Mechanisms of hypersensitivity to sound-induced cochlear damage

University Of Pittsburgh At Pittsburgh, Pittsburgh PA

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Abstract

Project Summary Sexually mature females have enhanced auditory nerve encoding of loud sounds compared to males. While there is evidence that this sex difference is mediated by gonad-derived hormones, there has been little progress in the field to understand mechanistically how these hormones mediate their effects. Our published and preliminary data in mice show sex differences in hearing sensitivity in adolescence. Also, in adolescence, we find structural sex differences in the maturation of cochlear afferent synapses. Adolescence is a critical period in humans and other mammals where distinct structural and functional changes coincide with behavioral maturation. In fact, long-lasting behavioral deficits in response to diminished adolescent sensory experience occur in rodents. We will use state-of-the-art anatomical approaches at the light and electron microscopy (EM) levels, including serial EM-tomography, Xenium in situ hybridization, confocal imaging, and electrophysiological studies to determine underlying sex differences in adolescents. Aim 1 will test the hypothesis of a distinct structural and molecular refinement of cochlear ribbon synapses in adolescent females and males. These studies will increase our understanding of why females exhibit greater discharge synchrony or are better protected from noise- induced hearing loss than males, especially before menopause. In Aim 2, we will test that gonad-derived estradiol and androgens refine the relative ratios of Type I spiral ganglion neuron (SGN) subtypes by regulating the expression of genes relating to cell excitability. With these studies, we will begin understanding the role of sex hormones on SGN synchrony via the classical genomic effects of steroids. Studies in Aim 3 will test that reduced sensory experience in adolescence differentially alters key pre- and post-synaptic structural and molecular features of modiolar and pillar-side cochlear ribbon synapses in females and males. These studies will increase our understanding of sex differences in cochlear adaptation to sensory experience from adolescence to adulthood. This project will provide unique information to understand the sex-specific cellular and molecular mechanisms underlying sound coding's temporal precision in normal and hearing-impaired adolescent mice, which are still largely unknown.