Synaptic Mechanisms of Vestibular Efferent Responses

前庭传出反应的突触机制

• 批准号: 7526984
• 负责人: Joseph Christopher Holt
• 金额: $ 34.81万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-15 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7526984
• 关键词: Brain Stem; Calcium; Cholinergic Receptors; Class; Cues; Defect; Disease; Efferent Neurons; Electric Stimulation; Electrodes; Fiber; Fishes; Hair Cells; Head; Human; Kinetics; Knowledge; Label; Light; Localized; Mechanical Stimulation; Mediating; Microscopy; Movement; Muscarinics; Neurons; Organ; Output; Peripheral; Phyllanthus emblica; Physiological; Physiology; Positioning Attribute; Posture; Potassium Channel; Preparation; Prevalence; Process; Property; Recruitment Activity; Rest; Role; Semicircular canal structure; Speed; Staging; Stimulus; Structure; Synapses; System; Thinking; Trees; Turtles; Vestibule; Vial device; Work; base; foot; gaze; insight; millisecond; nerve supply; patch clamp; receptor; research study; response; vestibular pathway

DESCRIPTION (provided by applicant): Vestibular organs, via their hair cells and afferent innervation, transmit information about the direction, speed, and magnitude of head and body movements, which are critical for maintaining our posture and stabilizing our gaze. The vestibular organs of nearly every vertebrate also receive a prominent efferent innervation which begins as a few hundred neurons within the brainstem and extensively collateralizes in the periphery to end as several thousands of bouton terminals on both hair cells and afferents. That this efferent innervation is positioned at such an early stage in the peripheral vestibular pathway suggests it is poised to modulate the initial processing of vestibular cues. Electrical stimulation of efferent neurons results in a diverse panel of profound, yet distinct, excitatory and inhibitory afferent responses where the kinetics of both activation and duration can vary from milliseconds to minutes. To date, three pharmacologically-distinct nicotinic ACh receptors, a muscarinic ACh receptor, at least two classes of potassium channels, and the release of calcium from hair cell internal stores (e.g., subsynaptic cisterns) are thought to underlie the different efferent responses. However, there is a clear gap in our knowledge in relating how and when these different efferent-mediated components impact the responses of vestibular afferents to their natural stimulus. To facilitate an understanding of efferent function in vestibular physiology, three major studies will be performed in the turtle semicircular canal where a strong pharmacological basis for some of the efferent actions has been established, and both hair cell and afferent morphophysiology have been adequately described. The specific aims are: (1) Identify the synaptic mechanisms underlying afferent responses to electrical activation of efferent fibers, (2) Establish how vestibular output is modified by electrical activation of efferent fibers, and (3) Characterize the morphophysiological properties of efferent neurons. To complete specific aims 1 and 2, sharp-electrode and patch clamp recordings will be made from primary afferents, afferent terminals, and hair cells during efferent and mechanical stimulation. Pharmacological agents will be applied to identify the receptors and downstream effectors as well as defining how each efferent synaptic mechanism impacts vestibular stimulation. Parallel immunohistochemical studies will be used to localize the different components implicated by our physiological and pharmacological experiments. For specific aim 3, sharp-electrodes will be used to record efferent activity and label single efferent fibers in a decerebrate preparation. Light and EM microscopy will be used to reconstruct terminal trees and to examine the distribution and synaptic structure of efferent terminals. These studies will provide insights into the mechanisms that the efferent system recruits to modulate afferent discharge as well as identifying synaptic processes that may be targeted pharmacologically for the treatment of diseases and functional defects of the peripheral vestibular apparatus. Given its anatomical prevalence from jawless fish to humans, an efferent innervation of the peripheral vestibular apparatus is necessary for normal vestibular function. Deciphering how and when the vestibular efferent system modifies the initial stages of vestibular processing are crucial to understanding its role in vestibular physiology.

描述（由申请人提供）：前庭器官通过其毛细胞和传入神经支配，传输有关头部和身体运动的方向、速度和幅度的信息，这对于保持我们的姿势和稳定我们的视线至关重要。几乎所有脊椎动物的前庭器官也接受显着的传出神经支配，该神经支配始于脑干内的数百个神经元，并在外周广泛侧支，最终以毛细胞和传入细胞上的数千个布顿终端结束。这种传出神经支配位于外周前庭通路的早期阶段，表明它准备调节前庭线索的初始处理。传出神经元的电刺激会产生一系列深刻但独特的兴奋性和抑制性传入反应，其中激活和持续时间的动力学可以从毫秒到几分钟不等。迄今为止，三种药理学上不同的烟碱型乙酰胆碱受体、一种毒蕈碱型乙酰胆碱受体、至少两类钾通道以及毛细胞内部储存（例如突触下池）的钙释放被认为是不同传出反应的基础。然而，在这些不同的传出介导的成分如何以及何时影响前庭传入神经对其自然刺激的反应方面，我们的知识存在明显的差距。为了促进对前庭生理学中传出功能的理解，将在乌龟半规管中进行三项主要研究，其中已经为某些传出作用建立了强有力的药理学基础，并且毛细胞和传入形态生理学都已得到充分描述。具体目标是：（1）确定对传出纤维电激活传入反应的突触机制，（2）确定传出纤维电激活如何改变前庭输出，以及（3）表征传出神经元的形态生理学特性。为了完成具体目标 1 和 2，将在传出和机械刺激期间从初级传入神经、传入末梢和毛细胞进行尖锐电极和膜片钳记录。将应用药物来识别受体和下游效应器，并确定每种传出突触机制如何影响前庭刺激。平行免疫组织化学研究将用于定位我们的生理学和药理学实验所涉及的不同成分。对于具体目标 3，将使用尖锐电极记录传出活动并标记去大脑制剂中的单个传出纤维。光学和电磁显微镜将用于重建末端树并检查传出末端的分布和突触结构。这些研究将深入了解传出系统招募来调节传入放电的机制，并确定可在药理学上靶向治疗外周前庭器官疾病和功能缺陷的突触过程。鉴于其从无颌鱼到人类的解剖学普遍性，外周前庭器官的传出神经支配对于正常的前庭功能是必要的。破译前庭传出系统如何以及何时改变前庭处理的初始阶段对于理解其在前庭生理学中的作用至关重要。