Mechanisms of cochlear synaptopathy after noise or blast trauma

噪音或爆炸创伤后耳蜗突触病的机制

• 批准号: 10307056
• 负责人: John S Oghalai
• 金额: $ 57.44万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-01-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10307056
• 关键词: Acoustic Nerve; Acute; Affect; American; Anatomy; Auditory; Auditory Brainstem Responses; Auditory Threshold; Basilar Membrane; Caliber; Cell Death; Cells; Clinical; Clinical Trials; Cochlea; Cochlear duct; Data; Dendrites; Endolymph; Endolymphatic Hydrops; Exposure to; Functional disorder; Glutamates; Hair Cells; Hour; Image; Immunohistochemistry; Impairment; Ions; Loudness; Measures; Metabolic; Methodology; Mus; Nerve Fibers; Neurons; Neurotransmitters; Noise; Noise-Induced Hearing Loss; Optical Coherence Tomography; Pathway interactions; Pattern; Physiological; Physiology; Presynaptic Terminals; Research; Residual state; SLC17A8 gene; Saline; Signal Transduction; Surrogate Markers; Swelling; Synapses; Testing; Time; Transmission Electron Microscopy; Trauma; Water; base; blast trauma; cochlear synaptopathy; effective therapy; excitotoxicity; extracellular; hearing impairment; hidden hearing loss; human subject; in vivo; in vivo imaging; innovation; mechanical energy; nerve damage; noise exposure; noise trauma; permanent hearing loss; pressure; prevent hearing loss; relating to nervous system; response; ribbon synapse; sound; two photon microscopy

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.

项目总结/摘要 大约15%的美国人因噪音暴露而听力损失。经典的解释是创伤 耳蜗毛细胞噪声引起的听力损失的另一种机制是耳蜗突触病。那里 临床上还没有有效的治疗方法来预防创伤性噪音后通过这两种机制造成的听力损失 exposure.最近，我们发现内淋巴积水发生在爆炸或噪音创伤后， 内淋巴积水与耳蜗突触病相关。我们的中心假设是内淋巴管 水肿是响应谷氨酸而发生的听神经树突肿胀的替代标志物 兴奋性毒性我们将以三个目标来检验这一假设。首先，我们将确定是否肿胀的听觉 神经树突与内淋巴积水有关。我们将测量活体中阶的体积 使用体积光学相干断层扫描和振动测量（VOCTV）。我们将同时想象 用双光子显微镜观察在体听神经纤维终末并测量其直径。二是 确定急性毛细胞功能障碍是否是产生以下生理后果所必需的： 耳蜗突触病我们将使用VOCTV测量基底膜振动调谐曲线，以评估 耳蜗生理学我们还将测量波1听觉脑干反应（ABR）峰-峰 振幅以评估听觉神经生理学。第三，我们将确定是否煽动机制， 耳蜗突触病是谷氨酸、内淋巴积水或树突肿胀。我们将测量scala 噪声或低渗刺激后受损小鼠的中膜容积、耳蜗增益和突触计数 转导或受损的谷氨酸释放在IHC-听觉神经突触。因此，我们建议 证明或反驳我们的假设此外，我们将了解生理后果 以及内淋巴水肿和突触病的机制。