Three-dimensional and Multiscale Organ of Corti Biomechanics

描述（由申请人提供）：目前还没有一个统一的耳蜗放大理论与Corti细胞结构、基底膜力学和耳声发射（oae）器官相一致。我们的中心假设是，Corti器官网状层和基底膜之间系统组织的y形结构元件共同形成了基底膜最佳频率区域的耳蜗放大机制，其中有角度的外毛细胞（ohc）提供了指向顶端的累积“前馈”力，而相反角度的指骨突提供了指向基部的“反馈”力。前馈和后馈（FF/FB）放大理论将使用解剖学上真实的流体耦合3D有限元计算模型对Corti的小鼠和沙鼠器官进行测试，该模型由双光子共聚焦显微镜图像构建。在与先前的生理测量和建模结果进行验证后，新模型将用于测试FF/FB力对耳蜗放大的影响，以及耳膜和基底膜力学的影响。FF/FB放大器概念与刺激频率oae和扭曲产物oae的理论和测量相兼容的假设，以及对Corti器官结构的选择性修饰将产生可预测的结果，将在模型和实验中进行测试，使用野生型小鼠和具有缩短被膜特征的α - TectaC1509G/+小鼠。耳蜗模型通常假定OHC力输出与输入的立体耳蜗力成正比，增益假定与耳蜗位置和频率无关。我们将在此基础上进行改进，创建一个考虑基底侧电导和细胞壁电容的OHC受体电位模型，然后将其与解剖学和生理学上真实的体细胞运动模型相结合，以确定¿作为位置和频率函数的真实值。然后将得到的¿（x,r,f）模型集成到我们的FF/FB建模框架中，作为对中心假设的进一步检验。直接从这项研究中产生的科学贡献预计将是：1)对Corti器官中横跨不同OHC行，从底部到顶部的Y形元素进行详细的3D描述；2)将这些信息纳入计算模型，以测试FF/FB放大器理论与现实解剖；3)提高了对声发射产生和传播机制与FF/FB放大理论的理解；4)增强了对OHC基底外侧电导、受体电位和躯体运动对耳蜗放大的贡献的理解。由此产生的模型将为未来的耳蜗力学研究提供强大的新工具，包括那些涉及正常，转基因和再生小鼠耳蜗的研究，以及由于人类和小鼠之间的同源性，人类耳蜗也是如此。

DESCRIPTION (provided by applicant): There is not yet a single unifying theory of cochlear amplification consistent with the organ of Corti cytoarchitecture, basilar membrane mechanics, and otoacoustic emissions (OAEs). Our central hypothesis is that the systematically organized Y-shaped structural elements between the reticular lamina and basilar membrane in the organ of Corti collectively form a mechanism for cochlear amplification in the best-frequency region of the basilar membrane, in which the angled outer hair cells (OHCs) provide an accumulating "feed- forward" force directed apically, and the oppositely angled phalangeal processes provide a "feed-backward" force directed basally. The feed-forward and feed-backward (FF/FB) amplification theory will be tested using anatomically realistic fluid-coupled 3D finite element computational models for the mouse and gerbil organs of Corti, constructed from two-photon and confocal microscopy images. After validation against previous physiological measurements and modeling results, the new models will be used to test the effects of FF/FB forces on cochlear amplification, as well as the effects of tectorial and basilar membrane mechanics. The hypothesis that the FF/FB amplifier concepts are compatible with theories and measurements of stimulus- frequency OAEs and distortion-product OAEs, and that selective modifications to the structure of the organ of Corti will produce predictable results, will be tested both in the model and experimentally using wild-type mice and alpha-tectorin protein mutated mice (TectaC1509G/+) that feature a shortened tectorial membrane. Cochlear models have typically assumed that the OHC force output is proportional to the stereociliary force input, with a gain ¿ assumed to be independent of cochlear location and frequency. We will improve upon this by creating a model for the OHC receptor potential that accounts for the basolateral conductances and cell wall capacitance, which we will then combine with an anatomically and physiologically realistic model for somatic motility in order to determine realistic values for ¿ as a function of location and frequency. The resulting ¿(x,r,f) model will then be integrated into our FF/FB modeling frameworks as a further test of our central hypothesis. The scientific contributions stemming directly from this research are expected to be 1) a detailed 3D description of the Y- shaped elements in the organ of Corti across the different OHC rows, from base to apex; 2) an incorporation of this information into computational models for testing the FF/FB amplifier theories with realistic anatomy; 3) an improved understanding of how mechanisms of OAE generation and propagation relate to the FF/FB amplification theory; and 4) an enhanced understanding of the contributions of OHC basolateral conductances, receptor potential, and somatic motility to cochlear amplification. The resulting models will provide powerful new tools for future cochlear mechanics studies, including those involving normal, genetically modified, and regenerated mouse cochleae, and, due to homologs between humans and mice, the human cochlea as well.