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.

项目摘要/摘要 噪声引起的听力损失（NIHL）是影响的人的最普遍的听力条件之一 所有年龄段。作为主要危险因素，生命早期的噪音侮辱会加速听觉功能障碍，并加剧听力 损失随着年龄的增长。了解早期NIHL的机制对于临床的发展至关重要 预防或改善听觉系统的永久损害的干预措施。 NIHL的病理生理学 在耳蜗中大多有报道，包括感觉毛细胞的有害变化，螺旋神经节 神经元（SGN）和连接两者的人工耳蜗突触。一个重要的发现是耳蜗 低自发率SGN的突触很脆弱，可以因噪声而优先损坏 在发生永久明显听力损失的发生之前。目前尚不清楚这种噪声引起的外围如何 在中央听觉系统中与结构和功能变化的变化链接有助于受到损害 听力感知。作为所有SGN的唯一目标和中央听觉处理的起始站点， 人工耳蜗核（CN）有望改变噪声损伤后的形态和生理学 选择性SGN更改并影响整个中央听觉系统的信号处理。长期 该项目的目标是通过识别噪声诱导的 来自不同亚型SGN的中央突触的突触病，并阐明 对CN电路的结构和功能的影响。我们假设来自低自发的突触 噪声侮辱时的速率SGN会受到更深刻的突触病，这导致更加戏剧性 随着神经加工的改变，链接的CN神经元的形态和生理变化有助于 NIHL。我们进一步假设来自高自发率SGN和链接的CN神经元的突触是 在中度噪声暴露造成的隐藏听力损失中没有变化，但在公开听力期间受损 创伤性噪音暴露后的损失。在遗传学上将电生理学与免疫组织化学结合 修改后的小鼠，该项目研究了CN中鉴定出的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AIM1中，我们将确定噪声引起的中央 在形态和生理上的突触病在巨大的持有突触的巨型圆布上。 I型SGN的亚型。在AIM 2中，我们将表征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，并确定NIHL期间CN输出的改变。目标 3，我们将通过表征噪声诱导的CN抑制神经网络中NIHL的机制 BOUTON突触的突触病在D型固定神经元上，并识别出弱的抑制作用 浓密的神经元。该项目的结果将填补我们对噪声引起的中央突触病的知识差距， 澄清CN电路的连接变化，并最终阐明了CN中NIHL的中心机制。