Role of tonic outer hair cell motility in cochlear amplification

项目概要/摘要 哺乳动物的听觉灵敏度取决于外毛细胞（OHC），它改变长度并产生力量， 放大耳蜗内的声音诱发振动。虽然人们通常认为放大取决于 由于OHC的运动性是一个周期接一个周期的，这种机制在体内以足够高的频率运作的能力具有 一直受到质疑，以及OHC如何与周围的Corti器官结构相互作用， 扩增仍不清楚。澄清OHC的工作方式对于理解和恢复 听力损失的主要原因是听力损失。作为实现这一目标的一步， 拟议的工作将确定，除了快速的、逐周期的长度变化外，OHC是否还经历了 在声音刺激过程中持续的、紧张性的长度变化。这种紧张性运动可能发挥重要的，未被认识到的 在放大过程中的作用，如果它与Corti几何器官的变化有关， 力学性能拟议的工作将专门测试的假设，声音electrical紧张OHC 运动通过相同的电运动过程，驱动一个周期一个周期的运动，这种紧张性运动， 通过Corti器官硬度的变化影响耳蜗放大。这一假设将是 通过使用基于光学相干断层扫描的方法来测量来自完整内部的振动， 小鼠耳蜗。目的1将充分表征紧张，声音诱发的变形的器官的Corti 作为刺激频率和水平的函数。如果假设是正确的，OHC区域的顶部和底部 将在声音刺激期间在相反方向上紧张地移动。目标2将决定这种补药是否 运动需要普雷斯廷（运动蛋白，基础的周期由周期OHC运动）和正常 机械转导，这是产生驱动普雷斯廷的受体电位所必需的。这将受到考验 通过测量具有异常普雷斯廷或受损机械传导的突变小鼠的振动。如果 假设是真的，则这些小鼠中的强直性运动将减少或不存在。目标3将评估强直性OHC是否 运动性通过Corti硬度器官的相关变化影响耳蜗放大。这将受到考验 通过呈现极低频音调来缓慢调节OHC长度和刚度， 器官的频率响应。如果假设是正确的，那么OHC长度的缓慢变化将是可能的。 与器官频率响应的特定变化有关。追求这些目标可能会揭示新的OHC 用于调整耳蜗放大的频率调谐和增益的机制，从而挑战 放大器如何工作的最新观点。最终，获得的知识可以为未来的设计提供信息， 生物启发的康复假肢以及恢复听力的再生方法。

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.