An Investigation of the Cellular Mechanisms Underlying Hearing Sensitivity and Resistance to Noise Induced Traumas.

Ramirez, Miguel Angel

doi:https://doi.org/10.21985/n2-td5j-y896

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An Investigation of the Cellular Mechanisms Underlying Hearing Sensitivity and Resistance to Noise Induced Traumas.

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Perturbations to the physiology or impairments in the formation of synapses within the cochlea, specifically the ribbon synapses, result in decreased sensitivity to auditory stimuli. In example, prolonged exposure to moderately intense auditory stimuli, like power tools, can result in the swelling of nerve terminals, retraction of the postsynaptic membrane, and eventually the loss of ribbon synapses driving permanent hearing loss. Thus, understanding proteins which physically tether and organize these synaptic membranes, such as neuroligins and neurexins, will broaden our understanding of potentially protective mechanisms against the loss of hearing sensitivity. Moreover, we lack even a basic characterization of the molecular changes distinguishing permeant from temporary sensory hearing loss. Therefore, the goal of this thesis is two parts, the first is to characterize the impact of neuroligins with respect to ribbon synapse maturation and physiology. The second, is to broaden our understanding of the cochlear proteome with respect to noise exposure and recovery from noise induced trauma. In chapters 3 and 4, I determined that Nlgn3 expression dramatically increases throughout cochlear development, and that Nlgn1 and Nlgn3 are present at many of the same ribbon synapses. Nlgn3 and Nlgn1 single knock out (KO) cochleae have fewer ribbon synapses and mild hearing phenotypes based on auditory brain stem response recordings. Double KO cochlear phenotypes generally exceed the additive effects of the individual KO’s, with the latency of sound-response being particularly severe. These observations indicate that Nlgn1 and Nlgn3 have largely overlapping yet essential functions in the maturation and function of cochlear ribbon synapses. In chapter 5 I discuss the results of our quantitative proteomics analysis, which revealed that moderate and severe intensity noise cause proteotoxicity within the cochlea. Transcriptomic analysis determined that a subset of genes encoding proteins with elevated levels also have increased gene expression, including numerous proteasome subunits. Recovery period proteomics revealed that protein synthesis machinery is selectively up regulated. We report that over stimulation of the auditory system drives a robust cochlear proteotoxic stress response. In chapter 6 I discussed preliminary data collected while investigating the protective effects of a drug known to induce the heat shock response with respect to noise exposure. In the latter portion of this chapter, I then discuss the presence of long-lived proteins within the cochlea and strategies for detecting low abundance proteins within the cochlea. Together these chapters outline key efforts made during my doctoral training and reflect novel bodies of work which expand our understanding of cellular mechanisms underlying hearing and our sensitivity to noise induced hearing loss.

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