Developmental Determination of Central Auditory Physiology by the Inner Ear

内耳中枢听觉生理学的发育决定

• 批准号: 10610316
• 负责人: R. Michael Burger
• 金额: $ 37.6万
• 依托单位: LEHIGH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-01 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10610316
• 关键词: Ablation; Acoustic Nerve; Address; Anatomy; Animals; Apoptotic; Architecture; Auditory; Auditory Physiology; Auditory system; Basilar Papilla; Biophysics; Birds; Bone Morphogenetic Proteins; Brain; Brain Stem; Brain region; Cell Nucleus; Central Nervous System; Characteristics; Chick; Cochlea; Cochlear nucleus; Cues; Data; Dependence; Development; Ear; Early Intervention; Electrophysiology (science); Embryo; Epithelium; Exhibits; Failure; Frequencies; Genetic; Goals; Hair Cells; Health; Hearing; Hearing problem; Human; Intervention; Investigation; Ion Channel; Knowledge; Labyrinth; Mammals; Maps; Methods; Mission; Modeling; Molecular; Morphology; National Institute on Deafness and Other Communication Disorders; Neurons; Pathway interactions; Pattern; Peripheral; Phenotype; Physiology; Population; Process; Property; Research; Role; Sensory; Signal Transduction; Source; Structure; Synapses; System; Testing; Therapeutic; Therapeutic Intervention; Time; Work; biophysical properties; childhood hearing loss; chordin; cochlear development; critical period; deaf; deafening; deafness; experimental study; genetic manipulation; hearing impairment; hearing preservation; innovation; insight; juvenile animal; morphogens; nerve supply; neural; neural patterning; neurodevelopment; neuron loss; otoconia; overexpression; preservation; response; sound; tool

Project Summary: A longstanding and fundamental question of neural development in sensory pathways is: What is the role of the organization of the sensory epithelium in establishing central topographic organization? In the auditory system a direct approach to addressing this question has been elusive because it has not been possible to manipulate the input to the brain from the auditory periphery without either complete ablation of the inner ear or induction of hearing dysfunction. The proposed experiments will establish for the first time, a model of repatterned frequency representation in the chick inner ear by utilizing a new genetic manipulation in embryos. This manipulation takes advantage of the known genetic factors that establish the organization of the ear at a very early developmental stage that precedes the auditory nerve innervation of the central nervous system. By overexpressing one of these factors, bone morphogenic protein 7 (BMP7), inner ears develop almost exclusively low frequency hair cell phenotypes. In the first brain structure to receive auditory nerve input, the cochlear nucleus, neurons express a number of well characterized biophysical and morphological specializations for processing sound in specific frequencies. Frequency specific tuning is topographically mapped in both the ear and auditory brain regions, a feature known as 'tonotopy.' Thus, neural specialization occurs along an orderly tonotopic map in the cochlear nucleus. The central hypothesis of this proposal is that tonotopic refinement of specializations in the cochlear nucleus is developmentally determined by patterned input from the inner ear, and is not independently induced by local cues in the developing brain. This hypothesis is now testable using animals with tonotopically altered inner ears. The first aim of this proposal is to examine whether the BMP7 manipulation indeed induces repatterning of hair cell tuning mechanism in the inner ear. The second aim investigates the electrical input response properties of cochlear nucleus neurons in animals that have developed with tonotopically altered inner ears. Finally, the third aim will investigate the dependence of cochlear nucleus structure on normal topographic innervation from the auditory nerve. These research objectives, if successful, will provide new insights into the mechanisms that establish the functional organization of auditory structures. Revelation of these mechanisms may be informative to optimization strategies for therapeutic interventions in early deafness or hearing loss that aim to preserve normal function and capacity in auditory circuitry.

项目总结： 感觉通路中神经发育的一个长期而基本的问题是：什么是 感觉上皮组织在建立中央地形图组织中的作用？在 听觉系统解决这个问题的直接方法一直难以捉摸，因为它还没有 有可能操纵从听觉外周到大脑的输入，而不需要完全消融 内耳或诱发听力障碍。拟议中的实验将首次建立一个模型 利用一种新的遗传操作在雏鸡内耳中重塑频率表示 胚胎。这种操作利用了已知的遗传因素，这些因素建立了 耳朵处于非常早期的发育阶段，在中枢神经支配听神经之前 系统。通过过度表达其中一种因子--骨形态发生蛋白7(BMP7)，内耳发育 几乎完全是低频毛细胞表型。在第一个接受听神经的大脑结构中 输入后，耳蜗核、神经元表现出许多良好的生物物理和形态特征 在特定频率下处理声音的专门技术。特定频率的调谐在拓扑结构上 在耳朵和听觉脑区都有映射，这是一种被称为强直性复制的特征。因此，神经专门化 在耳蜗核中沿着一个有序的音调地图发生。这项提议的中心假设是 耳蜗核特化的纯音精化是由图案化的发展决定的 来自内耳的输入，而不是由发育中的大脑中的局部线索独立诱导的。这 假说现在可以用内耳音调改变的动物来检验。这项提议的第一个目的是 为了检查BMP7操作是否确实诱导了毛细胞调节机制的重塑 内耳。第二个目的是研究大鼠耳蜗核神经元的电输入反应特性。 已经发育成内耳强直改变的动物。最后，第三个目标将调查 耳蜗核结构依赖于听神经的正常地形性神经支配。这些 研究目标，如果成功，将提供对建立功能的机制的新见解 听觉结构的组织。这些机制的揭示可能会对优化有所帮助 旨在保护正常功能的早期耳聋或听力损失的治疗干预策略 以及听觉回路的容量。