SYNAPTIC COMPUTATIONS IN CENTRAL VESTIBULAR NEURONS

中央前庭神经元的突触计算

• 批准号: 9927486
• 负责人: Martha W Bagnall
• 金额: $ 38.13万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-06-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9927486
• 关键词: Address; Anatomy; Animals; Behavior; Behavioral; Brain; Brain Stem; Cell Nucleus; Cells; Characteristics; Clinical; Computer Models; Data; Data Set; Development; Environment; Equilibrium; Exhibits; Fertilization; Fishes; Force of Gravity; Hair Cells; Head Movements; Image; Labyrinth; Lateral; Literature; Mammals; Measures; Modeling; Motor output; Movement; Musculoskeletal Equilibrium; Neurons; Neurosciences; Output; Pattern; Peripheral; Physiological; Physiology; Posture; Preparation; Process; Property; Research; Role; Seeds; Sensory; Sensory Deprivation; Shapes; Signal Transduction; Slice; Spinal Cord; Stereotyping; Stimulus; Structure; Synapses; System; Testing; Time; To specify; Vertebrates; Whole-Cell Recordings; Work; Zebrafish; base; clinical application; design; experimental study; in vivo; in vivo evaluation; juvenile animal; mutant; otoconia; patch clamp; postsynaptic; presynaptic; reconstruction; response; sensor; sensory input; sensory stimulus; vestibular prosthesis; voltage clamp

Project Summary Animals must cope with the pervasive force of gravity as they navigate the environment. To sense and respond to this force, vertebrates rely on signals from the inner ear, where gravito-inertial sensors called otoliths drive activity in peripheral vestibular circuits. This information is then processed by central vestibular neurons in the brainstem and transformed into postural outputs via projections to the spinal cord. Although studies in slice preparation have indicated that vestibular neurons make linear computations of their inputs, this concept has not been tested in vivo. The objective of this proposal is to determine how vestibulospinal neurons carry out computations of sensory inputs. To surmount the technical challenges of examining synaptic and cellular properties of this circuit, I propose to use the larval zebrafish. Zebrafish are an excellent system for this line of research because of their accessibility, transparency, and homology to other vertebrates. Furthermore, we can carry out many experiments that are not feasible in mammalian models, including in vivo whole cell patch- clamp analysis of synaptic responses to sensory stimuli. This technical advance permits us to record sensory- evoked activity in the intact brain, over the time period in which postural behaviors develop. In addition, we can exploit a mutant fish line in which otolith development is delayed by two weeks, providing in effect a high selective sensory deprivation to vestibular circuits. The proposed experiments will therefore reveal how sensory information is encoded during development, both under normal conditions and those of sensory delay. In Aim 1, we will use a combination of behavior, imaging, and physiology to define the anatomy, sensory responses, and functional role of vestibulospinal neurons in vivo. These experiments will define the homology between zebrafish and mammalian vestibulospinal nuclei. In Aim 2, we will quantify how sensory afferents converge to produce central tuning. We will further ask how this convergence develops over the time period in which animals begin to self-right with respect to gravity. Here we will use both ultrastructural reconstructions of vestibular afferents to the central vestibulospinal neurons as well as physiological analyses of the development of sensory encoding. Finally, in Aim 3 we will examine the functional contributions of inhibition to sensory tuning and develop a highly constrained model of vestibular computations. Together, the proposed experiments will provide a rigorous and quantitative analysis of how sensory tuning is constructed in central vestibular neurons.

项目概要 动物在环境中航行时必须应对普遍存在的重力。感知并做出反应 对于这种力，脊椎动物依赖于来自内耳的信号，其中称为耳石的重力惯性传感器驱动 外周前庭回路的活动。然后，该信息由中枢前庭神经元处理 脑干并通过投射到脊髓转化为姿势输出。虽然研究是切片 准备工作表明前庭神经元对其输入进行线性计算，这个概念已经 未经过体内测试。该提案的目的是确定前庭脊髓神经元如何执行 感觉输入的计算。克服检查突触和细胞的技术挑战 根据该电路的特性，我建议使用斑马鱼幼虫。斑马鱼是这一系列的优秀系统 由于其可访问性、透明度以及与其他脊椎动物的同源性而受到研究。此外，我们还可以 进行许多在哺乳动物模型中不可行的实验，包括体内全细胞贴片- 对感觉刺激的突触反应的钳位分析。这项技术进步使我们能够记录感官 在姿势行为发展的时间段内，在完整的大脑中诱发活动。此外，我们 可以利用突变鱼系，其中耳石发育延迟两周，实际上提供了高 前庭回路的选择性感觉剥夺。因此，拟议的实验将揭示感官如何 信息在发育过程中被编码，无论是在正常条件下还是在感觉延迟的条件下。瞄准 1，我们将结合行为、成像和生理学来定义解剖学、感觉反应、 和体内前庭脊髓神经元的功能作用。这些实验将定义之间的同源性 斑马鱼和哺乳动物前庭脊髓核。在目标 2 中，我们将量化感觉传入如何汇聚到 产生中央调音。我们将进一步询问这种趋同在这段时间内是如何发展的 动物开始在重力方面自我纠正。在这里我们将使用超微结构重建 前庭传入中央前庭脊髓神经元以及发育的生理分析 的感觉编码。最后，在目标 3 中，我们将研究抑制对感觉的功能贡献 调整并开发高度受限的前庭计算模型。共同提出的 实验将为中枢神经系统如何构建感觉调节提供严格的定量分析。 前庭神经元。