Synaptic Mechanisms of Mammalian Vestibular Efferent Responses

哺乳动物前庭传出反应的突触机制

• 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
• 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

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.

项目总结