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

Abstract

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.

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

“…Moreover, recent data support the role of endogenous inflammation following vestibular damage, in regulating neurogenesis and vestibular compensation. Indeed, pharmacological blockade or reinforcement of inflammation during the acute phase of vestibular compensation is accompanied by a worsening of the vestibular syndrome and a delay in vestibular compensation correlated with impaired vestibular neurogenesis [77,78]. However, more studies are needed to confirm these results but also to validate these findings in other models of vestibular damage.…”

What Predictability for Animal Models of Peripheral Vestibular Disorders?

“…The UVN model generates central vestibular inflammation that essentially affects the vestibular nuclei disconnected from 8th nerve [ 50 , 68 , 69 , 70 , 71 , 72 , 73 ] ( Figure 4 ). This model systematically reproduces the typical behavioral phenotype of an AUPV.…”

“…This model systematically reproduces the typical behavioral phenotype of an AUPV. It represents a model of interest for studying the role of central inflammation in vestibular physiopathology, but also the effect of pharmacological modulation of inflammation on the expression of the pathology [ 71 , 72 ]. Other vestibulopathy models are known to generate central vestibular inflammation, such as the arsanilate model [ 74 ], and the surgical labyrinth destruction model [ 50 , 75 , 76 , 77 ].…”

Adult-Onset Alexander Disease With Late-Presenting Vestibulopathy: A Case Report

“…16 Based on these findings, we conclude that vestibular system involvement, including flocculus following minor head trauma, resulted in observed neurotological findings and that the recovery of vestibular dysfunction may be attributed to microglial regulation of AxD pathology and the 6 compensatory mechanism. 15,16 In this report, we present a first case of adult-onset AxD with late-presenting vestibulopathy.…”

“…A recent study revealed that the compensation mechanism for vestibulopathy involves microglia-associated neuroinflammation. 15 Additionally, a mice modelstudy showed that microglia detectAxD astrocyte dysfunction, inducing alterations in morphology and Ca 2+ signaling, which can regulate the expression of various AxD pathologies. 16 Based on these findings, we conclude that vestibular system involvement, including flocculus following minor head trauma, resulted in observed neurotological findings and that the recovery of vestibular dysfunction may be attributed to microglial regulation of AxD pathology and the 6 compensatory mechanism.…”