Auditory nerve synaptopathy and the central mechanisms underlying noise-induced hearing loss

听神经突触病和噪声性听力损失的中枢机制

基本信息

批准号：
10511106
负责人：
Ruili Xie
金额：
$ 45.41万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-01 至 2027-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10511106
关键词：
3-Dimensional Acoustic Nerve Affect Age Auditory Auditory Perception Auditory system Cell physiology Cells Cellular Morphology Clinical Closure by clamp Cochlea Cochlear nucleus Code Confocal Microscopy Development Electrophysiology (science)Exhibits Functional disorder Goals Hair Cells Hearing Hearing problem Hyperacusis Image Immunofluorescence Immunologic Immunohistochemistry Individual Intervention Knowledge Label Lead Life Link Membrane Modification Morphology Mus Neurons Noise Noise-Induced Hearing Loss Outcome Output Pathologic Peripheral Persons Physiological Physiology Presbycusis Property Reporting Risk Factors Role Sensory Hair Site Specificity Speech Structure Synapses Synaptic Transmission Techniques Whole-Cell Recordings Work auditory nuclei auditory processing base clinical development confocal imaging experimental study hearing impairment hidden hearing loss inhibitory neuron insight neural network noise exposure normal hearing permanent hearing loss postsynaptic postsynaptic neurons prevent relating to nervous system sensory input signal processing spiral ganglion transmission process voltage clamp

项目摘要

PROJECT SUMMARY/ABSTRACT Noise-induced hearing loss (NIHL) is one of the most prevalent hearing conditions that affects people of all ages. As a major risk factor, noise insult early in life accelerates auditory dysfunction and exacerbates hearing loss with age. Understanding the mechanisms of NIHL at early stages is crucial for the development of clinical interventions to prevent or ameliorate permanent damage of the auditory system. Pathophysiology of NIHL has been mostly reported in the cochlea, including detrimental changes in the sensory hair cells, the spiral ganglion neurons (SGN), and the cochlear synapses connecting the two. One significant finding was that cochlea synapses of the low spontaneous rate SGNs are vulnerable and can be preferentially damaged by noise, preceding the occurrence of permanent overt hearing loss. It remains unclear how such noise-induced peripheral changes link to structural and functional alterations in the central auditory system in contributing to compromised hearing perception. As the only target for all SGNs and the starting site of central auditory processing, the cochlear nucleus (CN) is expected to alter in morphology and physiology after noise insult in conjunction with selective SGN changes and impact the signal processing of the entire central auditory system. The long-term goal of this project is to elucidate the central mechanisms of NIHL in the CN by identifying noise-induced synaptopathy at the auditory nerve (AN) central synapses from different subtypes of SGNs, and clarifying the impact on the structure and function of the CN circuits. We hypothesize that AN synapses from low spontaneous rate SGNs are subject to more profound synaptopathy upon noise insult, which lead to more dramatic morphological and physiological changes in linked CN neurons with altered neural processing that contribute to NIHL. We further postulate that AN synapses from high spontaneous rate SGNs and linked CN neurons are unchanged during hidden hearing loss caused by moderate noise exposure, but damaged during overt hearing loss after traumatic noise exposure. Combining electrophysiology with immunohistochemistry in genetically modified mice, this project investigates the structure and function of identified AN synapses and neurons in CN circuits after moderate or traumatic noise exposure. In Aim1, we will identify noise-induced AN central synaptopathy both morphologically and physiologically at the giant endbulb of Held synapses from different subtypes of type I SGNs. In Aim 2, we will characterize noise-induced changes in cellular morphology and physiological properties of CN principal bushy neurons, and identify the altered CN output during NIHL. In Aim 3, we will elucidate the mechanisms of NIHL in CN inhibitory neural network by characterizing the noise-induced synaptopathy at AN bouton synapses onto D-stellate neurons and identifying the weakened inhibition onto CN bushy neurons. The outcome of this project will fill our knowledge gap on noise-induced AN central synaptopathy, clarify the linked changes in CN circuits, and ultimately elucidate the central mechanisms of NIHL in the CN.

项目概要/摘要噪声性听力损失 (NIHL) 是影响人群的最常见听力状况之一所有年龄段。作为一个主要的危险因素，生命早期的噪音侵害会加速听觉功能障碍并加剧听力随着年龄的增长而流失。早期了解 NIHL 的机制对于临床治疗的发展至关重要预防或改善听觉系统永久性损伤的干预措施。 NIHL 的病理生理学主要报道在耳蜗，包括感觉毛细胞、螺旋神经节的有害变化神经元（SGN），以及连接两者的耳蜗突触。一项重要发现是耳蜗低自发率 SGN 的突触很脆弱，可能会优先被噪声损坏，在发生永久性明显听力损失之前。目前尚不清楚这种噪声如何引起外周与中枢听觉系统结构和功能改变相关的变化会导致受损听觉感知。作为所有 SGN 的唯一目标和中央听觉处理的起始站点，噪声损伤后，耳蜗核（CN）预计会在形态和生理学上发生变化选择性 SGN 变化会影响整个中枢听觉系统的信号处理。长期来看该项目的目标是通过识别噪声引起的 NIHL 来阐明 CN 中 NIHL 的核心机制来自不同亚型 SGN 的听神经 (AN) 中枢突触的突触病，并阐明了 CN 电路的结构和功能的影响。我们假设 AN 突触来自低自发性 SGN 在噪声损伤时会遭受更严重的突触病变，从而导致更严重的相连的 CN 神经元的形态和生理变化以及神经处理的改变有助于 NIHL。我们进一步假设来自高自发率 SGN 和连接的 CN 神经元的 AN 突触是在中度噪音暴露引起的隐性听力损失期间没有变化，但在显性听力损失期间受损创伤性噪音暴露后的损失。电生理学与免疫组织化学在遗传学中的结合改造小鼠，该项目研究了 CN 中已识别的 AN 突触和神经元的结构和功能中度或创伤性噪声暴露后的电路。在目标 1 中，我们将识别噪声引起的 AN 中枢来自不同来源的 Held 突触的巨大端球在形态上和生理上都存在突触病 I 型 SGN 的亚型。在目标 2 中，我们将描述噪声引起的细胞形态变化和 CN 主要浓密神经元的生理特性，并识别 NIHL 期间 CN 输出的改变。瞄准 3、我们将通过表征噪声引起的噪声来阐明 CN 抑制神经网络中 NIHL 的机制 AN bouton 突触到 D 星状神经元的突触病并鉴定对 CN 的抑制减弱浓密的神经元。该项目的成果将填补我们关于噪声引起的 AN 中枢突触病的知识空白，阐明 CN 回路的相关变化，并最终阐明 CN 中 NIHL 的中心机制。