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

基本信息

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
项目类别：
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

项目摘要

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.

项目摘要/摘要大约15％的美国人因噪音暴露而造成听力损失。经典的解释是对耳蜗毛细胞。人工耳蜗突触病是噪声引起的听力丧失的另一种机制。那里在创伤噪声后，没有在临床上使用任何一种机制来防止听力损失的有效治疗方法接触。最近，我们确定内淋巴水滴发生在爆炸或噪声创伤之后，并且内淋巴水力与人工耳蜗突触病有关。我们的中心假设是内淋巴结水力流是响应谷氨酸的听觉神经树突肿胀的替代标记兴奋性毒性。我们将以三个目标检验这一假设。首先，我们将确定听觉肿胀是否神经树突与内淋巴水流相关。我们将在体内测量Scala介质的体积使用体积光学相干断层扫描和振动法（VOCTV）。我们将同时映像带有两光子显微镜的体内听觉神经纤维末端并测量其直径。第二，我们会的确定急性毛细胞功能障碍是否需要产生生理后果人工耳蜗突触病。我们将使用VOCTV测量基底膜振动调整曲线来评估人工耳蜗生理。我们还将测量波1听觉的脑干响应（ABR）峰峰评估听觉神经生理的振幅。第三，我们将确定是否煽动机制耳蜗突触病是谷氨酸，内淋巴水力或树突状肿胀。我们将测量Scala 在噪声或低音挑战后，媒体体积，人工耳蜗增益和突触计数有受损 IHC原告神经突触处的转导或谷氨酸释放受损。因此，我们建议明确证明或反驳我们的假设。此外，我们将了解生理后果和内聚合水力和突触病的机制。