Peripheral vestibular hypofunction and neurosensory coding

周围前庭功能减退和神经感觉编码

基本信息

批准号：
10397624
负责人：
LARRY F HOFFMAN
金额：
$ 59.9万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-05-01 至 2026-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10397624
关键词：
Address Afferent Neurons Ally Animal Model Animals Antibodies Apical Architecture Autoimmune Behavior Behavior Therapy Behavioral Bilateral Characteristics Code Contralateral Crista ampullaris Development Docking Dose Electrophysiology (science)Epithelial Exhibits Foundations Frequencies Functional disorder General Population Gentamicins Hair Cells Histologic Immunohistochemistry Investigation Ipsilateral Label Laboratories Labyrinth Lesion Lighting Measures Meta-Analysis Microscopy Morphology Na(+)-K(+)-Exchanging ATPase Neurobiology OTOF gene Outcome Pathologic Patients Peripheral Phase Phenotype Physiological Prevalence Production Recovery Reproducibility Research Resolution Response to stimulus physiology Salvelinus Scanning Sensory Shapes Specimen Stimulus Structure Synapses Synaptic Cleft Testing Time Transmission Electron Microscopy Tubulin Type I Hair Cell Utricle structure Vestibular Function Tests Vestibular Neuronitis Work base behavior test calyx structure insight light microscopy neurosensory ototoxin postsynaptic presynaptic public health relevance rehabilitation strategy relating to nervous system response ribbon synapse uptake vestibulo-ocular reflex

项目摘要

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.

项目概要拟议的研究解决了与前庭感觉上皮（称为外周感觉上皮）部分功能障碍的机制和结果该研究计划利用了趋化毒素引起的前庭功能减退，这是其基础。 PI 实验室最近在动物模型中的工作确定了这一点，从而实现了精确的外淋巴内给药导致产生高度可重复的病变，这提供了基础。在感觉神经上皮内产生分级程度的损伤，记录如下这些病变的生理结果将通过记录进行评估。单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。证明传入神经元花萼对病理损害高度不稳定，这归因于其对塑造未经治疗的上皮细胞的神经动力学有重要贡献，它是评估病理学的重点目前的研究计划将使传入放电动力学与临界损伤直接相关。花萼的细胞成分，包括其形态以及 KCNQ4 和钠钾的表达此外，我们将检查病变上皮毛细胞内突触带的分布，测试系统性突触病是否也会导致前庭功能受损。总之，本研究提供了对前庭神经组织病理学底物的重要见解功能减退和感觉编码的改变是功能损害的基础。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。