Long-lasting spatial memory deficits and impaired hippocampal plasticity following unilateral vestibular loss.

Unilateral vestibular loss (UVL) induces a characteristic vestibular syndrome composed of various posturo-locomotor, oculomotor, vegetative and perceptivo-cognitive symptoms. Functional deficits are progressively recovered over time during vestibular compensation, that is supported by the expression of multiscale plasticity mechanisms. While the dynamic of post-UVL posturo-locomotor and oculomotor deficits is well characterized, the expression over time of the cognitive deficits, and in particular spatial memory deficits, is still debated. In this study we aimed at investigating spatial memory deficits and their recovery in a rat model of unilateral vestibular neurectomy (UVN), using a wide spectrum of behavioral tasks. In parallel, we analyzed markers of hippocampal plasticity involved in learning and memory. Our results indicate the UVN affects all domains of spatial memory, from working memory to reference memory and object-in-place recognition. These deficits are associated with long-lasting impaired plasticity in the ipsilesional hippocampus. These results highlight the crucial role of symmetrical vestibular information in spatial memory and contribute to a better understanding of the cognitive disorders observed in vestibular patients.

Zn2+ inhibits spatial memory and hippocampal place cell representation through high-affinity binding to the NMDA receptor GluN2A subunit.

A subset of glutamatergic neurons in the forebrain uses labile Zn2+ as a co-transmitter alongside glutamate. Synaptic Zn2+ plays a key role in learning and memory processes, but its mechanisms of action remain poorly understood. Here, we used a knock-in (KI) mouse line carrying a point mutation at the GluN2A Zn2+ binding site that selectively eliminates zinc inhibition of NMDA receptors. Ablation of Zn2+-GluN2A binding improves spatial memory retention and contextual fear memory formation. Electrophysiological recording of hippocampal neurons in the CA1 area revealed a greater proportion of place cells and substantial place field remapping in KI mice compared to wildtype littermates. Persistent place cell remapping was also seen in KI mice upon repeated testing suggesting an enhanced ability to maintain a distinct representation across multiple overlapping experiences. Together, these findings reveal an original molecular mechanism through which synaptic Zn2+ negatively modulates spatial cognition by dampening GluN2A-containing NMDA receptor signaling.

Medial entorhinal cortex lesions induce degradation of CA1 place cell firing stability when self-motion information is used.

The entorhinal-hippocampus network plays a central role in navigation and episodic memory formation. To investigate these interactions, we examined the effect of medial entorhinal cortex lesions on hippocampal place cell activity. Since the medial entorhinal cortex is suggested to play a role in the processing of self-motion information, we hypothesised that such processing would be necessary for maintaining stable place fields in the absence of environmental cues. Place cells were recorded as medial entorhinal cortex-lesioned rats explored a circular arena during five 16-min sessions comprising a baseline session with all sensory inputs available followed by four sessions during which environmental (i.e. visual, olfactory, tactile) cues were progressively reduced to the point that animals could rely exclusively on self-motion cues to maintain stable place fields. We found that place field stability and a number of place cell firing properties were affected by medial entorhinal cortex lesions in the baseline session. When rats were forced to rely exclusively on self-motion cues, within-session place field stability was dramatically decreased in medial entorhinal cortex rats relative to SHAM rats. These results support a major role of the medial entorhinal cortex in processing self-motion cues, with this information being conveyed to the hippocampus to help anchor and maintain a stable spatial representation during movement.

Dorsal, but not ventral, hippocampal inactivation alters deliberation in rats.

When facing a choice at a decision point in a maze, rats often display hesitations, pauses and reorientations. Such "vicarious trial and error" (VTE) behavior is thought to reflect decision making about which choice option is best, and thus a deliberation process. Although deliberation relies on a wide neural network, the dorsal hippocampus appears to play a prominent role through both its neural activity and its dynamic interplay with other brain areas. In contrast, the involvement of the ventral hippocampus in deliberation is unexplored. Here, we compared directly the effects of dorsal (dHPC) and ventral intermediate (vHPC) hippocampal inactivations induced by intracerebral muscimol injections on VTE behavior as a model of deliberation. To this aim, we analyzed VTE events as rats were required to switch strategy to a new unlearned reward rule. We used a protocol in which task performance in muscimol-injected animals was minimally altered so as to evidence specific effects on VTE behavior. Our results show subtle alterations in VTE behavior following dHPC, but not vHPC, inactivations, therefore suggesting a specific contribution of the dorsal hippocampus to deliberation through its role in prospective evaluation of future actions.

Merging information in the entorhinal cortex: what can we learn from robotics experiments and modeling?

Place recognition is a complex process involving idiothetic and allothetic information. In mammals, evidence suggests that visual information stemming from the temporal and parietal cortical areas ('what' and 'where' information) is merged at the level of the entorhinal cortex (EC) to build a compact code of a place. Local views extracted from specific feature points can provide information important for view cells (in primates) and place cells (in rodents) even when the environment changes dramatically. Robotics experiments using conjunctive cells merging 'what' and 'where' information related to different local views show their important role for obtaining place cells with strong generalization capabilities. This convergence of information may also explain the formation of grid cells in the medial EC if we suppose that: (1) path integration information is computed outside the EC, (2) this information is compressed at the level of the EC owing to projection (which follows a modulo principle) of cortical activities associated with discretized vector fields representing angles and/or path integration, and (3) conjunctive cells merge the projections of different modalities to build grid cell activities. Applying modulo projection to visual information allows an interesting compression of information and could explain more recent results on grid cells related to visual exploration. In conclusion, the EC could be dedicated to the build-up of a robust yet compact code of cortical activity whereas the hippocampus proper recognizes these complex codes and learns to predict the transition from one state to another.

Path integration maintains spatial periodicity of grid cell firing in a 1D circular track.

Entorhinal grid cells are thought to provide a 2D spatial metric of the environment. In this study we demonstrate that in a familiar 1D circular track (i.e., a continuous space) grid cells display a novel 1D equidistant firing pattern based on integrated distance rather than travelled distance or time. In addition, field spacing is increased compared to a 2D open field, probably due to a reduced access to the visual cue in the track. This metrical modification is accompanied by a change in LFP theta oscillations, but no change in intrinsic grid cell rhythmicity, or firing activity of entorhinal speed and head-direction cells. These results suggest that in a 1D circular space grid cell spatial selectivity is shaped by path integration processes, while grid scale relies on external information.

Medial entorhinal cortex and medial septum contribute to self-motion-based linear distance estimation.

Path integration is a navigation strategy that requires animals to integrate self-movements during exploration to determine their position in space. The medial entorhinal cortex (MEC) has been suggested to play a pivotal role in this process. Grid cells, head-direction cells, border cells as well as speed cells within the MEC collectively provide a dynamic representation of the animal position in space based on the integration of self-movements. All these cells are strongly modulated by theta oscillations, thus suggesting that theta rhythmicity in the MEC may be essential for integrating and coordinating self-movement information during navigation. In this study, we first show that excitotoxic MEC lesions, but not dorsal hippocampal lesions, impair the ability of rats to estimate linear distances based on self-movement information. Next, we report similar deficits following medial septum inactivation, which strongly impairs theta oscillations in the entorhinal-hippocampal circuits. Taken together, these findings demonstrate a major role of the MEC and MS in estimating distances to be traveled, and point to theta oscillations within the MEC as a neural mechanism responsible for the integration of information generated by linear self-displacements.

Retrosplenial and postsubicular head direction cells compared during visual landmark discrimination.

BACKGROUND: Visual landmarks are used by head direction (HD) cells to establish and help update the animal's representation of head direction, for use in orientation and navigation. Two cortical regions that are connected to primary visual areas, postsubiculum (PoS) and retrosplenial cortex (RSC), possess HD cells: we investigated whether they differ in how they process visual landmarks. METHODS: We compared PoS and RSC HD cell activity from tetrode-implanted rats exploring an arena in which correct HD orientation required discrimination of two opposing landmarks having high, moderate or low discriminability. RESULTS: RSC HD cells had higher firing rates than PoS HD cells and slightly lower modulation by angular head velocity, and anticipated actual head direction by ~48 ms, indicating that RSC spiking leads PoS spiking. Otherwise, we saw no differences in landmark processing, in that HD cells in both regions showed equal responsiveness to and discrimination of the cues, with cells in both regions having unipolar directional tuning curves and showing better discrimination of the highly discriminable cues. There was a small spatial component to the signal in some cells, consistent with their role in interacting with the place cell navigation system, and there was also slight modulation by running speed. Neither region showed theta modulation of HD cell spiking. CONCLUSIONS: That the cells can immediately respond to subtle differences in spatial landmarks is consistent with rapid processing of visual snapshots or scenes; similarities in PoS and RSC responding may be due either to similar computations being performed on the visual inputs, or to rapid sharing of information between these regions. More generally, this two-cue HD cell paradigm may be a useful method for testing rapid spontaneous visual discrimination capabilities in other experimental settings.

An independent, landmark-dominated head-direction signal in dysgranular retrosplenial cortex.

We investigated how landmarks influence the brain's computation of head direction and found that in a bidirectionally symmetrical environment, some neurons in dysgranular retrosplenial cortex showed bidirectional firing patterns. This indicates dominance of neural activity by local environmental cues even when these conflicted with the global head direction signal. It suggests a mechanism for associating landmarks to or dissociating them from the head direction signal, according to their directional stability and/or utility.

Vestibular control of entorhinal cortex activity in spatial navigation.

Navigation in rodents depends on both self-motion (idiothetic) and external (allothetic) information. Idiothetic information has a predominant role when allothetic information is absent or irrelevant. The vestibular system is a major source of idiothetic information in mammals. By integrating the signals generated by angular and linear accelerations during exploration, a rat is able to generate and update a vector pointing to its starting place and to perform accurate return. This navigation strategy, called path integration, has been shown to involve a network of brain structures. Among these structures, the entorhinal cortex (EC) may play a pivotal role as suggested by lesion and electrophysiological data. In particular, it has been recently discovered that some neurons in the medial EC display multiple firing fields producing a regular grid-like pattern across the environment. Such regular activity may arise from the integration of idiothetic information. This hypothesis would be strongly strengthened if it was shown that manipulation of vestibular information interferes with grid cell activity. In the present paper we review neuroanatomical and functional evidence indicating that the vestibular system influences the activity of the brain network involved in spatial navigation. We also provide new data on the effects of reversible inactivation of the peripheral vestibular system on the EC theta rhythm. The main result is that tetrodotoxin (TTX) administration abolishes velocity-controlled theta oscillations in the EC, indicating that vestibular information is necessary for EC activity. Since recent data demonstrate that disruption of theta rhythm in the medial EC induces a disorganization of grid cell firing, our findings indicate that the integration of idiothetic information in the EC is essential to form a spatial representation of the environment.