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

• 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
• 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

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.

项目总结/摘要 噪声性听力损失（NIHL）是影响老年人的最常见的听力状况之一， 所有年龄段作为一个主要的危险因素，早期的噪声损伤会加速听觉功能障碍，并使听力恶化 随着年龄的流失。了解NIHL的早期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 大多数在耳蜗中报道，包括感觉毛细胞、螺旋神经节 神经元（SGN）和连接两者的耳蜗突触。一个重要的发现是， 低自发率SGN的突触是脆弱的并且可以优先被噪声损伤， 在发生永久性明显听力损失之前。目前尚不清楚这种噪声诱导的外周神经元 这些变化与中枢听觉系统的结构和功能改变有关， 听觉感知作为所有SGN的唯一靶点和中枢听觉处理的起始部位， 耳蜗核（CN）预期在噪声损伤后结合 选择性SGN改变并影响整个中枢听觉系统的信号处理。长期 本项目的目标是通过识别噪声诱导的神经元， 突触病在听觉神经（AN）中枢突触从不同亚型的SGN，并澄清 影响CN电路的结构和功能。我们假设来自低自发性的AN突触 率SGN受到更深刻的突触损伤后，噪音的侮辱，这导致更显着的 改变了神经加工过程的连接CN神经元的形态学和生理学变化， NIHL。我们进一步假设，从高自发率SGN和连接CN神经元的AN突触是 在中度噪声暴露引起的隐性听力损失期间不变，但在显性听力期间受损 创伤性噪音暴露后的损失。电生理学与免疫组织化学相结合在遗传学中的应用 改良小鼠，本项目研究了CN中已鉴定的AN突触和神经元的结构和功能 电路后，中度或创伤性噪声暴露。在Aim 1中，我们将识别噪声诱导的AN中枢 不同来源的Held突触巨大端球的形态学和生理学突触病 I型SGN的亚型。在目标2中，我们将描述噪声诱导的细胞形态学变化， 生理特性的CN主要神经丛神经元，并确定在NIHL改变CN输出。在Aim中 3、通过对噪声诱导的神经元网络的特性分析，阐明CN抑制性神经网络中NIHL的机制。 在AN结的突触病突触到D-星状神经元上，并确定对CN的减弱抑制 浓密的神经元该项目的结果将填补我们在噪声诱导的AN中枢突触病方面的知识空白， 阐明CN电路的相关变化，并最终阐明CN中NIHL的中枢机制。