Human Cochlear Structure & Function

项目摘要 虽然耳蜗的内部工作负责听觉的最基本方面，包括听力 灵敏度和频率调谐，我们对人类耳蜗力学的直接知识是有限的。缺少资料 迫使研究人员依靠动物实验来推断人类耳蜗的行为， 假设耳蜗分区（CP）的运动，包括基底膜（BM）和Corti器官 (OoC)人类和实验室动物之间是相似的。然而，我们最近发现了惊人的差异， 与实验室动物相比，人类CP解剖和运动。动物的骨髓附着在一个狭窄的固定骨 骨螺旋板（OSL）是一个复杂的结构，几乎占所有的CP运动。相反，人类的OSL 更宽，是移动的，并通过新发现的软组织结构连接到BM，我们将其命名为CP “桥”。这座桥在实验室动物身上是不存在的，它和BM一样宽，震动也一样大。 结合OSL本身是移动的的事实，BM因此仅占总CP运动的一小部分， 人类这些新发现的人类CP解剖和运动方面挑战了长期以来的假设， 哺乳动物的耳蜗力学可以被认为是相似的。 由于CP结构，如OSL，桥，以及覆膜（TM）附着于 利姆布斯在人类中都是移动的，但在实验室动物中不是，我们假设OoC结构的运动， 包括网状层和TM，在人类中是不同的，从而改变了驱动转导过程的输入 在内外毛细胞的毛束上。为了测试这一点，光学相干断层扫描（OCT）将允许我们 在非常新鲜的人类尸体标本中原位确定各种CP结构的解剖结构和相对运动。我们 还将调查和阐明力学和解剖学之间的关系，在人类CP使用各种 技术来表征CP的形态测量学、结构架构和材料组成。 我们将进一步测试我们的假设，通过开发人类耳蜗的有限元模型， 测量解剖学和CP力学。由于我们的测量是从死后的耳朵，他们不能揭示的影响， 活跃的进程。然而，我们的模型可以根据预测的活体动物结果来近似主动行为。 在功能上与人类相似，因为这些结构具有相似的解剖结构。将对由此产生的模型进行测试 并根据心理声学数据对已知的人类调谐能力进行了验证，为未来的应用打开了大门 其中可以以前所未有的逼真度模拟人类耳蜗病理、操纵和治疗。 这项研究将极大地推进我们对人类CP结构如何共同工作以定义 由毛细胞形成的传感器的输入。它还将使我们能够更好地了解适用性， 在人类听觉研究中，动物实验的局限性，以及更好地利用动物模型进行科学研究。 此外，所提出的计算模型将是有价值的科学调查的听力现象， 为未来听力疾病的理解、诊断和治疗提供帮助。

PROJECT SUMMARY Although the inner workings of the cochlea are responsible for the most fundamental aspects of hearing, including hearing sensitivity and frequency tuning, our direct knowledge of human cochlear mechanics is limited. This lack of information has forced researchers to rely on animal experiments to make inferences about cochlear behavior in humans, under the assumption that the motions of the cochlear partition (CP), including the basilar membrane (BM) and the organ of Corti (OoC), are similar between humans and laboratory animals. However, we have recently found surprising differences in human CP anatomy and motion as compared to laboratory animals. The BM in animals is attached to a narrow fixed bony structure, the osseous spiral lamina (OSL), and accounts for almost all of the CP motion. In contrast, the OSL in humans is much wider, is mobile, and connects to the BM via a newly identified soft-tissue structure that we have named the CP “bridge”. The bridge, which is non-existent in laboratory animals, is as wide as and vibrates as much as the BM. Combined with the fact that the OSL itself is mobile, the BM therefore only accounts for a fraction of total CP motion in humans. These newly discovered aspects of human CP anatomy and motion challenge the long-held assumption that cochlear mechanics can be regarded as similar across mammals. Because CP structures such as the OSL, bridge, and location where the tectorial membrane (TM) attaches to the limbus are all mobile in humans but not in laboratory animals, we hypothesize that the motions of the OoC structures, including the reticular lamina and TM, are different in humans, thereby altering the input driving the transduction process at the hair bundles of the inner and outer hair cells. To test this, Optical Coherence Tomography (OCT) will allow us to determine the anatomy and relative motion of various CP structures in situ in very fresh human cadaveric specimens. We will also investigate and elucidate the relationships between mechanics and anatomy in the human CP using a variety of techniques to characterize the morphometry, structural architecture, and material composition of the CP. We will further test our hypothesis by developing finite-element models of the human cochlea that incorporate the measured anatomy and CP mechanics. As our measurements are from postmortem ears, they cannot reveal the effects of active processes. However, our models can approximate active behavior based on live-animal results, which are predicted to be functionally similar to human given the similar anatomies of these structures. The resulting models will be tested and validated against known human tuning capabilities from psychoacoustic data, opening the door to future applications in which human cochlear pathologies, manipulations, and treatments can be simulated with unprecedented fidelity. This research will greatly advance our understanding of how the structures of the human CP work together to define the inputs to the transducers formed by the hair cells. It will also enable us to better understand the applicability and limitations of animal experiments in the study of human hearing, and to better utilize animal models for scientific inquiry. Moreover, the proposed computational models will be valuable both for scientific investigation of hearing phenomena and for future improvements in the understanding, diagnosis and treatment of hearing disease.