Pierre-Yves Jacob

Le travail de recherche réalisé au cours de cette thèse s'intéresse à la nature des représentations spatiales formées par le cortex entorhinal médian (CEM). Tout d'abord, nous montrons que le CEM code spécifiquement une information de distance, l'une des composantes nécessaires pour que l'animal puisse réaliser un type de navigation reposant sur les informations idiothétiques, appelé intégration des trajets. Puis, nous observons que le système vestibulaire, une source importante d'informations idiothétiques, influence l'activité thêta du CEM et permet la modulation de ce rythme thêta par la vitesse de déplacement des animaux. Ensuite, nous montrons que l'activité du CEM est nécessaire à la stabilité de l'activité des cellules de lieu. Parallèlement, nous observons que l'activité des cellules grilles du CEM est modifiée par les informations contenues dans l'environnement (allothétiques).Dans leur ensemble, nos résultats montrent que le CEM traite et intègre des informations idiothétiques mais aussi des informations allothétiques. Ces données suggèrent que la carte spatiale du CEM ne fournit pas une métrique universelle reposant sur les informations idiothétiques, mais possède un certain degré de flexibilité en réponse aux changements environnementaux. De plus, cette carte spatiale entorhinale n'est pas requise pour la formation de l'activité spatiale des cellules de lieu, contrairement à ce que suggère l'hypothèse dominante.

In everyday life, mammals navigate through environments composed of multiple interconnected spaces. Understanding how the brain encodes space in such complex settings is essential to uncover the mechanisms that support flexible navigation in the real world. In this study, we investigated how the retrosplenial cortex (RSC) and the hippocampus (HPC) encode spatial information in multi-room environments by recording neuronal activity in rats exploring environments composed of two or four connected rooms. These environments varied both in their structural layout and in their sensory features, allowing us to disentangle the influence of environmental geometry from that of local sensory cues. We found that two types of directional coding coexist within the RSC: classical head direction cells maintained a stable preferred firing direction across all rooms, while multidirectional cells expressed room-specific directional tuning that followed the geometric structure of the environment (e.g., 180° or 90° rotations). In addition, non-directional RSC neurons displayed room-specific spatial firing patterns that repeated across rooms following geometric transformations, similar to the activity observed in multidirectional cells. In contrast, hippocampal place cells either remapped between rooms or showed simple translational repetition, without preserving any geometric alignment. Taken together, these findings reveal a functional dissociation between retrosplenial and hippocampal spatial codes. The RSC supports a structured, multi-scale representation of space, segmenting the environment into locally anchored reference frames embedded within a coherent global geometry. The HPC, by contrast, encodes room-specific representations independently for each compartment. This division may support flexible navigation in complex environments by integrating geometry-based spatial segmentation and unification in the RSC with context-specific encoding in the HPC, thereby enabling multi-level spatial coding across interconnected spaces.

Mole-rats are subterranean rodents that have evolved remarkable sensory adaptations to life in underground tunnel systems, yet their neural mechanisms remain largely unexplored. Here, we present a protocol for in vivo electrophysiological recordings in awake, head-fixed, and freely moving African mole-rats ( Fukomys anselli/micklemi ), overcoming unique challenges of studying the neurobiology of subterranean species. We find that mole-rat brain physiology impacts survival after surgeries, with higher carbon dioxide concentrations required for recovery compared to other rodents, likely due to a mutation in the chloride-potassium symporter KCC2. Having addressed these challenges through our optimized methodology, we used tetrodes and Neuropixels probes to record single-unit activity and local field potentials (LFP) across several cortical and subcortical regions for several weeks. We observed single units responsive to auditory and visual stimuli in the superior colliculus, and hippocampal recordings in freely moving mole-rats revealed prominent theta rhythms at frequencies lower than those observed in any other rodent species to date. Finally, we performed integrated three-dimensional and two-dimensional probe-track analysis within the same brain using tissue clearing, light sheet imaging, rehydration, and vibratome sectioning, and we present a newly developed stereotaxic brain atlas for implantation and histological alignment. This established methodology will guide future studies in comparative rodent neurobiology, providing further insights into neurobiological adaptations to subterranean environments. Given their phylogenetic and ecological similarities, we expect our protocols to be transferable to other subterranean species, including the widely studied naked mole-rat ( Heterocephalus glaber ).

Head direction cells (HDCs) encode the animal’s orientation in space and form a core component of the brain’s navigation system. While their dependence on vestibular input is well established, how directional circuits respond to unilateral vestibular loss (UVL) — the most frequent and ecologically relevant form of vestibular imbalance — remains largely unknown. UVL offers a powerful model to investigate how spatial circuits adapt to asymmetric sensory disruption and partial deafferentation. To explore this, we examined the impact of UVL on anterior thalamic nuclei (ATN) activity and spatially tuned neurons in freely moving rats following unilateral vestibular neurectomy (UVN). UVN induced long-lasting alterations in ATN firing dynamics, including reduced theta modulation, diminished burst firing, and selective disruption across functionally defined neuronal classes: head-direction and speed-modulated cells were strongly affected, while angular head velocity and position cells remained largely preserved. Despite initial degradation, HDCs persisted and progressively regained directional tuning. Crucially, spike waveform analysis revealed two distinct HDC subtypes with markedly different vulnerabilities: one subtype showed reduced prevalence and degraded tuning, whereas the other remained resilient and supported the recovery of directional coding. These findings uncover a previously unrecognized heterogeneity within the head direction system and show that compensation following UVL is partial, cell type–specific, and functionally selective. Together, they offer new insight into sensory plasticity within thalamic navigation circuits and provide a framework to understand spatial deficits associated with vestibular imbalance.

In everyday life, mammals navigate through environments composed of multiple interconnected spaces. Understanding how the brain encodes space in such complex settings is essential to uncover the mechanisms that support flexible navigation in the real world. In this study, we investigated how the retrosplenial cortex (RSC) and the hippocampus (HPC) encode spatial information in multi-room environments by recording neuronal activity in rats exploring environments composed of two or four connected rooms. These environments varied both in their structural layout and in their sensory features, allowing us to disentangle the influence of environmental geometry from that of local sensory cues. We found that two types of directional coding coexist within the RSC: classical head direction cells maintained a stable preferred firing direction across all rooms, while multidirectional cells expressed room-specific directional tuning that followed the geometric structure of the environment (e.g., 180° or 90° rotations). In addition, non-directional RSC neurons displayed room-specific spatial firing patterns that repeated across rooms following geometric transformations, similar to the activity observed in multidirectional cells. In contrast, hippocampal place cells either remapped between rooms or showed simple translational repetition, without preserving any geometric alignment. Taken together, these findings reveal a functional dissociation between retrosplenial and hippocampal spatial codes. The RSC supports a structured, multi-scale representation of space, segmenting the environment into locally anchored reference frames embedded within a coherent global geometry. The HPC, by contrast, encodes room-specific representations independently for each compartment. This division may support flexible navigation in complex environments by integrating geometry-based spatial segmentation and unification in the RSC with context-specific encoding in the HPC, thereby enabling multi-level spatial coding across interconnected spaces.

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.

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.

Since their discovery in the early ‘70s ¹ , hippocampal place cells have been studied in numerous animal and human spatial memory paradigms ^2–4 . These pyramidal cells, along with other spatially tuned types of neurons (e.g. grid cells, head direction cells), are thought to provide the mammalian brain a unique spatial signature characterizing a specific environment, and thereby a memory trace of the subject’s place ⁵ . While grid and head direction cells are found in various brain regions, only few hippocampal-related structures showing ‘place cell’-like neurons have been identified ^6,7 , thus reinforcing the central role of the hippocampus in spatial memory. Concurrently, it is increasingly suggested that visual areas play an important role in spatial cognition as recent studies showed a clear spatial selectivity of visual cortical (V1) neurons in freely moving rodents ^8–10 . We therefore thought to investigate, in the rat, such spatial correlates in a thalamic structure located one synapse upstream of V1, the dorsal Lateral Geniculate Nucleus (dLGN), and discovered that a substantial proportion (ca. 30%) of neurons exhibits spatio-selective activity. We found that dLGN place cells maintain their spatial selectivity in the absence of visual inputs, presumably relying on odor and locomotor inputs. We also found that dLGN place cells maintain their place selectivity across sessions in a familiar environment and that contextual modifications yield separated representations. Our results show that dLGN place cells are likely to participate in spatial cognition processes, creating as early as the thalamic stage a comprehensive representation of one given environment.

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.