The Role of the Organ of Corti for Cochlear Power Transmission

项目摘要 在美国，每七个成年人中就有一个患有听力障碍。大多数听力损失与 内耳功能障碍听力损失的一个显著特征是外毛细胞受损，这可能导致听力损失。 40-60 dB的听力损失。外毛细胞被称为耳蜗所需的细胞致动器 放大外毛细胞位于耳蜗感觉上皮中，称为Corti器官。的 Corti器夹在两个富含胶原纤维的基质之间，称为基底和顶盖 膜。传统上，关于耳蜗放大的研究集中在基底膜的运动， 但新的证据表明，我们只看到了故事的一面（外层的基底面）， 毛细胞）。成像和测速技术的最新进展使科学家能够“看穿” 耳蜗，使他们能够捕捉器官的Corti运动超出基底膜。新的观察结果使用 最近的技术既令人兴奋又令人困惑。例如，在外毛细胞的顶端， 与基底膜运动或神经响应相比，振动被广泛地调谐。功能 机械调谐和神经调谐之间的不一致的后果尚不清楚。两个挑战是 阻碍了听觉科学在耳蜗放大方面的进步。首先，尽管最近取得了进展， 速度测量技术的分辨率不足以确定单个外毛细胞。二是 在活体动物实验中，控制外毛细胞生理学的手段非常有限。 这个项目解决了这两个挑战。我们已经开发了新的体外方法， 在电、化学和机械控制下测量单个外毛细胞的运动， 条件实验结果由我们的虚拟耳蜗-一套计算机解释和扩展 模型来分析耳蜗机械传导。通过结合这些实验和计算机 我们可以确保研究的科学严谨性，同时最大限度地减少动物使用。为了提高透明度， 将向公众提供数据和计算机程序。 该提案的三个目标旨在量化最需要的生物物理属性， 以解决关于耳蜗放大和调谐的公开问题。它们是：（1）静纤毛偏转 （毛细胞的机械感受性细胞器），2）由于外毛细胞运动性， 顶盖膜和Deiters细胞（与外毛细胞串联的结构），以及3）操作范围 静纤毛机械转导（静纤毛偏转饱和毛细胞机械转导）。的 在测试我们的总体目标之前，通过与三个目标的测量结果进行比较来验证虚拟CODERA。 假设Corti器官必须像外毛细胞一样柔顺，以便外毛细胞产生 用于耳蜗放大的功率。

Project Summary One out of seven adults in the United States suffers difficulty in hearing. Most hearing loss is related to inner ear dysfunction. A prominent signature of hearing loss is damage of outer hair cells, which can result in 40-60 dB of hearing loss. Outer hair cells are known as cellular actuators that are needed for cochlear amplification. Outer hair cells are situated in the cochlear sensory epithelium called the organ of Corti. The organ of Corti is sandwiched between two collagen-fiber-rich matrices called the basilar and tectorial membranes. Traditionally, studies on cochlear amplification were focused on motion of the basilar membrane, but new evidence is suggesting that we have been seeing only one-side of the story (basal-side of the outer hair cells). Recent advancement in imaging and velocimetry techniques enables scientists to ‘see-through’ the cochlea so that they can capture organ of Corti motion beyond the basilar membrane. New observations using recent techniques are both exciting and puzzling. For example, at the apical side of the outer hair cell, vibrations are broadly tuned as compared to basilar membrane motion or neural responses. Functional consequences of the incongruence between mechanical and neural tuning are unclear. Two challenges are impeding the progress of hearing science regarding cochlear amplification. First, despite recent progress, the resolution of velocity measurement techniques is insufficient to specify individual outer hair cells. Second, in experiments with live animals, there are very limited means to control outer hair cell physiology. This project resolves those two challenges. We have developed novel in vitro methods that enable us to measure the motion of individual outer hair cells under electrically, chemically and mechanically controlled conditions. Experimental outcomes are explained and extended by our Virtual Cochlea—a set of computer models to analyze cochlear mechano-transduction. By combining these experiments and the computer models, we can ensure scientific rigor of our research while minimizing animal use. For transparency, acquired data and computer programs will be made available to public. The three aims of this proposal are designed to quantify the most needed biophysical attributes needed to address open questions regarding cochlear amplification and tuning. They are 1) the deflection of stereocilia (mechano-receptive organelle of the hair cells) due to outer hair cell motility, 2) mechanical properties of the tectorial membrane and the Deiters cell (structures in series with the outer hair cell), and 3) the operating range of stereocilia mechano-transduction (stereocilia deflection to saturate hair cell mechano-transduction). The Virtual Cochlea is validated by comparing with the measurements of three aims before testing our overarching hypothesis—the organ of Corti must be as compliant as the outer hair cells for the outer hair cells to generate power for cochlear amplification.