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

测量和模拟网状层灵活性对外毛细胞束相位和耳蜗放大的影响

• 批准号: 10676401
• 负责人: Gabriel Alberts
• 金额: $ 4.17万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-01 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10676401
• 关键词: 3-Dimensional; Affect; Air; Anatomy; Animals; Apical; Auditory system; Autopsy; Basilar Membrane; Binding; Biological; Cells; Characteristics; Cochlea; Computer Models; Data; Diagnosis; Diameter; Elements; Epithelium; External auditory canal; Frequencies; Future; Gerbils; Hearing; Human; Hydrogen; Image; Imaging technology; Knowledge; Labyrinth; Length; Location; Measurement; Measures; Mechanics; Membrane; Methods; Modeling; Modernization; Motion; Mus; Nature; Optical Coherence Tomography; Organ of Corti; Outer Hair Cells; Output; Pathology; Persons; Phalanx; Phase; Physics; Pillar Cell; Process; Radial; Research; Resolution; Rest; Sensory; Shapes; Source; Stapes; Structure; Structure-Activity Relationship; System; Technology; Testing; Tissues; Wild Type Mouse; base; bone; capsule; cell motility; flexibility; hearing impairment; improved; in vivo; insight; meter; microCT; mosaic; nanometer; nanoscale; normal hearing; novel imaging technology; particle; pressure; response; round window; sound; tectorial membrane; three-dimensional modeling; vibration

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.

抽象的 哺乳动物的听觉系统已演变为具有高灵敏度的生物学奇迹，在很大程度上可以 通过Corti（OOC）的器官（OOC）追溯到非线性扩增。 内耳。尽管进行了数十年的研究，但内耳的骨胶囊的无法访问和技术 在多物理系统中测量和建模纳米尺度振动的挑战使它成为现实 难以发现OOC结构功能关系。但是，增加了计算能力和 新型成像技术，例如光学连贯性层析成像（OCT），现在可以捕获OOC 运动比以往任何时候都更详细，这彻底改变了我们对人工耳蜗的理解。 放大的最有理解的方面是外毛细胞的躯体运动（OHC）和最新数据 测量OOC跨三行OHC的运动表明网状层（RL）是灵活的，而不是 一个多世纪以来的僵硬板。我们的中心假设是RL灵活性设置了OHC的阶段 束运动，因此是人工耳蜗的必要条件。为了检验这一假设，我们将测量 使用高分辨率的活着，正常听力小鼠的健康凝胶中的多个角度的OOC运动 小鼠的低频顶端区域和高频基本区域中的OCT系统。我们将 测量沿RL以及OHC和Deiters细胞之间的连接处的不同径向位置 对应于多个频率和声压水平的三个OHC行。我们还将衡量 沿着基底膜（BM）完全表征与BM和其他运动有关的RL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 在两个不同的频率和水平的径向和横向方向上的RL灵活性 人工耳蜗。我们还将使用测量结果来开发详细的多物理学，有限元的人工耳蜗 模型，这将使​​我们深入了解RL和Tectorial膜之间的关系以及动力 ohc捆。顶端模型和基本模型都将包含OOC细胞结构的关键要素，包括 由OHC，Deiters的细胞和Deiters的指向过程制成的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 与验尸后（被动）和体内（活动）OCT测量相媲美，并将研究 RL刚度在OHC-BUNDLE相位和人工耳蜗放大。这些目标的完成将具有广泛的范围 含义。这项研究不仅会发现听力本质的基本知识，而且还可以 有助于改善人工耳蜗病理学的理解，诊断和治疗的潜力。