Early Rehabilitation Exercise Promotes Vestibular Compensation in UVN Mice by Regulating Microglial Polarization Balance via the PGC-1α/FNDC5/BDNF Pathway.

Acute unilateral vestibular lesions cause disabling vertigo, postural imbalance, and gait instability. Functional recovery depends on vestibular compensation (VC), a neuroplastic process whose cellular and molecular mechanisms remain incompletely understood. Although vestibular rehabilitation effectively accelerates recovery in clinical practice, the underlying pathways are still elusive. Here, we investigated how exercise-based vestibular rehabilitation modulates neuroinflammation and microglial polarization within the medial vestibular nucleus (MVN) in a mouse model of unilateral vestibular neurectomy (UVN), focusing on the PGC‑1α/FNDC5/BDNF axis in promoting VC. Mice underwent a progressive running-wheel training protocol, and behavioural recovery was assessed using rotarod, beam-walk, and open-field tests. At the molecular and cellular levels, we combined mRNA sequencing, bioinformatic analysis, Western blotting, and immunofluorescence to evaluate pathway activation, inflammatory mediators, and microglial morphology and phenotype. Exercise upregulated the PGC‑1α/FNDC5/BDNF cascade and inhibited NF‑κB/NLRP3-mediated neuroinflammation. It also shifted microglia from a pro-inflammatory M1-like phenotype toward an anti-inflammatory M2-like state, increased microglial process complexity, and improved postural balance recovery. Intracerebroventricular administration of the PGC‑1α inhibitor SR‑18292 abrogated these effects, aggravating inflammation and delaying VC. These findings demonstrate that the PGC‑1α/FNDC5/BDNF pathway is a key mediator of exercise-promoted VC and a promising target for improving rehabilitation strategies for vestibular disorders.