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Role of tonic outer hair cell motility in cochlear amplification

强直外毛细胞运动在耳蜗放大中的作用

基本信息

批准号：
10466970
负责人：
James Braden Dewey
金额：
$ 16.5万
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：
2020-09-23 至 2024-08-31
项目状态：
已结题

项目摘要

PROJECT SUMMARY/ABSTRACT Mammalian hearing sensitivity depends on outer hair cells (OHCs), which change length and generate force to amplify sound-evoked vibrations within the cochlea. While it is often assumed that amplification depends on cycle-by-cycle OHC motility, the ability of this mechanism to operate at sufficiently high frequencies in vivo has been questioned, and exactly how OHCs interact with the surrounding organ of Corti structures to produce amplification remains unclear. Clarifying how OHCs work is critical to understanding and restoring what is missing in ears with OHC damage, which is a common cause of hearing loss. As a step toward this, the proposed work will determine whether, in addition to fast, cycle-by-cycle length changes, OHCs undergo sustained, tonic length changes during sound stimulation. Such tonic motility may play a vital, unrecognized role in the amplification process if it is associated with changes in the organ of Corti’s geometry and mechanical properties. The proposed work will specifically test the hypothesis that sound elicits tonic OHC motility via the same electromotile process that drives cycle-by-cycle motility, and that this tonic motility influences cochlear amplification via changes in the stiffness of the organ of Corti. This hypothesis will be tested by using an optical coherence tomography-based approach to measure vibrations from within the intact mouse cochlea in vivo. Aim 1 will fully characterize the tonic, sound-evoked deformations of the organ of Corti as a function of stimulus frequency and level. If the hypothesis is correct, the top and bottom of the OHC region will tonically move in opposite directions during sound stimulation. Aim 2 will determine whether this tonic motility requires prestin (the motor protein that underlies cycle-by-cycle OHC motility) and normal mechanotransduction, which is needed to produce the receptor potential that drives prestin. This will be tested by measuring vibrations in mutant mice with abnormal prestin or impaired mechanotransduction. If the hypothesis is true, tonic motility will be reduced or absent in these mice. Aim 3 will assess whether tonic OHC motility influences cochlear amplification via associated changes in organ of Corti stiffness. This will be tested by presenting a very low frequency tone to slowly modulate OHC length and stiffness, and assessing changes in the organ’s frequency response over time. If the hypothesis is correct, slow OHC length changes will be associated with specific shifts in the organ’s frequency response. Pursuit of these aims may reveal novel OHC mechanisms for adjusting the frequency-tuning and gain of cochlear amplification, and thus challenge the current view of how amplification works. Ultimately, the knowledge gained could inform the design of future, biologically-inspired rehabilitative prosthetics as well as regenerative approaches to restoring hearing.

项目概要/摘要哺乳动物的听力敏感性取决于外毛细胞 (OHC)，它会改变长度并产生力量放大耳蜗内声音引起的振动。虽然通常假设放大取决于逐周期 OHC 运动性，该机制在体内以足够高的频率运行的能力受到质疑，以及 OHC 到底如何与周围的 Corti 结构器官相互作用以产生放大仍不清楚。阐明 OHC 的工作方式对于理解和恢复现状至关重要 OHC 损伤导致耳朵缺失，这是听力损失的常见原因。作为实现这一目标的一步，拟议的工作将确定除了快速的逐周期长度变化之外，OHC 是否会经历声音刺激期间持续的主音长度变化。这种强直的动力可能发挥着至关重要的、未被认识到的作用。如果与柯蒂氏几何器官的变化相关，则在放大过程中的作用机械性能。拟议的工作将专门测试声音引发强直 OHC 的假设通过驱动逐周期运动的相同电动过程实现运动，并且这种强直运动通过改变柯蒂氏器的硬度来影响耳蜗放大。这个假设将是通过使用基于光学相干断层扫描的方法来测量完整内部的振动进行测试小鼠耳蜗体内。目标 1 将充分表征柯蒂氏器的强直、声音诱发变形作为刺激频率和水平的函数。如果假设正确，OHC 区域的顶部和底部在声音刺激期间将沿相反方向进行音调移动。目标 2 将确定该补品是否运动需要 prestin（构成逐周期 OHC 运动基础的运动蛋白）和正常机械转导，这是产生驱动 prestin 的受体电位所必需的。这将被测试通过测量具有异常 prestin 或受损机械转导的突变小鼠的振动。如果假设成立，这些小鼠的强直运动将会减少或消失。目标 3 将评估是否有补品 OHC 运动通过柯蒂氏器硬度的相关变化影响耳蜗放大。这将被测试通过呈现非常低频的音调来缓慢调节 OHC 长度和刚度，并评估变化器官随时间的频率响应。如果假设正确，OHC 长度的缓慢变化将是与器官频率响应的特定变化相关。追求这些目标可能会揭示新的 OHC 调节耳蜗放大的频率调谐和增益的机制，从而挑战当前关于放大如何工作的观点。最终，所获得的知识可以为未来的设计提供信息，受生物学启发的康复假肢以及恢复听力的再生方法。