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：
10186081
负责人：
LARRY F HOFFMAN
金额：
$ 64.21万
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/10186081
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.

项目摘要拟议的研究探讨了有关涉及高度转化重要性的关键问题前庭感觉上皮的部分功能障碍的机制和结果，称为外周前庭功能不全。研究计划利用趋化毒素诱导的功能障碍，其基础通过Pi的实验室的最新工作中的动物模型确定了精度腹腔剂量导致产生高度可重复的病变。这为基础提供了通过记录在感官神经上皮中的分级尺寸的病变，记录在组织病理学分析。这些病变的生理结果将通过记录来评估单个传入的神经元电生理学和前庭反射，提供了建立的基础组织学和物理生理学与前庭功能的直接行为测试相关。以前的工作有证明传入的神经花萼高度标记为病理妥协，并且由于其对未经治疗上皮的神经动力学的重要贡献，这是评估病理学的重点损害。本研究计划将使传入排放动力与关键的直接相关花萼的细胞成分，包括其KCNQ4和钠钾的形态和表达 ATPase。此外，我们将检查在病变上皮毛细胞中突触带的分布，测试系统的突触病是否也有助于折衷的前庭功能。在摘要，本研究提供了对前庭组织病理学基材的重要洞察力功能妥协构成的感觉编码的功能障碍和变化。同时，但是，这项投资将揭示正常需要的重要细胞和生理指标前庭功能，解决前庭神经生物学中的长期问题。