Synaptic Mechanisms of Mammalian Vestibular Efferent Responses

项目摘要 前庭器官通过其驻留的毛细胞和传入神经将信息传递到中央 关于头部和身体运动的方向、速度和大小的神经系统，这是必要的 用于保持姿势、稳定凝视和指导导航任务。前庭器官也是 具有健壮的传出神经，始于脑干背侧的几百个神经元 并在周围广泛分布，最终形成数千条静脉曲张，与毛细胞和 传入器。在哺乳动物中，传出前庭系统(EVS)的激活最终刺激初级前庭 两个不同时标上的传入信号。而乙酰胆碱(ACh)在其他EVS中起着许多作用 脊椎动物，哺乳动物对EVS刺激的传入反应的突触机制还没有 已被确认身份。因此，在我们的知识中有一个明显的空白来描述不同的电动汽车是如何中介的 行为的启动，以及它们对前庭传入对自然反应的后续反应有什么影响 刺激物。为了促进对EVS在哺乳动物前庭生理学中的功能的理解，三个主要的 将在小鼠的外周前庭系统中寻找方向。第一个具体目标将建立 EVS激活对前庭传入神经自发放电影响的药理学基础。这个 第二个特定目标将通过使用指定这些EVS操作所需的EVS突触后机制 转基因动物的个体信号成分，与我们的药理学数据有关 缺席。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修改 哺乳动物传入神经对前庭刺激的反应。为了完成这些特定的目标，出院 在EVS激活过程中，麻醉小鼠的初级前庭传入的特性将被表征 无论有没有前庭刺激。将应用选择性药理学试剂来识别受体 以及下游效应器，并确定它们如何影响这两种刺激范例。以识别和 定位特定的信号通路，并行的电生理和免疫组织化学研究将是 在转基因动物中进行，其中蛋白质的功能与突触机制的完整性有关 被药理中的第一个特定目的，都打乱了。电刺激EVS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EV配对来表征 对照和转基因动物在药理学询问过程中的刺激范例。这些 研究具有重要意义，因为它们将提供对多种突触机制的迫切需要的见解 EVS招募新成员来调节哺乳动物的传入放电。此提案捕获的数据对于 探讨EVS在前庭生理中的功能作用以及识别新的突触突起 在药理学上可以作为对抗前庭功能障碍的靶点。

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.