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高度敏感的生物奇迹，在很大程度上可以 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，内耳骨囊的不可及和技术上的 在多物理系统中测量纳米级振动并对其进行建模的挑战使得 难以揭示OOC的结构-功能关系。然而，增加的计算能力和 光学相干层析成像(OCT)等新的成像技术使得捕获OOC成为可能 运动比以往任何时候都更详细，这正在彻底改变我们对耳蜗放大的理解。这个 扩增最广为人知的方面是外毛细胞的体细胞运动，以及最近的数据 通过测量三排毛囊的OOC运动表明，网状板(RL)是灵活的，而不是 一个多世纪以来人们一直认为的坚硬的盘子。我们的中心假设是，RL的灵活性决定了OHC的阶段 束运动，因此是耳蜗放大所必需的。为了检验这一假设，我们将测量 健康听力正常小鼠耳蜗声发射的高分辨率研究 小鼠低频顶区和高频基底区的OCT系统。我们会 测量沿RL的不同的放射状位置以及沿心毛细胞和Deiters细胞之间的交界处 对应于三个OHC行，在多个频率和声压级下。我们还将衡量 沿着基底膜(BM)，以充分表征RL相对于BM和其他运动的运动 OOC结构。这些测量将通过提供经验证据来检验我们的假设 RL在径向和横向上跨两个不同频率和电平的灵活性 耳蜗的位置。我们还将利用测量结果来开发详细的、多物理的、有限元的人工耳蜗。 模型，这将使我们深入了解RL和覆盖膜之间的关系，以及驱动 OHC捆绑包。顶端和基础模型都将包含OOC细胞结构的关键元素，包括 由毛囊、Deiters细胞和Deiters指突组成的交叉型Y形积木 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 可与死后(被动)和体内(主动)OCT测量相媲美，并将调查 RL僵硬对OHC-束相和耳蜗声放大的影响。这些目标的实现将具有广泛的影响 这意味着什么。这项研究不仅将揭示关于听力本质的基本知识，而且它 有助于改善对人类耳蜗病的理解、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.