Date of Award

2026

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Neuroscience

First Advisor

Eileen Foecking

Abstract

Vestibular dysfunction is a prevalent and persistent consequence of mild traumatic brain injury (mTBI). Clinical reports reveal that women experience vestibular deficits more frequently than men following mTBI. Despite the high prevalence and debilitating nature of vestibular symptoms, preclinical literature evaluating mTBI-associated vestibular impairments is limited. Emerging evidence demonstrates that cellular senescence is involved in the pathological molecular sequela of mTBI. It has been shown that senescence contributes to cognitive deficits following repetitive mTBI (rmTBI); however, its role in rmTBI-associated vestibular dysfunction remains unexplored. This body of work investigated the role of cellular senescence on rmTBI-induced vestibular dysfunction in both sexes. Eight-week-old male and female Long-Evans rats underwent five closed-head mTBIs administered at 48-hour intervals. Sham control rats received anesthesia but did not receive impacts. The senolytic agent ABT-263 was administered via intraperitoneal injection to assess if removal of senescent cells could prevent the development of vestibular impairments and restore normal vestibular function in animals with existing rmTBI-induced vestibular deficits. Vestibular performance was assessed using a reflex-based battery of 5 vestibular tests. Vestibular nuclei were analyzed for senescence-associated markers using reverse transcription quantitative polymerase chain reaction (RT-qPCR), histochemistry, and immunofluorescence. Both male and female rats developed significant vestibular impairments following rmTBI. Acutely, females exhibited greater vestibular deficits than males; however, these vestibular sex differences were transient and diminished over time while persistent vestibular dysfunction was maintained in both sexes. Animals subjected to rmTBI displayed increased expression of senescence-related transcriptional markers within the vestibular nuclei, supporting activation of senescence pathways. The basal expression of these senescence markers was higher in males than in females. Immunofluorescent and histochemical analyses revealed that females exhibit a neuroimmune phenotype following rmTBI that is driven by microglia, while males are preferentially susceptible to experience neuronal loss. ABT-263 administration immediately following injury prevented the development of vestibular dysfunction in both sexes. Importantly, ABT-263 treatment restored normal vestibular function in animals with persisting rmTBI-induced vestibular deficits. These findings identify cellular senescence as a mechanistic driver of vestibular dysfunction following rmTBI and support senolytic therapy as a potential treatment strategy for persistent vestibular impairment.

Download

Included in

Biology Commons

Share

COinS