Influence of hair bundle properties on cochlear mechanics

项目总结/摘要 正常的听力依赖于内耳毛细胞的精密机械传导装置-- 静纤毛毛束。耳蜗振动使发束偏转，这将机械刺激转化为 通过机械敏感离子通道的门控产生电信号。毛束传导对听力至关重要， 因为它是由内毛细胞传入信号所必需的，也是激活内毛细胞的电动反应所必需的。 外毛细胞，用于放大耳蜗振动。然而，目前还不清楚头发是否 束简单地检测由周围耳蜗结构施加在其上的力，或者如果机械 发束本身的特性在形成这些振动中起重要作用。为了解决这个问题， 拟议的工作将使用一种创新的，基于光学相干断层扫描的技术来测量声音- 在小鼠的完整耳蜗中诱发振动，包括那些针对毛束的突变。 具体地说，我们将测试的假设，被动，非线性刚度的头发束显着 影响耳蜗振动。在目标1中，我们将估计野生型CBA/CaJ中的被动毛束刚度。 小鼠，以及缺乏静纤毛尖端连接（Salsa小鼠）和小根（Triobp小鼠）的小鼠，以确定 这些单独的发束组件如何对总刚度做出贡献。发束硬度将是 通过将从耳蜗模型估计的施加到束上的力除以产生的毛发来计算 束偏转，这将通过测量覆膜的径向运动来估计 和网状层。在目标2中，我们将研究被动发束刚度如何有助于非线性 耳蜗内的失真。我们将在基底膜的振动中检查谐波失真， CBA/CaJ、Salsa和Triobp小鼠中的顶盖膜和网状层。为了检验 单独的毛束，将使用最小化外毛细胞影响的条件进行测量 体细胞电运动，以及在普雷斯廷499敲入小鼠，缺乏电运动。追求这些目标 将揭示特定的发束特性如何影响振动的幅度和非线性， 耳蜗，并将提供第一个在体内估计的毛束刚度，以及第一个详细的 检查小鼠耳蜗中的机械变形。这些发现将是重要的，因为我们的许多人 关于毛束力学的知识来自体外制备， 可能与体内遇到的情况有很大不同。

PROJECT SUMMARY/ABSTRACT Normal hearing depends on the delicate mechanotransduction apparatus of inner ear hair cells – the stereociliary hair bundle. Cochlear vibrations deflect the hair bundle, which converts mechanical stimulation to electrical signals via gating of mechanosensitive ion channels. Hair bundle transduction is critical for hearing, as it is required for afferent signaling by inner hair cells, and for activation of the electromotile response of the outer hair cells, which serve to amplify cochlear vibrations. However, it remains unclear whether the hair bundle simply detects the forces imposed on it by the surrounding cochlear structures, or if the mechanical properties of the hair bundle itself play an important role in shaping these vibrations. To address this, the proposed work will use an innovative, optical coherence tomography-based technique to measure sound- evoked vibrations in the intact cochleae of mice, including those with mutations targeting the hair bundle. Specifically, we will test the hypothesis that the passive, nonlinear stiffness of the hair bundle significantly influences cochlear vibrations. In Aim 1, we will estimate the passive hair bundle stiffness in wild-type CBA/CaJ mice, as well as mice lacking stereociliary tip links (Salsa mice) and rootlets (Triobp mice), so as to determine how these individual hair bundle components contribute to the total stiffness. Hair bundle stiffness will be calculated by dividing the force applied to the bundle, as estimated from a cochlear model, by the resulting hair bundle deflection, which will be estimated from measurements of the radial motions of the tectorial membrane and reticular lamina. In Aim 2, we will examine how passive hair bundle stiffness contributes to nonlinear distortion within the cochlea. Harmonic distortions will be examined in the vibrations of the basilar membrane, tectorial membrane, and reticular lamina in CBA/CaJ, Salsa, and Triobp mice. To examine the influence of the hair bundle alone, measurements will be made using conditions which minimize the influence of outer hair cell somatic electromotility, as well as in Prestin 499 knockin mice, which lack electromotility. Pursuit of these aims will reveal how specific hair bundle properties influence the magnitude and nonlinearity of vibrations within the cochlea, and will provide the first in vivo estimates of hair bundle stiffness, as well as the first detailed examinations of mechanical distortion in the mouse cochlea. The findings will be significant, as much of our knowledge about hair bundle mechanics comes from in vitro preparations where the hair bundle’s environment may differ considerably from that encountered in vivo.