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.

项目摘要： 感官途径中神经发展的长期和基本问题是：什么是 感觉上皮组织在建立中央地形组织中的作用？在 听觉系统一种直接解决这个问题的方法是难以捉摸的，因为它没有 可以从听觉外围操纵对大脑的输入，而无需完全消融 内耳或听力功能障碍的诱导。提出的实验将首次建立 通过利用新的遗传操纵，在雏鸡内耳中重新划定的频率表示 胚胎。这种操纵利用了已知的遗传因素，这些因素建立了 耳朵在中枢神经的听觉神经支配之前的早期发育阶段 系统。通过过表达这些因素之一，骨形态蛋白7（BMP7），内耳发展 几乎完全低频毛细胞表型。在第一个接收听觉神经的大脑结构中 输入，神经元的耳蜗核表达了许多表征良好的生物物理和形态学 特定频率处理声音的专业。特定频率特定的调整在地形上是 在耳朵和听觉大脑区域中映射，这是一种称为“ Tonotopicy”的功能。因此，神经专业化 沿着人工耳蜗核中的有序的吨位图发生。该提议的核心假设是 在人工耳蜗核中专业化的体点完善是由图案化确定的 内耳的输入，并且不是由发育中的大脑中局部线索独立引起的。这 现在，使用具有补充倍率改变内耳的动物可以检验假设。该提议的第一个目的是 检查BMP7的操纵是否确实诱导了毛细胞调整机制的重新处理 内耳。第二个目的研究了耳蜗核神经元中的电输入响应特性 随着构思范围内的内耳改变而发展的动物。最后，第三个目标将调查 耳蜗核结构对听觉神经正常地形神经的依赖性。这些 研究目标（如果成功）将为建立功能的机制提供新的见解 听觉结构的组织。这些机制的启示可能是优化的信息 旨在保持正常功能的早期耳聋或听力损失的治疗干预策略 和听觉电路的容量。