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

项目摘要/摘要 我们对耳蜗力学的知识目前正在经历一场革命。而基底膜(BM) 长期以来一直被认为是耳蜗运动的主要结构，光学相干等新技术 断层扫描(OCT)不仅揭示了网状板(RL)以不同的模式移动 从BM，但它的移动在低输入声级3-10倍以上。此外，RL运动更接近于 内毛细胞(IHC)立体纤毛，使其与BM运动更相关，以触发 耳蜗骨。与BM相比，RL的运动更大，也表明RL运动可能是主要的 耳声发射(OAES)的来源。另一个长期持有的观点--现在意识到是不充分的--是 IHC立体纤毛仅由RL和覆盖膜(TM)之间的剪切作用驱动。当前 证据表明，RL的旋转和RL之间的次覆盖空间中的振荡流体流动 TM也驱动IHC立体纤毛，甚至可能比RL-TM剪切更重要。我们假设 IHC的立体纤毛束受到多种机制的刺激，包括经典的RL-TM 次盖层空间中的剪切、振荡流体流动以及RL在IHC束附近的倾斜； 这些机制的相对影响随着频率、声级和物种的变化而变化；而OAE 世代以RL运动为主。为了验证这些假设，一个高分辨率的OCT系统(约3微米 轴向分辨率)将用于成像和测量正常听力中的Corti器官(OOC)的运动 沙鼠和小鼠，以及在三个小鼠品种中具有影响结构和机械性能的基因突变 TM的属性。我们将测量BM、RL和TM的横向和径向运动 多个声级和多个耳蜗处的声刺激。用于与人类进行比较 听力方面，将在沙土鼠的0.5至12 khz位置测量反应，并在 老鼠。将测量到的OOC运动转化为对相关机制的详细了解 对于IHC和OHC刺激以及刺激频率的OAE产生，我们将使用OCT图像来构建 为沙土鼠和每一种老鼠建立3D耳蜗有限元模型，并将针对OCT测试模型 振动测量。这些模型将在粘性流体环境中包含OOC的关键要素 夹在BM和RL之间的细胞结构，包括柱状细胞，三排外毛细胞， 和IHC，以及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。这将有助于我们更好地理解 听力的不同机械阶段，将允许OOC的健康和结构与OAEs相关 用于诊断目的，并将提供适用于未来的强大而高效的建模框架 利用无创听阈值和耳声发射技术建立可验证的人类耳蜗病模型 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.