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Control of cochlear amplification by cellular and acellular elements of the mammalian cochlea

哺乳动物耳蜗的细胞和非细胞元件对耳蜗放大的控制

基本信息

批准号：
MR/W028956/1
负责人：
Andrei Lukashkin
金额：
$ 137.38万
依托单位：
University of Brighton
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2022
资助国家：
英国
起止时间：
2022 至无数据
项目状态：
未结题

来源：
https://gtr.ukri.org/projects?ref=MR%2FW028956%2F1
关键词：
Control cochlear amplification cellular acellular

项目摘要

The hearing organ of mammals, the cochlea, permits them to listen to sounds with remarkable acuity and sensitivity over enormous frequency and dynamic ranges. This ability is due to the novel design of the mammalian cochlea which facilitates electromechanical interaction between sensory hair cells, supporting cells of the sophisticated cellular architecture of the sensory organ of Corti, and the extracellular matrixes of the tectorial and basilar membranes that sandwich the organ of Corti. The basilar membrane, which supports the organ of Corti, separates sounds into constituent frequency components and underlies cochlear tonotopicity. Viscous damping in the fluid filled cochlea is counteracted through the action of sensory-motor outer hair cells, which boost and sharpen cochlear responses that are sensed by the inner hair cells. Resultant inner hair cell excitation and consequent transmitter release generates a flow of signals in the auditory nerve to the brain. Hair cells die when damaged by exposure to intense sounds, ototoxicity, disease, age and genetic disorders. According to WHO, 5% of the world population suffer from irrecoverable hearing loss. Exciting possibilities for hair cell regeneration and hearing restoration are now becoming available. Understanding of the complex in vivo interaction between the sensory hair cells, supporting cells and tectorial and basilar membranes is essential for the future development of successful treatments for hearing loss, especially those involving recovery of damaged, or replacement of, dead sensory hear cells. Therefore, our prime objective is to study this complex interaction between elements of the cochlear sensory epithelium underlying the unique features of mammalian audition using in vivo measurements supported by ex vivo measurements. This research proposal is motivated by recent discoveries from our laboratory and elsewhere showing that the frequency and level-dependent interaction between different elements of the cochlea are far more complex than is presented in classical models of cochlear function, with the basilar membrane passively separating the frequency constituents of sounds and outer hair cells amplifying and sharpening the basilar membrane responses, which are then seen as sharp, sensitive, neural responses. To achieve our goals we record mechanical, acoustic, electrical and neural cochlear responses and combine them with predictive modelling to validate our ideas and gain further insights into the functional significance of interaction between different structures of the organ of Corti. More specifically, we will determine the timing of outer hair cell excitatory input which is optimised to deliver energy to the movement of cochlear structures at the appropriate time and place. We will investigate the significance of extracellular voltage for controlling outer hair cell motility and electrical and mechanical interaction between hair cells, which permits them to boost cochlear responses at ultrasonic frequencies with very sharp frequency resolution. Accordingly, the electrical properties of the organ of Corti will be characterised. Mechanical properties of the tectorial membrane, their dependence on the stimulus parameters and contribution to the build-up of cochlear amplification and sharpening of cochlear response will be determined. Using optogenetic mice that express channel rhodopsins in supporting cells, we will derive the mechanisms by which supporting cells regulate hair cell operation and regulate the longitudinal flow of energy within the organ of Corti.

哺乳动物的听力器官--耳蜗，使它们能够在巨大的频率和动态范围内以非凡的敏锐度和敏感度聆听声音。这种能力归功于哺乳动物耳蜗的新颖设计，它促进了感觉毛细胞、Corti感觉器官复杂细胞结构的支持细胞以及覆盖Corti器官的覆盖膜和基底膜的细胞外基质之间的机电相互作用。支撑Corti器官的基底膜将声音分离成组成频率的分量，并构成耳蜗声调性的基础。充满液体的耳蜗中的粘性衰减通过感觉-运动外毛细胞的作用被抵消，外毛细胞促进和锐化由内毛细胞感知的耳蜗反应。由此产生的内毛细胞兴奋和随之而来的递质释放会在听神经中产生信号流到大脑。毛细胞因暴露在强烈的声音、耳毒性、疾病、年龄和遗传疾病中而受损时会死亡。根据世界卫生组织的数据，5%的世界人口患有无法恢复的听力损失。毛细胞再生和听力恢复的令人兴奋的可能性现在已经成为可能。了解感觉毛细胞、支持细胞以及顶盖和基底膜之间的复杂体内相互作用对于未来成功的听力损失治疗方法的发展至关重要，特别是涉及受损的感觉HAR细胞的恢复或替代死亡的感觉HAR细胞的治疗。因此，我们的主要目标是利用活体测量和体外测量相结合的方法来研究哺乳动物听力独特特征背后的耳蜗感觉上皮元素之间的这种复杂的相互作用。这项研究建议的动机是来自我们实验室和其他地方的最新发现，这些发现表明耳蜗不同元素之间的频率和水平相关的相互作用比经典的耳蜗功能模型中所呈现的要复杂得多，基底膜被动地分离声音的频率成分，外毛细胞放大和锐化基底膜的反应，然后将其视为尖锐、敏感的神经反应。为了实现我们的目标，我们记录了机械、声学、电学和神经耳蜗反应，并将它们与预测模型相结合，以验证我们的想法，并进一步深入了解Corti器官不同结构之间相互作用的功能意义。更具体地说，我们将确定外毛细胞兴奋性输入的时间，这是优化的，以在适当的时间和地点为耳蜗结构的运动提供能量。我们将研究细胞外电压对控制外毛细胞运动和毛细胞之间的电气和机械相互作用的意义，这使得毛细胞能够在频率分辨率非常高的超声波频率下增强耳蜗反应。因此，科尔蒂器官的电学特性将被表征。将确定覆盖膜的机械性能，它们对刺激参数的依赖，以及对建立耳蜗放大和增强耳蜗反应的贡献。利用在支持细胞中表达通道视紫红质的光遗传小鼠，我们将得出支持细胞调节毛细胞运行和调节Corti器官内能量纵向流动的机制。