The Vestibular Nuclei: A Cerebral Reservoir of Stem Cells Involved in Balance Function in Normal and Pathological Conditions.

In this review, we explore the intriguing realm of neurogenesis in the vestibular nuclei-a critical brainstem region governing balance and spatial orientation. We retrace almost 20 years of research into vestibular neurogenesis, from its discovery in the feline model in 2007 to the recent discovery of a vestibular neural stem cell niche. We explore the reasons why neurogenesis is important in the vestibular nuclei and the triggers for activating the vestibular neurogenic niche. We develop the symbiotic relationship between neurogenesis and gliogenesis to promote vestibular compensation. Finally, we examine the potential impact of reactive neurogenesis on vestibular compensation, highlighting its role in restoring balance through various mechanisms.

Thyroid Axis and Vestibular Physiopathology: From Animal Model to Pathology.

A recent work of our group has shown the significant effects of thyroxine treatment on the restoration of postural balance function in a rodent model of acute peripheral vestibulopathy. Based on these findings, we attempt to shed light in this review on the interaction between the hypothalamic-pituitary-thyroid axis and the vestibular system in normal and pathological situations. Pubmed database and relevant websites were searched from inception through to 4 February 2023. All studies relevant to each subsection of this review have been included. After describing the role of thyroid hormones in the development of the inner ear, we investigated the possible link between the thyroid axis and the vestibular system in normal and pathological conditions. The mechanisms and cellular sites of action of thyroid hormones on animal models of vestibulopathy are postulated and therapeutic options are proposed. In view of their pleiotropic action, thyroid hormones represent a target of choice to promote vestibular compensation at different levels. However, very few studies have investigated the relationship between thyroid hormones and the vestibular system. It seems then important to more extensively investigate the link between the endocrine system and the vestibule in order to better understand the vestibular physiopathology and to find new therapeutic leads.

Oxytocin Disturbs Vestibular Compensation and Modifies Behavioral Strategies in a Rodent Model of Acute Vestibulopathy.

Unilateral inner ear injury is followed by behavioral recovery due to central vestibular compensation. The therapeutic effect of oxytocin (OT) on vestibular compensation was investigated by behavioral testing in a rat model of unilateral vestibular neurectomy (UVN). Animals in the oxytocin group (UVN-OT) exhibited delayed vestibular compensation on the qualitative scale of vestibular deficits and aggravated static postural deficits (bearing surface) compared to animals in the NaCl group (UVN-NaCl). Surprisingly, oxytocin-treated animals adopt a different postural strategy than untreated animals. Instead of shifting their weight to the ipsilesional paws (left front and hind paws), they shift their weight to the front paws (right and left) without modification along the lateral axis. Furthermore, some locomotor strategies of the animals to compensate for the vestibular loss are also altered by oxytocin treatment. UVN-OT animals do not induce an increase in the distance traveled, their mean velocity is lower than that in the control group, and the ipsilesional body rotations do not increase from 7 to 30 days after UVN. This study reveals that oxytocin treatment hinders the restoration of some postural and locomotor deficits while improving others following vestibular lesions. The mechanisms of the action of oxytocin that support these behavioral changes remain to be elucidated.

Vestibular Nuclei: A New Neural Stem Cell Niche?

We previously reported adult reactive neurogliogenesis in the deafferented vestibular nuclei following unilateral vestibular neurectomy (UVN) in the feline and the rodent model. Recently, we demonstrated that UVN induced a significant increase in a population of cells colocalizing the transcription factor sex determining region Y-box 2 (SOX2) and the glial fibrillary acidic protein (GFAP) three days after the lesion in the deafferented medial vestibular nucleus. These two markers expressed on the same cell population could indicate the presence of lesion-reactive multipotent neural stem cells in the vestibular nuclei. The aim of our study was to provide insight into the potential neurogenic niche status of the vestibular nuclei in physiological conditions by using specific markers of stem cells (Nestin, SOX2, GFAP), cell proliferation (BrdU) and neuronal differentiation (NeuN). The present study confirmed the presence of quiescent and activated adult neural stem cells generating some new neurons in the vestibular nuclei of control rats. These unique features provide evidence that the vestibular nuclei represent a novel NSC site for the generation of neurons and/or glia in the adult rodent under physiological conditions.

Microglial Dynamics Modulate Vestibular Compensation in a Rodent Model of Vestibulopathy and Condition the Expression of Plasticity Mechanisms in the Deafferented Vestibular Nuclei.

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.

L-Thyroxine Improves Vestibular Compensation in a Rat Model of Acute Peripheral Vestibulopathy: Cellular and Behavioral Aspects.

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 TRß) 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.

Sensorimotor Rehabilitation Promotes Vestibular Compensation in a Rodent Model of Acute Peripheral Vestibulopathy by Promoting Microgliogenesis in the Deafferented Vestibular Nuclei.

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.

SK Channels Modulation Accelerates Equilibrium Recovery in Unilateral Vestibular Neurectomized Rats.

We have previously reported in a feline model of acute peripheral vestibulopathy (APV) that the sudden, unilateral, and irreversible loss of vestibular inputs induces selective overexpression of small conductance calcium-activated potassium (SK) channels in the brain stem vestibular nuclei. Pharmacological blockade of these ion channels by the selective antagonist apamin significantly alleviated the evoked vestibular syndrome and accelerated vestibular compensation. In this follow-up study, we aimed at testing, using a behavioral approach, whether the antivertigo (AV) effect resulting from the antagonization of SK channels was species-dependent or whether it could be reproduced in a rodent APV model, whether other SK channel antagonists reproduced similar functional effects on the vestibular syndrome expression, and whether administration of SK agonist could also alter the vestibular syndrome. We also compared the AV effects of apamin and acetyl-DL-leucine, a reference AV compound used in human clinic. We demonstrate that the AV effect of apamin is also found in a rodent model of APV. Other SK antagonists also produce a trend of AV effect when administrated during the acute phase of the vertigo syndrome. Conversely, the vertigo syndrome is worsened upon administration of SK channel agonist. It is noteworthy that the AV effect of apamin is superior to that of acetyl-DL-leucine. Taken together, these data reinforce SK channels as a pharmacological target for modulating the manifestation of the vertigo syndrome during APV.

Breaking a dogma: acute anti-inflammatory treatment alters both post-lesional functional recovery and endogenous adaptive plasticity mechanisms in a rodent model of acute peripheral vestibulopathy.

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 neurectomy induces a remodeling of somatosensory cortical maps.

Unilateral Vestibular Neurectomy (UVN) induces a postural syndrome whose compensation over time is underpinned by multimodal sensory substitution processes. However, at a chronic stage of compensation, UVN rats exhibit an enduring postural asymmetry expressed by an increase in the body weight on the ipsilesional paws. Given the anatomo-functional links between the vestibular nuclei and the primary somatosensory cortex (S1), we explored the interplay of vestibular and somatosensory cortical inputs following acute and chronic UVN. We determined whether the enduring imbalance in tactilo-plantar inputs impacts response properties of S1 cortical neurons and organizational features of somatotopic maps. We performed electrophysiological mapping of the hindpaw cutaneous representations in S1, immediately and one month after UVN. In parallel, we assessed the posturo-locomotor imbalance during the compensation process. UVN immediately induces an expansion of the cortical neuron cutaneous receptive fields (RFs) leading to a partial dedifferentiation of somatotopic maps. This effect was demonstrated for the ventral skin surface representations and was greater on the contralesional hindpaw for which the neuronal threshold to skin pressure strongly decreased. The RF enlargement was amplified for the representation of the ipsilesional hindpaw in relation to persistent postural asymmetries, but was transitory for the contralesional one. Our study shows, for the first time, that vestibular inputs exert a modulatory influence on S1 neuron's cutaneous responses. The lesion-induced cortical malleability highlights the influence of vestibular inputs on tactile processing related to postural control.

Adult and endemic neurogenesis in the vestibular nuclei after unilateral vestibular neurectomy.

We previously revealed adult reactive neurogenesis in deafferented vestibular nuclei following unilateral vestibular neurectomy (UVN) in the feline model. We recently replicated the same surgery in a rodent model and aimed to elucidate the origin and fate of newly generated cells following UVN. We used specific markers of cell proliferation, glial reaction, and cell differentiation in the medial vestibular nucleus (MVN) of adult rats. UVN induced an intense cell proliferation and glial reaction with an increase of GFAP-Immunoreactive (Ir), IBA1-Ir and Olig2-Ir cells 3 days after the lesion in the deafferented MVN. Most of the newly generated cells survived after UVN and differentiated into oligodendrocytes, astrocytes, microglial cells and GABAergic neurons. Interestingly, UVN induced a significant increase in a population of cells colocalizing SOX2 and GFAP 3 days after lesion in the deafferented MVN indicating the probable presence of multipotent cells in the vestibular nuclei. The concomitant increase in BrdU- and SOX2-Ir cells with the presence of SOX2 and GFAP colocalization 3 days after UVN in the deafferented MVN may support local mitotic activity of endemic quiescent neural stem cells in the parenchyma of vestibular nuclei.

Corrigendum: Quantitative Evaluation of a New Posturo-Locomotor Phenotype in a Rodent Model of Acute Unilateral Vestibulopathy.

[This corrects the article DOI: 10.3389/fneur.2020.00505.].

[The adult brain produces new neurons to restore balance after vestibular loss]. / Le cerveau adulte produit de nouveaux neurones pour restaurer l'équilibre après une perte vestibulaire.

Following partial or total loss of peripheral vestibular inputs, a phenomenon called central vestibular compensation takes place in the hours and days following the injury. This neuroplasticity process involves a mosaic of profound rearrangements within the brain stem vestibular nuclei. Among them, the setting of a new neuronal network is maybe the most original and unexpected, as it involves an adult reactive neurogenesis in a brain area not reported as neurogenic so far. Both the survival and functionality of this newly generated neuronal network will depend on its integration to pre-existing networks in the deafferented structure. Far from being aberrant, this new structural organization allows the use of inputs from other sensory modalities (vision and proprioception) to promote the restoration of the posture and equilibrium. We choose here to detail this model, which does not belong to the traditional niches of adult neurogenesis, but it is the best example so far of the reparative role of the adult neurogenesis. Not only it represents an original neuroplasticity mechanism, interesting for basic neuroscience, but it also opens new medical perspectives for the development of therapeutic approaches to alleviate vestibular disorders.

TITLE: Le cerveau adulte produit de nouveaux neurones pour restaurer l'équilibre après une perte vestibulaire. ABSTRACT: Un phénomène appelé « compensation vestibulaire ¼ se produit après une atteinte vestibulaire périphérique. Ce processus, qui permet un retour progressif de l'équilibre, se produit principalement au sein des noyaux vestibulaires du tronc cérébral, et met en jeu une mosaïque de réarrangements structurels. Parmi ceux-ci, la neurogenèse vestibulaire réactionnelle (NGVR) adulte est peut-être la plus inattendue, car elle se produit dans une région du cerveau qui n'a jamais été signalée auparavant comme neurogène. La survie et la fonctionnalité de ce réseau neuronal nouvellement généré dépendent de son intégration dans les réseaux préexistants des noyaux désafférentés. Cette organisation permet au cerveau d'utiliser les apports d'autres modalités sensorielles pour faciliter le rétablissement de la posture et de l'équilibre. C'est à ce jour le meilleur exemple du rôle réparateur de la neurogenèse adulte. Ces observations soulèvent de nombreuses questions sur la pertinence physiologique de la NGVR.

Identification of New Biomarkers of Posturo-Locomotor Instability in a Rodent Model of Vestibular Pathology.

The vestibular system plays a crucial role in maintaining postural balance. Unilateral vestibular lesions result in a typical syndrome characterized by postural imbalance, altered locomotor patterns and gaze stabilization, as well as cognitive and neurovegetative disorders. One of the main difficulties encountered in the development of new anti-vertigo drugs is the lack of sensitivity in the evaluation of this syndrome. Qualitative assessments of the vestibular syndrome have been developed, but methods of conducting quantitative evaluations are critically lacking. Recently, assessments with a dynamic weight-bearing device (DWB®, Bioseb) revealed postural alterations in rats subjected to unilateral vestibular neurectomy (UVN). Our team is evaluating a new version of this device capable of quantifying additional parameters of postural and locomotor equilibrium. The objective of this study was to use this device to assess these new posturo-locomotor parameters in a rat model of a vestibular pathology. The biomarkers measured by this device are as follows: the barycenter, the support surface and the weight distribution of the rats when they were moving or stationary. Before UVN, the rats showed a symmetric distribution of their weight along the lateral axis. In the acute phase after UVN on the left side, the rats distributed more weight on the right side than on the left side and then distributed more weight on the left side. These results corroborate those presented in our previous study. The support surface of the rats increased between 1 day and 30 days after UVN, and the barycenter distribution reflected the weight distribution. In addition, our results show smaller changes in the weight distributions when the animals are moving compared with when they are stationary in the acute phase after UVN. This study provides new information on the static and dynamic postural balance patterns observed after unilateral vestibular loss in rats. These data are relevant because they objectively quantify the posturo-locomotor component of vestibular syndrome as well as the compensatory strategies used after vestibular loss. These results may guide the development of rehabilitation protocols for vestibular patients and the validation of pharmacological compounds favoring the restoration of equilibrium.

Quantitative Evaluation of a New Posturo-Locomotor Phenotype in a Rodent Model of Acute Unilateral Vestibulopathy.

Vestibular pathologies are difficult to diagnose. Existing devices make it possible to quantify and follow the evolution of posturo-locomotor symptoms following vestibular loss in static conditions. However, today, there are no diagnostic tools allowing the quantitative and spontaneous analysis of these symptoms in dynamic situations. With this in mind, we used an open-field video tracking test aiming at identifying specific posturo-locomotor markers in a rodent model of vestibular pathology. Using Ethovision XT 14 software (Noldus), we identified and quantified several behavioral parameters typical of unilateral vestibular lesions in a rat model of vestibular pathology. The unilateral vestibular neurectomy (UVN) rat model reproduces the symptoms of acute unilateral peripheral vestibulopathy in humans. Our data show deficits in locomotion velocity, distance traveled and animal mobility in the first day after the injury. We also highlighted alterations in several parameters, such as head and body acceleration, locomotor pattern, and position of the body, as well as "circling" behavior after vestibular loss. Here, we provide an enriched posturo-locomotor phenotype specific to full and irreversible unilateral vestibular loss. This test helps to strengthen the quantitative evaluation of vestibular disorders in unilateral vestibular lesion rat model. It may also be useful for testing pharmacological compounds promoting the restoration of balance. Transfer of these novel evaluation parameters to human pathology may improve the diagnosis of acute unilateral vestibulopathies and could better follow the evolution of the symptoms upon pharmacological and physical rehabilitation.

Adjustment of the dynamic weight distribution as a sensitive parameter for diagnosis of postural alteration in a rodent model of vestibular deficit.

Vestibular disorders, by inducing significant posturo-locomotor and cognitive disorders, can significantly impair the most basic tasks of everyday life. Their precise diagnosis is essential to implement appropriate therapeutic countermeasures. Monitoring their evolution is also very important to validate or, on the contrary, to adapt the undertaken therapeutic actions. To date, the diagnosis methods of posturo-locomotor impairments are restricted to examinations that most often lack sensitivity and precision. In the present work we studied the alterations of the dynamic weight distribution in a rodent model of sudden and complete unilateral vestibular loss. We used a system of force sensors connected to a data analysis system to quantify in real time and in an automated way the weight bearing of the animal on the ground. We show here that sudden, unilateral, complete and permanent loss of the vestibular inputs causes a severe alteration of the dynamic ground weight distribution of vestibulo lesioned rodents. Characteristics of alterations in the dynamic weight distribution vary over time and follow the sequence of appearance and disappearance of the various symptoms that compose the vestibular syndrome. This study reveals for the first time that dynamic weight bearing is a very sensitive parameter for evaluating posturo-locomotor function impairment. Associated with more classical vestibular examinations, this paradigm can considerably enrich the methods for assessing and monitoring vestibular disorders. Systematic application of this type of evaluation to the dizzy or unstable patient could improve the detection of vestibular deficits and allow predicting better their impact on posture and walk. Thus it could also allow a better follow-up of the therapeutic approaches for rehabilitating gait and balance.