Synaptic Mechanisms of Mammalian Vestibular Efferent Responses

项目摘要 前庭器官通过其常驻毛细胞和传入神经支配将信息传递到中枢 神经系统对头部和身体运动的方向，速度和幅度，这是必要的 用于保持姿势、稳定视线和引导导航任务。前庭器官也是 它具有强大的传出神经支配，始于背侧脑干内的几百个神经元 并广泛地在外周侧支化，以成千上万的终末静脉曲张邻接毛细胞， 传入神经在哺乳动物中，传出前庭系统（EVS）的激活最终刺激初级前庭神经元， 沿着两个不同的时间尺度传入。虽然乙酰胆碱（ACh）占许多EVS行动在其他 在脊椎动物中，哺乳动物对EVS刺激的传入反应的突触机制还没有 被识别。因此，在我们的知识中存在明显的差距，涉及各种EVS介导的 动作的启动，以及它们对前庭传入神经对自然的 刺激。为了便于理解EVS在哺乳动物前庭生理学中的功能， 将在小鼠的外周前庭系统中进行指导。第一个具体目标是建立 EVS激活对前庭传入神经自发放电影响的药理学基础。的 第二个具体目标将通过使用以下方法来指定这些EVS动作所需的EVS突触后机制： 转基因动物中，我们的药理学数据所暗示的单个信号成分， 无托叶最后，最后一个具体的目标将确定如何激活每个EVS突触机制修改 哺乳动物传入神经对前庭刺激的反应。为了实现这些具体目标， 将在EVS激活期间表征麻醉小鼠中初级前庭传入的特性 有或没有前庭刺激。选择性药理学试剂将被应用于识别受体 和下游效应器，并确定它们如何影响两种刺激模式。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 在转基因动物中进行，其中蛋白质的功能，与突触机制有关， 被药理学中的第一个特定目标所破坏。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EVS配对来表征 在对照和转基因动物中药理学询问期间的刺激范例。这些 这些研究是重要的，因为它们将提供对不同突触机制的迫切需要的见解， EVS募集调节哺乳动物的传入放电。本提案所收集的数据对于以下方面至关重要： 探索前庭生理学中EVS的功能作用以及识别新的突触过程 可以作为治疗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.