Chemoanatomic bases for peripheral vestibular function

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DESCRIPTION (provided by applicant): The search for the origins of diversity in primary vestibular afferent response dynamics has been a dominant theme of vestibular research and is the major subject of the present proposal. The long-term goal of the work is to study the role of transmitter systems in shaping afferent responses, and the immediate objective is to identify the impact of GABA and glutamate as hair cell transmitters. The central hypothesis of the research is that the crista performs a mathematical differentiation (differential calculus) of some velocity-sensitive input signals in processing convergent excitatory (glutamatergic) and inhibitory (GABAergic) hair cell synapses onto dendrites of single afferent neurons and that this push-pull input accounts, at least in part, for the wide range of observed afferent responses. Three specific aims will be pursued. These aims embrace a multidisciplinary approach utilizing techniques and experimental models selected for their particular suitability for the experiments, the research experience of the investigators, and the applicability of the results to understanding human vestibular disorders. Anatomical, physiological, pharmacological and mathematical tools are employed concomitantly to address the aims and test hypotheses from multiple perspectives. The first aim is to relate the chemical anatomy of the hair cells in the horizontal canal crista ampullaris to primary afferent response dynamics. The second aim is to identify the relationship between hair cell transmitter phenotype, hair cell morphology, and hair cell activation and response kinetics. The third specific aim is to evaluate the effects of pharmacological manipulation of GABA transmission on the horizontal canal nerve and on individual afferent fibers. The role of transmitter phenotype in shaping primary afferent activity is a fundamentally and clinically important aspect of vestibular function that is poorly understood. Most studies will be conducted in toadfish, which are experimentally advantageous because of their availability, the ease of exposing and extracting their labyrinths, and the similarity of vestibular endorgans throughout the vertebrate phyla. Additional studies in mouse are proposed in order to relate findings in toadfish to a mammalian vestibular system, thus establishing the generality and human health relevance of the results. The proposed research is unique, and will have direct bearing on the development of more effective therapeutic interventions, both medicinal and device-oriented, for peripheral vestibular disorders.