Measuring and Modeling the Cochlear Organ-of-Corti Motions Responsible for Inner-and Outer-Hair-Cell Drives and Amplification

项目摘要/摘要 我们对耳蜗科尔蒂器官(OOC)力学的知识正在经历重大的反思。最新发现 结果表明，网状板(RL)的运动比基底膜(BM)多得多，并且具有不同的时相 比之前想象的要好。我们的高分辨率光学相干断层扫描(OCT)成像和振动测量 沙土鼠高频基底区的测量表明，外毛细胞(OHC)第3行(RL3)的RL 移动幅度明显大于OHC第1行(RL1)。这一新发现表明，RL的马赛克结构， 由底部倾斜的外毛细胞和顶部倾斜的指骨突起的角质板组成 不是僵硬，而是弯曲和/或伸展。我们的中心假设是Deiters细胞的PHP扩展 (分布式控制系统)影响RL马赛克的径向和纵向运动，以提供运动相位和/或大小 在每个耳蜗行所需的放大，和敏感的听力。这一假设将通过以下方式检验 测量和模型以确定：(1)RL3运动是否具有更大的径向分量，从而增加 (2)RL马赛克以下的细胞结构差异(例如，放射状和 纵向PHP角)导致三个OHC行的径向和纵向运动不同；(3) 外隧道(OT)流体空间是对RL径向运动有实质性影响的共振系统的一部分；以及 (4)OOC区改变了Scala介质中的压力以产生放大，以及(5)这些运动是如何 影响内毛细胞(IHC)立体纤毛束的驱动。一种高分辨率、高帧速率的OCT系统 )2.3微米的轴向分辨率)将用于成像和测量沙土鼠和小鼠的OOC运动。我们 将测量BM、OHC-DC的横向和径向运动和/或径向和纵向运动 连接、RL、OT和覆盖膜(TM)对多声级声刺激的响应；以及 将在大约对应于0.5 kHz(顶端)、2 khz(中间)和45 khz的耳蜗处这样做 沙土鼠的(基本)位置，以及小鼠的10-kHz(顶端)、20-kHz(中间)和60-khz(基本)位置，到 确定我们假设的适用性。这两个部位的中转点和心尖点的测量值 物种将跨越人类听力的0.02-20千赫频率范围的大部分。转换测量的OOC的步骤 运动进入详细了解负责OHC和IHC刺激的机制，我们将使用 我们的OCT图像和测量用于建立和测试沙土鼠和 小鼠的耳蜗骨。这些模型将在粘性流体环境中结合详细的OOC显微解剖结构， 包括横跨三排的径向和纵向PHP角，柱状单元、IHC和TM。模特们 将允许在耳蜗功能与结构和材料之间建立明确的关系 OOC的属性。这项工作将把实验和建模工作结合起来，以加深我们对 耳蜗内产生放大和声音转导的复杂机械相互作用。

Project Summary/Abstract Our knowledge of cochlear organ-of-Corti (OoC) mechanics is undergoing major rethinking. Recent findings show that the reticular lamina (RL) moves much more than the basilar membrane (BM) and with a different phase than previously thought. Our high-resolution optical-coherence-tomography (OCT) imaging and vibrometry measurements in the gerbil high-frequency basal region reveal that the RL at outer-hair-cell (OHC) row 3 (RL3) moves significantly more than at OHC row 1 (RL1). This new discovery suggests that the RL’s mosaic structure, comprised of the cuticular plates of the basally tilted OHCs and apically tilted phalangeal processes (PhPs) is not stiff, but rather bends and/or stretches. Our central hypothesis is that the PhP extensions of the Deiters’ cells (DCs) influence radial and longitudinal motion of the RL mosaic to provide the motion phase and/or magnitude at each OHC row required for cochlear amplification, and sensitive hearing. This hypothesis will be tested by measurements and models to determine if: (1) RL3 motion has a bigger radial component that increases the drive to the OHC3 stereocilia; (2) cytoarchitectural differences below the RL mosaic (e.g., the radial and longitudinal PhP angles) cause the radial and longitudinal motions to differ across the three OHC rows; (3) the outer-tunnel (OT) fluid space is part of a resonant system that has a substantial effect on RL radial motion; and (4) the OoC area changes the pressure in the scala media to produce amplification, and (5) how these motions influence the drive to inner-hair-cell (IHC) stereocilium bundles. A high-resolution, high-framerate OCT system (approx. 2.3-µm axial resolution) will be used to image and measure motions of the OoC in gerbils and mice. We will measure the transverse and radial motions and/or the radial and longitudinal motions of the BM, OHC–DC junctions, RL, OT, and tectorial membrane (TM) in response to acoustic stimulation at multiple sound levels; and will do so at cochlear locations corresponding approximately to 0.5-kHz (apical), 2-kHz (middle), and 45-kHz (basal) locations in gerbil, and 10-kHz (apical), 20-kHz (middle), and 60-kHz (basal) locations in mouse, to determine the applicability of our hypotheses. The measurements from the middle and apical turns in these two species will span much of the 0.02–20 kHz frequency range of human hearing. To translate the measured OoC motions into a detailed understanding of the mechanisms responsible for OHC and IHC stimulation, we will use our OCT images and measurements to build and test passive and active 3D finite-element models of gerbil and mouse cochleae. The models will incorporate, in a viscous-fluid environment, the detailed OoC microanatomy, including the radial and longitudinal PhP angles across the three rows, pillar cells, IHCs, and TM. The models will allow clear relationships to be established between cochlear function and the structure and material properties of the OoC. This work will combine experimental and modeling efforts to deepen our understanding of the complex mechanical interactions within the cochlea that produce amplification and sound transduction.