Measuring and Modeling the Cochlear Motions that Drive the Inner and Outer Hair Cells and Produce Otoacoustic Emissions

项目概要/摘要 我们对耳蜗力学的认识正在经历一场革命。基底膜（BM） 长期以来被认为是耳蜗运动的主要结构，新技术，如光学相干， 断层扫描（OCT）不仅揭示了网状层（RL）以不同的模式移动， 从BM，但它移动3-10倍以上，在低输入声级。此外，RL运动更接近于 内毛细胞（IHC）静纤毛，使其比BM运动更相关的触发输出的 耳蜗与BM相比，RL的运动更大，这也表明RL运动可能是主要的 耳声发射（OAE）。另一个长期持有的想法-现在意识到是不够的-是， IHC静纤毛仅由RL和覆膜（TM）之间的剪切作用驱动。电流 有证据表明，RL的旋转和RL之间的亚盖层空间中的振荡流体流动 TM也驱动IHC静纤毛，甚至可能比RL-TM剪切更重要。我们假设 内毛细胞的静纤毛束受到多种机制的刺激，包括经典的RL-TM 剪切，振荡流体流在sub-ceptorial空间，和倾斜的RL附近的IHC束;， 这些机制的相对影响随频率、声级和物种而变化; OAE 生成由RL运动支配。为了测试这些假设，高分辨率OCT系统（约3 µm 轴向分辨率）将用于成像和测量正常听力下Corti器官（OoC）中的运动 沙鼠和小鼠，以及三种基因突变的小鼠，这些基因突变影响了结构和机械性能。 TM的属性。我们将测量BM、RL和TM的横向和径向运动， 在多个声级和多个耳蜗位置处的声刺激。与人类相比， 听觉，将在沙鼠中从0.5至12 kHz位置测量反应，并在 老鼠.将测量的OoC运动转化为对相关机制的详细理解 对于IHC和OHC刺激和刺激频率OAE产生，我们将使用OCT图像构建 沙鼠和每种小鼠的3D耳蜗有限元模型，并将根据OCT测试模型 振动测量这些模型将在粘性流体环境中包含面向对象的关键要素 细胞结构夹在BM和RL之间，包括柱细胞，三排外毛细胞， 和IHC，沿着TM，它们一起将允许在耳蜗之间建立明确的关系。 OoC的功能、结构和材料组成。这将有助于我们了解 听力的各种机械阶段，将允许OoC的健康和结构与OAE相关 为诊断目的，并将提供一个强大的和有效的建模框架，适用于未来 开发可以使用非侵入性听阈和OAE验证的人类耳蜗模型 测量.

Project Summary/Abstract Our knowledge of cochlear mechanics is currently undergoing a revolution. While the basilar membrane (BM) has long been considered the principal structure in cochlear motion, new techniques such as optical coherence tomography (OCT) have instead revealed not only that the reticular lamina (RL) moves in a different pattern from the BM, but that it moves 3–10 times more at low input sound levels. Additionally, RL motion is closer to the inner-hair-cell (IHC) stereocilia, making it more relevant than BM motion for triggering the output of the cochlea. The greater motion of the RL compared to the BM also suggests that RL motion may be the main source of otoacoustic emissions (OAEs). Another long-held idea – now realized to be inadequate – is that the IHC stereocilia are driven only by shearing action between the RL and tectorial membrane (TM). Current evidence suggests that rotation of the RL and oscillatory fluid flow in the sub-tectorial space between the RL and TM also drive IHC stereocilia, and may even be more important than RL–TM shearing. We hypothesize that the stereocilia bundles of the IHCs are stimulated by multiple mechanisms, including classic RL-TM shearing, oscillatory fluid flow in the sub-tectorial space, and tilting of the RL near the IHC bundles; that the relative influence of these mechanisms changes with frequency, sound level, and species; and that OAE generation is dominated by RL motion. To test these hypotheses, a high-resolution OCT system (approx. 3 µm axial resolution) will be used to image and measure motions in the organ of Corti (OoC) in normal-hearing gerbils and mice, and in three mouse varieties with genetic mutations that affect the structure and mechanical properties of the TM. We will measure the transverse and radial motions of the BM, RL, and TM in response to acoustic stimulation at multiple sound levels and multiple cochlear locations. For comparisons to human hearing, responses will be measured from 0.5 to 12 kHz locations in gerbil and from 9 to 20 kHz locations in mouse. To translate the measured OoC motions into a detailed understanding of the mechanisms responsible for IHC and OHC stimulation and stimulus-frequency OAE production, we will use the OCT images to construct 3D cochlea finite-element models for gerbil and each mouse variety, and will test the models against the OCT vibrometry measurements. The models will contain, in a viscous-fluid environment, the key elements of OoC cytoarchitecture sandwiched between the BM and RL, including the pillar cells, three rows of outer hair cells, and IHCs, along with the TM, which together will allow clear relationships to be established between cochlear function and the structure and material composition of the OoC. This will improve our understanding of the various mechanical stages of hearing, will allow the health and structure of the OoC to be correlated with OAEs for diagnostic purposes, and will provide a powerful and efficient modeling framework appropriate for the future development of human cochlear models that can be validated using non-invasive hearing-threshold and OAE measurements.