Synaptic Mechanisms of Mammalian Vestibular Efferent Responses

哺乳动物前庭传出反应的突触机制

基本信息

批准号：
10092148
负责人：
Joseph Christopher Holt
金额：
$ 32.71万
依托单位：
UNIVERSITY OF ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-03-01 至 2023-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10092148
关键词：
Abate Acetylcholine Acoustic Nerve Adult Affect Anatomy Animal Model Axon Bilateral Brain Stem Cholinergic Receptors Contralateral Control Animal Data Dizziness Dorsal Electrophysiology (science)Equilibrium Evoked Potentials External Canal Functional disorder Generations Goals Hair Cells Head Movements Impairment Individual Intervention Ipsilateral Knowledge Label Ligands Mammals Mediating Modeling Morphology Motion Sickness Movement Mus Muscarinics Neuraxis Neurons Organ Output Pathway interactions Peripheral Pharmacology Physiological Physiology Population Posture Potassium Channel Preparation Prevalence Process Property Proteins Recurrence Research Rest Role Rotation Sensory Sensory Hair Signal Pathway Signal Transduction Specific qualifier value Speed Stimulus Synapses System Testing Time Transgenic Animals Transgenic Mice Type II Hair Cell Varicosity Vertebrates base cholinergic experience extracellular gaze in vivo insight nerve supply novel postsynaptic prevent protein function receptor recruit response tool

项目摘要

Project Summary Vestibular organs, through their resident hair cells and afferent innervation, transmit information to the central nervous system about the direction, speed, and magnitude of head and body movements, which are necessary for maintaining posture, stabilizing gaze, and guiding navigational tasks. The vestibular organs are also endowed with a robust efferent innervation that begins as a few hundred neurons within the dorsal brainstem and extensively collateralizes in the periphery to end as thousands of bouton varicosities abutting hair cells and afferents. In mammals, activation of the efferent vestibular system (EVS) ultimately excites primary vestibular afferents along two distinct time scales. While acetylcholine (ACh) accounts for many EVS actions in other vertebrates, the synaptic mechanisms underlying afferent responses to EVS stimulation in mammals have not been identified. As a result, there is a clear gap in our knowledge in relating how the various EVS-mediated actions are initiated, and what impact they exert on the subsequent responses of vestibular afferents to natural stimuli. To facilitate an understanding of EVS function in mammalian vestibular physiology, three major directions will be pursued in the peripheral vestibular system of mice. The first specific aim will establish the pharmacological basis for the effects of EVS activation on spontaneous discharge of vestibular afferents. The second specific aim will specify EVS postsynaptic mechanisms required for these EVS actions by using transgenic animals where individual signaling components, implicated by our pharmacological data, are absent. Finally, the last specific aim will identify how the activation of each EVS synaptic mechanism modifies the responses of mammalian afferents to vestibular stimulation. To complete these specific aims, the discharge properties of primary vestibular afferents in the anesthetized mouse will be characterized during EVS activation with or without vestibular stimulation. Selective pharmacological agents will be applied to identify the receptors and downstream effectors and to determine how they impact both stimulation paradigms. To identify and localize specific signaling pathways, parallel electrophysiological and immunohistochemical studies will be performed in transgenic animals where the function of proteins, integral to the synaptic mechanisms implicated by the pharmacology in the first specific aim, are disrupted. The effects of EVS stimulation on afferent responses to vestibular stimulation will be characterized by pairing rotational and translational stimuli with EVS stimulation paradigms during pharmacological interrogation in both control and transgenic animals. These studies are significant as they will provide much needed insights into the diverse synaptic mechanisms that the EVS recruits to modulate afferent discharge in mammals. The data captured by this proposal is critical for probing the functional roles of the EVS in vestibular physiology as well as identifying novel synaptic processes that can be targeted pharmacologically for combatting vestibular dysfunction.

项目概要前庭器官通过其驻留的毛细胞和传入神经支配将信息传递到中枢关于头部和身体运动的方向、速度和幅度的神经系统，这是必要的用于保持姿势、稳定视线和指导导航任务。前庭器官也具有强大的传出神经支配，始于背侧脑干内的数百个神经元并在外围广泛抵押，最终形成数以千计的毛细胞附近的布顿静脉曲张，传入。在哺乳动物中，传出前庭系统 (EVS) 的激活最终会兴奋初级前庭系统沿着两个不同时间尺度的传入。虽然乙酰胆碱 (ACh) 在其他方面导致了许多 EVS 作用与脊椎动物相比，哺乳动物对 EVS 刺激的传入反应的突触机制尚未发现已被识别。因此，我们在了解各种 EVS 介导的机制方面存在明显的差距。动作被启动，以及它们对前庭传入对自然的后续反应产生什么影响刺激。为了促进对哺乳动物前庭生理学中 EVS 功能的理解，三个主要将在小鼠的外周前庭系统中寻找方向。第一个具体目标将确立 EVS 激活对前庭传入神经自发放电影响的药理学基础。这第二个具体目标将通过使用来指定这些 EVS 动作所需的 EVS 突触后机制转基因动物，其中单个信号成分与我们的药理学数据有关缺席的。最后，最后一个具体目标将确定每个 EVS 突触机制的激活如何改变哺乳动物传入神经对前庭刺激的反应。为了完成这些具体目标，放电麻醉小鼠初级前庭传入神经的特性将在 EVS 激活过程中得到表征有或没有前庭刺激。将应用选择性药物来鉴定受体和下游效应器，并确定它们如何影响两种刺激范式。识别和定位特定的信号通路，平行的电生理学和免疫组织化学研究将是在转基因动物中进行，其中蛋白质的功能是突触机制的组成部分由药理学中的第一个特定目标，被打乱。 EVS刺激对传入神经的影响对前庭刺激的反应将通过将旋转和平移刺激与 EVS 配对来表征对照和转基因动物药理学审讯期间的刺激范例。这些研究意义重大，因为它们将为研究不同的突触机制提供急需的见解。 EVS 招募来调节哺乳动物的传入放电。该提案捕获的数据对于探讨 EVS 在前庭生理学中的功能作用以及识别新的突触过程可以在药理学上靶向对抗前庭功能障碍。