Measuring and Modeling the Effects of Reticular Lamina Flexibility on Outer Hair Cell Bundle Phase and Cochlear Amplification

摘要 哺乳动物的听觉系统已经进化成一个生物奇迹，具有很高的灵敏度， 可追溯到Corti器官（OoC）的非线性放大-耳蜗内的感觉上皮 内耳尽管经过了几十年的研究，内耳骨囊的不可接近性和技术上的局限性仍然存在。 在多物理系统中测量和建模纳米级振动的挑战使得 很难揭示OoC的结构-功能关系。然而，增加的计算能力和 光学相干断层扫描（OCT）等新型成像技术使OoC的捕获成为可能 运动的细节比以往任何时候都要详细，这是我们对耳蜗放大的理解的革命。的 扩增的最好理解的方面是外毛细胞（OHC）的体细胞运动性，最近的数据 通过测量三排OHC的OoC运动表明，网状板（RL）是柔性的， 一个世纪以来一直被认为是坚硬的板块。我们的中心假设是，强化学习的灵活性设置了OHC的阶段 束运动，因此是耳蜗放大所必需的。为了验证这一假设，我们将测量 从多个角度从健康耳蜗的OoC运动，使用高分辨率的听力正常小鼠 OCT系统在小鼠的较低频率的顶区和较高频率的基底区。我们将 测量沿着RL和沿着OHC和Deiters细胞之间连接处的不同径向位置 对应于三个OHC行，在多个频率和声压级。我们还将测量 沿着基底膜（BM），以完全表征RL相对于BM的运动的运动，以及其他 OoC结构。这些测量将通过提供经验证据来检验我们的假设， 在两个不同的频率和水平下，在径向和横向方向上的RL柔性 耳蜗位置。我们还将使用这些测量来开发详细的、多物理场的、有限元的耳蜗 模型，这将使我们深入了解RL和顶盖膜之间的关系， OHC束。顶端和基底模型都将包含OoC细胞结构的关键要素，包括 由OHC、Deiters细胞和Deiters细胞的指骨突制成的交叉指状Y形构建块 细胞，夹在基底膜和RL马赛克之间。我们的目标是在模型中产生运动 与死后（被动）和体内（主动）OCT测量结果相当，并将研究 RL刚度对OHC束相位和耳蜗放大的影响。这些目标的实现将产生广泛的影响。 影响这项研究不仅将揭示关于听觉本质的基本知识，而且还将 有助于改善对人类耳蜗病理学的理解、诊断和治疗的潜力。

ABSTRACT The mammalian auditory system has evolved into a biological marvel with high sensitivity that can largely be traced to nonlinear amplification by the organ of Corti (OoC)—the sensory epithelium within the cochlea of the inner ear. Despite decades of research, the inaccessibility of the inner ear’s bony capsule and the technological challenges of measuring and modeling nanometer-scale vibrations in a multi-physics system have made it difficult to uncover OoC structure-function relationships. However, increased computational capabilities and novel imaging technologies such as optical coherence tomography (OCT) now make it possible to capture OoC motion in more detail than ever before, which is revolutionizing our understanding of cochlear amplification. The most well-understood aspect of amplification is the somatic motility of outer hair cells (OHCs), and recent data measuring OoC motion across the three rows of OHCs suggests that the reticular lamina (RL) is flexible and not a stiff plate as was thought for over a century. Our central hypothesis is that RL flexibility sets the phase of OHC bundle motion and is therefore necessary for cochlear amplification. To test this hypothesis, we will measure OoC motion from multiple angles from healthy cochleae of living, normal-hearing mice using a high-resolution OCT system in both the lower-frequency apical region and higher-frequency basal region of mice. We will measure distinct radial locations along the RL and along the junctions between OHCs and Deiters’ cells corresponding to the three OHC rows, at multiple frequencies and sound pressure levels. We will also measure along the basilar membrane (BM) to fully characterize RL motion in relation to the motion of the BM and other OoC structures. These measurements will test our hypothesis by providing empirical evidence for the degree of RL flexibility in the radial and transverse directions across different frequencies and levels at two different cochlear locations. We will also use the measurements to develop detailed, multi-physics, finite-element cochlear models, which will give us insight into the relationship between the RL and tectorial membrane and the drive to OHC bundles. Both the apical and basal models will contain key elements of OoC cytoarchitecture including the interdigitated Y-shape building blocks made from OHCs, Deiters’ cells, and the phalangeal processes of Deiters’ cells, sandwiched between the basilar membrane and the RL mosaic. We aim to produce motion in the models comparable to post-mortem (passive) and in-vivo (active) OCT measurements and will investigate the effects of RL stiffness on OHC-bundle phase and cochlear amplification. Completion of these aims will have wide-reaching implications. Not only will this research uncover fundamental knowledge about the nature of hearing, but it has the potential to contribute to improved understanding, diagnoses, and treatment of human cochlear pathologies.