Mechanisms of cochlear synaptopathy after noise or blast trauma

点击翻译按钮获取中文摘要

Project Summary/Abstract About 15% of Americans have hearing loss due to noise exposure. The classical explanation is trauma to the cochlear hair cells. An additional mechanism of noise-induced hearing loss is cochlear synaptopathy. There are no effective treatments used clinically to prevent hearing loss via either mechanism after traumatic noise exposure. Recently, we identified that endolymphatic hydrops occurs after blast or noise trauma, and that endolymphatic hydrops correlated with cochlear synaptopathy. Our central hypothesis is that endolymphatic hydrops is a surrogate marker for swelling of auditory nerve dendrites that occurs in response to glutamate excitotoxicity. We will test this hypothesis with three aims. First, we will determine whether swelling of auditory nerve dendrites correlates with endolymphatic hydrops. We will measure the volume of scala media in vivo using volumetric optical coherence tomography and vibrometry (VOCTV). We will simultaneously image auditory nerve fiber terminals in vivo with two-photon microscopy and measure their diameter. Second, we will determine whether acute hair cell dysfunction is necessary to produce the physiological consequences of cochlear synaptopathy. We will measure basilar membrane vibratory tuning curves using VOCTV to assess cochlear physiology. We will also measure the wave 1 auditory brainstem response (ABR) peak-to-peak amplitude to assess auditory nerve physiology. Third, we will determine whether the inciting mechanism of cochlear synaptopathy is glutamate, endolymphatic hydrops, or dendritic swelling. We will measure scala media volume, cochlear gain, and synaptic counts after noise or hypotonic challenge in mice with impaired transduction or impaired glutamate release at the IHC-auditory nerve synapse. Therefore, we are proposing to definitively prove or disprove our hypothesis. Furthermore, we will understand the physiological consequences and mechanisms of endolymphatic hydrops and synaptopathy.