Peripheral vestibular hypofunction and neurosensory coding

项目摘要 拟议的研究解决了具有高度翻译重要性的关于 前庭感觉上皮部分功能障碍的机制和转归 前庭功能减退。研究计划利用化学毒素诱导的功能减退，其基础是 是通过PI实验室最近在动物模型中进行的研究确定的，该模型能够 外淋巴内给药可产生高度可重复性的损伤。这为以下方面提供了基础 在感觉神经上皮细胞内产生分级损伤，通过 组织病理学分析。这些损伤的生理结果将通过记录 单个传入神经元电生理学和前庭-眼反射，为建立 组织学和生理学与前庭功能的直接行为测试相关。以前的工作有 表明传入神经元的花瓣对病理损害是高度不稳定的，并且由于其 在未处理的上皮细胞中形成神经动力学的重要贡献这是评估病理学的一个焦点 损坏。目前的研究计划将使传入放电动力学与临界放电直接相关 花萼的细胞成分，包括其形态及KCNQ4和钠钾的表达 ATPase。此外，我们还将研究受损上皮毛细胞内突触带的分布， 测试系统性突触病变是否也导致前庭功能受损。在……里面 摘要：目前的研究为前庭的组织病理学基础提供了重要的见解。 功能减退和感觉编码的改变是功能妥协的基础。同时， 然而，这项研究将揭示正常所需的重要细胞和生理指标 前庭功能，解决前庭神经生物学中长期存在的问题。

Project Summary The proposed research addresses critical issues of high translational importance concerning the mechanisms and outcomes of partial dysfunction of the vestibular sensory epithelia, referred to as peripheral vestibular hypofunction. The research plan utilizes chemotoxin- induced hypofunction, the foundation for which was identified through recent work from the PI’s laboratory in an animal model enabling precise intraperilymphatic dosing resulting in the production of highly reproducible lesions. This provides the basis for producing lesions of graded magnitudes within the sensory neuroepithelia, documented through histopathologic analyses. The physiologic outcome of these lesions will be evaluated through recordings of single afferent neuron electrophysiology and the vestibulo-ocular reflex, providing the bases for establishing histologic and physiologic correlates to a direct behavioral test of vestibular function. Previous work has demonstrated that the afferent neuron calyx is highly labile to pathologic compromise, and owing to its important contribution to shaping neural dynamics in untreated epithelia it is a focus for assessing pathologic damage. The present research plan will enable the direct correlate of afferent discharge dynamics to critical cellular components of the calyx, including its morphology and expression of KCNQ4 and sodium-potassium ATPase. In addition, we will examine the distribution of synaptic ribbons within hair cells of lesioned epithelia, testing whether a systematic synaptopathy also contributes to the compromised vestibular function. In summary, the present investigation provides critical insight into the histopathologic substrates of vestibular hypofunction and the alterations in sensory coding that underlies the functional compromise. At the same time, however, this investigation will reveal important cellular and physiologic metrics that are required for normal vestibular function, addressing longstanding question in vestibular neurobiology.