NMDAr upregulation. Such an increase could reflect a non-specific enhancement of synaptic efficacy, leading to a disruption of memory encoding, and therefore might underlie the memory deficits previously reported in rats and humans following vestibular loss.

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.

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.

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.

Coding for spatial goals in the prelimbic/infralimbic area of the rat frontal cortex.

Finding one's way in space requires a distributed neural network to support accurate spatial navigation. In the rat, this network likely includes the hippocampus and its place cells. Although such cells allow the organism to locate itself in the environment, an additional mechanism is required to specify the animal's goal. Here, we show that firing activity of neurons in medial prefrontal cortex (mPFC) reflects the motivational salience of places. We recorded mPFC neurons from rats performing a place navigation task, and found that a substantial proportion of cells in the prelimbic/infralimbic area had place fields. A much smaller proportion of cells with such properties was found in the dorsal anterior cingulate area. Furthermore, the distribution of place fields in prelimbic/infralimbic cells was not homogeneous: goal locations were overrepresented. Because such locations were spatially dissociated from rewards, we suggest that mPFC neurons might be responsible for encoding the rat's goals, a process necessary for path planning.

Study of CA1 place cell activity and exploratory behavior following spatial and nonspatial changes in the environment.

Changes in the spatial arrangement or identity of objects inside a familiar environment induce reexploration. The present study looks at modifications of place cell activity during such renewed exploration. Hungry rats foraged for food in a cylinder with a salient cue card attached to the wall and with two distinct objects at fixed positions on the floor relative to each other and to the cue card. Once a set of CA1 place cells was recorded in this standard configuration, additional sessions were done after two kinds of manipulation. In the first, the two objects were rotated as a rigid set 90 degrees counterclockwise around the cylinder center while leaving the cue card in place; this was considered a spatial change. The effects of rotating the objects were different for fields near the objects (near fields) and fields far from the objects (far fields). Object rotation altered most near fields in complex ways, including remapping and cessation of firing. Near fields that remained intact after object rotation underwent unpredictable rotations that frequently departed considerably from the expected value of 90 degrees CCW. In contrast, the only change induced in far fields was a reduction of discharge rate on day 1, but not day 2, exposures of the rat to the rotated objects. The effects on both near and far fields were reversed when the objects were returned to their standard position. In the second manipulation, substitution of one of the two familiar objects with a novel object, a nonspatial change, had no detectable effect on place cell activity, regardless of field location. The sensitivity of hippocampal place cells to spatial changes but not to nonspatial changes is in agreement with earlier results showing that hippocampal lesions abolish reexploration after spatial but not after nonspatial object manipulations. The fact that reexploration is accompanied by place cell changes after spatial but not nonspatial changes reinforces the role that the hippocampus is believed to play in navigational computing and is perfectly compatible with the idea that another brain structure, likely perirhinal cortex, is responsible for object recognition.

Independent coding of connected environments by place cells.

Place cells are hippocampal neurons that have a strong location-specific firing activity in the rat's current environment. Collectively, place cells also provide a signature of the rat's environment as their ensemble activity is markedly different when recorded in distinct apparatuses. This phenomenon, referred to as 'remapping', suggests that each environment activates a different hippocampal map. In this study, we sought to determine the independence of such maps. In Experiment 1, we used a cylinder apparatus that was divided into two equal halves by a central barrier with an aperture allowing the rat to freely commute between the two sides. A local change in one side failed to induce field remapping in the changed side, thus precluding any significant conclusion to be drawn. We therefore designed Experiment 2 in which place cells were first recorded while rats explored three distinct high-walled boxes. Most cells had distinctive firing fields in each box. A runway was then added to connect two initially unrelated boxes. This manipulation altered the firing of some cells but the fields in each box were still clearly distinguishable. The final manipulation consisted of changing one box and allowing the rat to commute freely between the changed and unchanged boxes. While the firing fields remapped in the changed box, they were most usually unaltered in the unchanged box. These results suggest that the hippocampus holds a set of independent maps for each box, and that each specific map is activated mainly according to the rat's current sensory environment.

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.

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.

Evidence for a relationship between place-cell spatial firing and spatial memory performance.

The rat hippocampus contains place cells whose firing is location-specific. Although many properties of place cells have been uncovered, little is known about their actual contribution to the animal's spatial performance. In this study, we addressed this issue by recording place cells while rats solved a continuous spatial alternation task in which they had to alternate between the two arms of a Y-maze to get a food reward in the third (goal) arm. By manipulating the information available to the animals, we induced the cells to establish their fields in locations that were out of register relative to their standard position, thus making them inconsistent with the learned spatial task. When this happened, the rats' performance in the alternation task was markedly decreased. In addition, the nature of the behavioral errors during inconsistent field placements also changed dramatically in a way that was highly indicative of the rats' spatial disorientation. These results suggest that there is a functional relationship between the spatial firing patterns of place cells and the spatial behavior of the rat, thus strengthening the idea that these cells are part of a navigational system.

Exploratory patterns of rats on a complex maze provide evidence for topological coding.

Rats' exploratory patterns on a complex elevated maze were analyzed in both light and dark conditions. Rats were less active in the light than in the dark. In the light, they spent more time exploring the outer areas of the maze than the inner areas whereas exploration of both regions was similar in the dark. In both light and dark, rats spent more time investigating choice points (which provided multiple directions for movements) than runways that allowed only simple movements. In addition, choice points that provided more connections with other distant places were associated with more exploration. While such effects might be the result of stimulus-seeking of distant information in the light, increased exploration times in the dark presumably reflect the processing of local information associated with the maze connectivity. These results suggest that exploratory patterns in the dark reflect processing of the topological structure of the maze.

Place-cell firing does not depend on the direction of turn in a Y-maze alternation task.

Hippocampal place cells were recorded while rats solved a continuous spatial alternation task requiring short-term spatial memory. All cells that had a firing field on the stem of the Y-shaped maze were found to have a very similar pattern of discharge whether the rat was about to make a right or a left turn, and whether the preceding turn was a right or a left turn. Thus, the view that place cells encode a variety of events (including the direction of turns) useful for solving memory tasks is not well supported by the present data. We suggest several possible explanations to account for the discrepancy with other recent studies showing turn-related modulation of place-cell activity.

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.

[Neural basis for spatial memory in animals: what do hippocampal neurons tell us?]. / Les bases neurales de la mémoire spatiale chez l'animal: que nous disent les neurones de l'hippocampe?

Recent studies relying on the recording of neuronal unit activity in freely moving rats show the existence of two populations of neurons signalling the animal's location or head direction: place cells found primarily in the hippocampus and head direction cells found in brain areas anatomically and functionally related to the hippocampus. The properties of these two neuronal populations suggest that their activity strongly depends upon information cues stemming from the spatial environment, and also suggest their involvement in spatial memory. Place cells and head direction cells would jointly participate in a neural network allowing the animal to orient in space and to store spatial locations in memory. This network would also be operating in humans, in particular for encoding specific events in episodic memory.

Hippocampal-parietal cortical interactions in spatial cognition.

Growing evidence suggests that the associative parietal cortex (APC) of the rat is involved in the processing of spatial information. This observation raises the issue of the respective functions of the APC and the hippocampus in spatial processing as well as of their possible interactions. In this paper, we review neuroanatomical, electrophysiological, and behavioral data that support the existence of such functional interactions. Our hypothesis is that the APC is involved in the initial combination of visuospatial information and self-motion information necessary for the integration of egocentrically acquired information into allocentrically coded information, the latter step being completed in the hippocampus. The dialogue between the hippocampus and the APC is therefore crucial, particularly when the elaboration and/or updating of an allocentric representation depends on complex combinations of visuospatial and self-motion information.

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.

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.

Contribution of multiple sensory information to place field stability in hippocampal place cells.

Hippocampal place cells in rats display spatially selective firing in relation to both external and internal cues. In the present study, we assessed the effects of removing visual and/or olfactory cues on place field stability. Place cell activity was recorded as rats searched for randomly scattered food in a cylinder. During an initial recording session, the lights were on and the only available cue was a single white cue card. Following this session, three sessions were run in a row with the cue card removed. In addition, the lights were either turned off or left on and the floor was either cleaned or left unchanged, thus creating four conditions: dark/cleaning, dark/no cleaning, light/cleaning, and light/no cleaning. A fifth session was run with the cue card back on the cylinder wall and the lights turned on. The rat remained in the cylinder during all sessions without being removed at any time. In the dark/cleaning and light/cleaning conditions, most place fields were not stable (i.e., abruptly shifted position). In addition, half of the cells stopped firing in the dark/cleaning condition. In contrast, in the dark/no cleaning and light/no cleaning conditions, most place fields remained stable across sessions. These results suggest that 1) rats are not able to rely on only movement-related information to maintain a stable place representation, 2) visual input is necessary for the firing of a large number of cells, and 3) olfactory information can be used to compensate for the lack of visuospatial information.