Exposure to loud noise causes degeneration in the cochlea involving hair cell death and ribbon synapse loss, resulting in permanent deficits that can be hidden or overt. The exact mechanisms by which noise-induced hearing loss occurs are not clear, and there is a need to identify the critical events that result in permanent cochlear degeneration. Vesicular zinc is important in the nervous system in fine-tuning synaptic transmission and sound processing, but in cases of nervous system injury, such as in the retina, vesicular zinc exacerbates neurodegeneration and hinders regeneration. Our preliminary audiometric and histological data indicate that removal of vesicular zinc via genetic deletion of ZnT3, the vesicular zinc transporter loading zinc in presynaptic terminals, results in resilience to- and improved recovery from noise-induced hearing loss, both in terms of structure and function. Furthermore, both cochlear and systemic chelation of zinc result in resilience to noise- induced hearing loss. Moreover, ZnT3 protein expression increases immediately following noise exposure, consistent with a role for vesicular zinc dysregulation in noise-induced hearing loss. This proposal aims to test the hypothesis that noise-induced dysregulation of zinc signaling contributes to noise-induced hearing loss by promoting degeneration and limiting regeneration in the cochlea. Using a combination of cochlear physiological recordings, histological analysis, and quantitative protein and RNA analysis, this proposal will examine the effects of vesicular zinc following harmful noise exposure. Results from this proposal will help to elucidate the mechanisms of degeneration within the cochlea that lead to temporary and permanent hearing impairments after noise-induced hearing loss. These data may provide novel therapeutic targets for treatment of noise-induced hearing loss and related disorders, such as tinnitus and hyperacusis, and further our understanding of cochlear vulnerability to noise.
Noise-induced hearing loss is among the most prevalent health problems in the U.S. and impacts social, psychological, and cognitive health, and yet methods for treating noise-induced hearing loss are lacking. The current proposal aims to study how ZnT3 and vesicular zinc may increase susceptibility to noise-induced hearing loss and if chelation of zinc after acoustic over-exposure may be neuroprotective. Results from the proposed experiments may illuminate novel mechanisms by which sound over-exposure leads to hearing loss and auditory disorders, thereby providing new therapeutic targets.
