Role of tonic outer hair cell motility in cochlear amplification

项目摘要/摘要 哺乳动物的听力敏感度取决于外毛细胞，外毛细胞改变长度并产生力量来 放大耳蜗内由声音引起的振动。虽然人们通常认为放大依赖于 循环OHC运动，这种机制在体内以足够高的频率工作的能力 被质疑，以及毛细胞到底是如何与周围的Corti结构器官相互作用产生 扩增情况仍不清楚。弄清HC的工作方式对于理解和恢复其本质是至关重要的 耳聋是耳聋的常见原因之一。作为迈向这一目标的一步， 拟议的工作将确定，除了快速、逐个周期的长度变化外，OHC是否经历了 在声音刺激过程中持续的主音长度变化。这种紧张性运动可能会起到一种重要的、未被认识的 在扩增过程中的作用，如果它与Corti的几何结构和 机械性能。这项拟议的工作将专门测试声音引起强音OHC的假设 通过相同的电动过程驱动循环运动，而这种紧张性运动 通过改变Corti器官的硬度来影响耳蜗的放大。这一假设将是 使用基于光学相干层析成像的方法从完整的内部测量振动进行测试 小鼠耳蜗体内。目标1将完全描述紧张性的、声音诱发的Corti器官变形 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 在声音刺激过程中会以相反的方向运动。目标2将决定这款补药是否 运动需要prestin(支持循环运动的运动蛋白)和正常运动。 机械转导，这是产生驱动Prestin的受体潜力所必需的。这将会被测试 通过测量压力蛋白异常或机械转导受损的突变小鼠的振动。如果 假说成立，这些小鼠的紧张性运动将减少或消失。目标3将评估补药OHC 运动性通过相关的Corti僵硬器官的变化来影响耳蜗放大。这将会被测试 通过呈现非常低的频率音调来缓慢地调节OHC的长度和硬度，并评估变化 器官的频率响应随时间的变化。如果假设是正确的，那么缓慢的OHC长度变化将是 与器官频率反应的特定变化有关。对这些目标的追求可能会揭示出新的OHC 调整频率调谐和耳蜗放大增益的机制，从而挑战 放大如何工作的当前视图。最终，所获得的知识可以为未来的设计提供信息， 以生物为灵感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.