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

项目摘要/摘要 噪声性听力损失(NIHL)是影响老年人听力的最常见的听力疾病之一 所有年龄段的人。作为一个主要的危险因素，早年的噪音侮辱会加速听觉功能障碍并加重听力。 随着年龄的增长而丧失。了解NIHL的早期发病机制对临床的发展至关重要。 预防或改善听力系统永久性损害的干预措施。NIHL的病理生理学有 主要在耳蜗处被报道，包括感觉毛细胞、螺旋神经节的有害变化 神经元(SGN)和连接两者的耳蜗突触。一项重要的发现是，耳蜗 低自发频率的SGN的突触是脆弱的，并且可以优先受到噪声的破坏， 在永久性显性听力损失发生之前。目前尚不清楚这种由噪音引起的外周 改变与中枢听觉系统的结构和功能改变有关，这是导致损害的原因 听觉知觉。作为所有SGN的唯一目标和中枢听觉处理的起点， 耳蜗核(Cn)在噪声刺激后的形态和生理上可能发生改变。 选择性SGN改变并影响整个中枢听觉系统的信号处理。长期的 本项目的目标是通过识别噪声诱导的NIHL来阐明CN中NIHL的中心机制 不同亚型SGN在听神经(AN)中枢突触的突触，并阐明 对CN电路的结构和功能的影响。我们假设一个突触是从低自发性 在噪音侮辱下，Rate SGN会受到更深刻的突触影响，这会导致更戏剧性的 相关的CN神经元的形态和生理变化与神经加工的改变有关 NIHL。我们进一步假设，来自高自发频率的SGN和连接的CN神经元的突触是 在中度噪声暴露引起的隐性听力损失期间没有变化，但在显性听力时受损 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的遗传学研究 经过改造的小鼠，本项目研究了已识别的CN内突触和神经元的结构和功能 中度或创伤性噪音暴露后的电路。在Aim1中，我们将识别噪声诱导的中央 不同来源的大突触的形态和生理上的突触 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和 CN主要丛状神经元的生理特性，并识别在NIHL过程中改变的CN输出。在AIM 3，我们将通过表征噪声诱导的噪声来阐明CN抑制神经网络中NIHL的机制 突触与D-星状神经元的突触及对CN抑制作用的减弱 浓密的神经元。这个项目的结果将填补我们在噪声诱导的中枢突触方面的知识空白， 阐明CN环路的连锁变化，最终阐明CN中NIHL的中枢机制。

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.