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: 10365728
• 负责人: R. Michael Burger
• 金额: $ 36.73万
• 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/10365728
• 关键词: Ablation; Acoustic Nerve; Address; Anatomy; Animals; Apoptotic; Architecture; Auditory; Auditory Physiology; Auditory system; Basilar Papilla; Biophysics; Birds; Brain; Brain Stem; Brain region; Cell Nucleus; Characteristics; Chick; Cochlea; Cochlear nucleus; Cues; Data; Dependence; Development; Ear; Early Intervention; Electrophysiology (science); Embryo; Epithelial; Exhibits; Failure; Frequencies; Genetic; Goals; Hair Cells; Health; Hearing; Hearing problem; Human; Instruction; Intervention; Investigation; Ion Channel; Knowledge; Labyrinth; Mammals; Maps; Methods; Mission; Modeling; Molecular; Morphology; National Institute on Deafness and Other Communication Disorders; Neuraxis; 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; base; bone morphogenic protein; 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 patterning; neurodevelopment; neuron loss; otoconia; overexpression; preservation; relating to nervous system; 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.

项目概要： 感觉通路中神经发育的一个长期存在的基本问题是： 感觉上皮的组织在建立中央地形组织中的作用？在 听觉系统直接解决这个问题的方法一直难以捉摸，因为它还没有 可以操纵从听觉外围到大脑的输入，而无需完全消融听觉外围。 内耳或诱发听力障碍。拟议的实验将首次建立一个模型， 利用一种新的遗传操作， 胚胎这种操纵利用了已知的遗传因素，这些遗传因素建立了细胞的组织结构。 在听觉神经支配中枢神经之前的非常早期的发育阶段的耳朵 系统通过过度表达这些因子之一，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。在第一个接受听觉神经的大脑结构中 输入，耳蜗核，神经元表达了许多良好的生物物理和形态特征， 专门处理特定频率的声音。频率特定调谐是地形学上 在耳朵和听觉大脑区域都有映射，这一特征被称为“音调映射”。因此，神经特化 沿着耳蜗核中有序的音调分布图发生。该提案的中心假设是， 耳蜗核中特化的音调定位细化是由模式化的 输入来自内耳，并且不是由发育中的大脑中的局部线索独立诱导的。这 这一假说现在可以用内耳音调改变的动物来验证。这项建议的第一个目的是 为了检查BMP 7的操作是否确实诱导了毛细胞调谐机制的重新模式化， 内耳第二个目的是研究耳蜗核神经元的电输入反应特性。 内耳发育成音调改变的动物。最后，第三个目标将调查 耳蜗核结构对听神经正常局部神经支配的依赖性。这些 研究目标，如果成功的话，将提供新的见解，建立功能的机制， 听觉结构的组织。揭示这些机理对优化设计具有一定的指导意义 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 和听觉回路的能力。