Neurobiology and Behavioral Consequences of Peripheral Vestibular Synaptopathy andRehabilitation

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This application to the Rehabilitation Research and Development Service includes a research plan to comprehensively investigate the condition of peripheral vestibular hypofunction, how it manifests in vestibular- related behaviors, and whether it is associated with the induction of synaptopathy in vestibular hair cells. Enhanced knowledge of vestibular hypofunction is critically important for two primary reasons. First, it appears to exhibit broad penetrance among US service personnel and veterans, largely because vestibular hypofunction may be associated with traumatic brain injury. And second, there is strong evidence that many forms of vestibular hypofunction may be associated with synaptopathies, for which rehabilitation strategies may be particularly effective for treatment. Therefore, in view of the heightened risk factors to which US service personnel may be exposed, research into diagnosis and treatment of vestibular hypofunction and the association with synaptopathies has the potential for broad impact on the lives of our Veterans. While investigations into cochlear hypofunction have provided a wealth of valuable information regarding their etiology, diagnosis, and treatment, information regarding vestibular hypofunction is in a nascent state. A recent investigation of aging mice has demonstrated that synaptopathies are a component of age-related vestibular hypofunction, thereby demonstrating that synaptopathies impact all inner ear sensory epithelia. Cochlear hypofunction and synaptopathies are also induced by mild aminoglycoside treatment, resulting in similar signature dysfunction as demonstrated for synaptopathies induced by mild acoustic trauma. The proposed research plan endeavors to comprehensively investigate vestibular hypofunction induced by low-dose gentamicin in a well-established animal model of normal vestibular function, implementing direct intraperilymphatic administration to precisely control the dose delivered to the labyrinth. Preliminary data demonstrated that vestibular hypofunction results from conditions that leave the vestibular sensory epithelia morphologically intact, a condition that parallels the findings in cochlear synaptopathy. The hypofunction is represented by attenuated coherence between stimulus and response in the discharge of afferent neurons, indicating compromise to signal-to-noise ratios and information transmission along vestibular afferent pathways. With this evidence, we proposed four hypotheses and associated Aims. In Aim I we will establish the direct association of vestibular hypofunction with changes in synapse density, under conditions of gentamicin administration for which we have functional evidence of potential synaptopathy from metrics derived from single neuron electrophysiology. Direct measures of synapse densities, assessed through quantitative immunohistochemistry, will be directly correlated with afferent physiology by intracellular labeling of physiologically characterized afferent neurons. The research under Aim II is directed toward the development of dynamic head stabilometry, a behavioral test of that we propose provides a window into the form of hypofunction we observe in afferent neuron recordings. We submit that this behavior test requires integration of multimodal CNS circuits that are affected by the increase in sensory uncertainty concomitant with conditions of synaptopathy. Through Aim III we will elucidate the dose-dependent outcomes of graded hypofunction, and establish the temporal course of synaptopathy development. Aim IV is directed toward testing the efficacy of using dynamic stabilometry as a training tool to improve head stabilization function and potentially provide synaptic rehabilitation. In summary, this study represents a comprehensive effort to ameliorate conditions that are likely to impact a large number of Veterans, and lay the groundwork for future therapies restoring synaptic efficacy and the conditions that compromise the activity of Veterans and the US population.