Aerobic Exercise Promotes Hippocampal Neurogenesis and Ameliorates Cognitive Dysfunction Induced by Unilateral Labyrinthectomy

AIMS: Vestibular dysfunction is strongly linked to cognitive impairment and dementia risk, yet its underlying mechanisms remain unclear, hindering treatment development. As a primary physical therapy intervention, aerobic exercise improves cognitive dysfunction. Thus, we investigated its potential to reverse cognitive deficits after vestibular dysfunction and explored the neurobiological mechanisms involved. METHODS: Behavioral experiments were conducted to assess the cognitive impairment induced by unilateral labyrinthectomy (UL). Immunofluorescence staining was performed to assess neural stem cell proliferation and newborn neuron maturation in the hippocampal dentate gyrus. Aerobic exercise was applied as an intervention to examine its effects on cognitive and neurogenic recovery. RNA sequencing followed by qRT-PCR was used to characterize transcriptional changes. Pharmacological manipulation is applied to demonstrate the necessity and sufficiency of key candidate genes in mediating the exercise-induced effects. RESULTS: UL induced significant cognitive dysfunction and hippocampal neurogenesis inhibition, whereas aerobic exercise intervention reversed these impairments. Transcriptomic profiling showed that aerobic exercise normalized UL-disrupted gene expression, with enrichment observed in MHC class I/II-related (H2-K1, H2-Eb1, CD74) and neurodevelopmental (Cntn5, Mid1) pathways. Pharmacological experiments established causality: inhibition of neuroinflammatory signaling with AZD1480 enhanced neurogenesis and improved cognition after UL, whereas LPS-mediated activation of inflammation attenuated the beneficial effects of aerobic exercise. CONCLUSION: These findings provide a novel non-pharmacological strategy for cognitive rehabilitation, as well as early cognitive screening and exercise rehabilitation intervention for patients with vestibular disorders.