Acute peripheral vestibulopathy leads to a cascade of symptoms involving balance and gait disorders that are particularly disabling for vestibular patients. Vestibular rehabilitation protocols have proven to be effective in improving vestibular compensation in clinical practice. Yet, the underlying neurobiological correlates remain unknown. The aim of this study was to highlight the behavioural and cellular consequences of a vestibular rehabilitation protocol adapted to a rat model of unilateral vestibular neurectomy. We developed a progressive sensory-motor rehabilitation task, and the behavioural consequences were quantified using a weight-distribution device. This analysis method provides a precise and ecological analysis of posturolocomotor vestibular deficits. At the cellular level, we focused on the analysis of plasticity mechanisms expressed in the vestibular nuclei. The results obtained show that vestibular rehabilitation induces a faster recovery of posturolocomotor deficits during vestibular compensation associated with a decrease in neurogenesis and an increase in microgliogenesis in the deafferented medial vestibular nucleus. This study reveals for the first time a part of the underlying adaptative neuroplasticity mechanisms of vestibular rehabilitation. These original data incite further investigation of the impact of rehabilitation on animal models of vestibulopathy. This new line of research should improve the management of vestibular patients.

Unilateral vestibular lesions induce a vestibular syndrome, which recovers over time due to vestibular compensation. The therapeutic effect of L-Thyroxine (L-T4) on vestibular compensation was investigated by behavioral testing and immunohistochemical analysis in a rat model of unilateral vestibular neurectomy (UVN). We demonstrated that a short-term L-T4 treatment reduced the vestibular syndrome and significantly promoted vestibular compensation. Thyroid hormone receptors (TRα and TRβ) and type II iodothyronine deiodinase (DIO2) were present in the vestibular nuclei (VN), supporting a local action of L-T4. We confirmed the T4-induced metabolic effects by demonstrating an increase in the number of cytochrome oxidase-labeled neurons in the VN three days after the lesion. L-T4 treatment modulated glial reaction by decreasing both microglia and oligodendrocytes in the deafferented VN three days after UVN and increased cell proliferation. Survival of newly generated cells in the deafferented vestibular nuclei was not affected, but microglial rather than neuronal differentiation was favored by L-T4 treatment.

Background: Due to their anti-inflammatory action, corticosteroids are the reference treatment for brain injuries and many inflammatory diseases. However, the benefits of acute corticotherapy are now being questioned, particularly in the case of acute peripheral vestibulopathies (APV), characterized by a vestibular syndrome composed of sustained spinning vertigo, spontaneous ocular nystagmus and oscillopsia, perceptual-cognitive, posturo-locomotor, and vegetative disorders. We assessed the effectiveness of acute corticotherapy, and the functional role of acute inflammation observed after sudden unilateral vestibular loss.Methods: We used the rodent model of unilateral vestibular neurectomy, mimicking the syndrome observed in patients with APV. We treated the animals during the acute phase of the vestibular syndrome, either with placebo or methylprednisolone, an anti-inflammatory corticosteroid. At the cellular level, impacts of methylprednisolone on endogenous plasticity mechanisms were assessed through analysis of cell proliferation and survival, glial reactions, neuron’s membrane excitability, and stress marker. At the behavioral level, vestibular and posturo-locomotor functions’ recovery were assessed with appropriate qualitative and quantitative evaluations.Results: We observed that acute treatment with methylprednisolone significantly decreases glial reactions, cell proliferation and survival. In addition, stress and excitability markers were significantly impacted by the treatment. Besides, vestibular syndrome’s intensity was enhanced, and vestibular compensation delayed under acute methylprednisolone treatment.Conclusions: We show here, for the first time, that acute anti-inflammatory treatment alters the expression of the adaptive plasticity mechanisms in the deafferented vestibular nuclei and generates enhanced and prolonged vestibular and postural deficits. These results strongly suggest a beneficial role for acute endogenous neuroinflammation in vestibular compensation. They open the way to a change in dogma for the treatment and therapeutic management of vestibular patients.

Unilateral vestibular loss (UVL) induces a vestibular syndrome composed of posturo-locomotor, oculomotor, vegetative, and perceptivo-cognitive symptoms. With time, these functional deficits progressively disappear due to a phenomenon called vestibular compensation, known to be supported by the expression in the deafferented vestibular nuclei (VNs) of various adaptative plasticity mechanisms. UVL is known to induce a neuroinflammatory response within the VNs, thought to be caused by the structural alteration of primary vestibular afferents. The acute inflammatory response, expressed in the deafferented VNs was recently proven to be crucial for the expression of the endogenous plasticity supporting functional recovery. Neuroinflammation is supported by reactive microglial cells, known to have various phenotypes with adverse effects on brain tissue. Here, we used markers of pro-inflammatory and anti-inflammatory phenotypes of reactive microglia to study microglial dynamics following a unilateral vestibular neurectomy (UVN) in the adult rat. In addition, to highlight the role of acute inflammation in vestibular compensation and its underlying mechanisms, we enhanced the inflammatory state of the deafferented VNs using systemic injections of lipopolysaccharide (LPS) during the acute phase after a UVN. We observed that the UVN induced the expression of both M1 proinflammatory and M2 anti-inflammatory microglial phenotypes in the deafferented VNs. The acute LPS treatment exacerbated the inflammatory reaction and increased the M1 phenotype while decreasing M2 expression. These effects were associated with impaired postlesional plasticity in the deafferented VNs and exacerbated functional deficits. These results highlight the importance of a homeostatic inflammatory level in the expression of the adaptative plasticity mechanisms underlying vestibular compensation. Understanding the rules that govern neuroinflammation would provide therapeutic leads in neuropathologies associated with these processes.

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.

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.