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SYNAPTIC COMPUTATIONS IN CENTRAL VESTIBULAR NEURONS

中央前庭神经元的突触计算

基本信息

批准号：
10399537
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
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-06-01 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10399537
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

项目摘要

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.

项目摘要动物在环境中航行时，必须应对无处不在的重力。去感知和回应对于这种力，脊椎动物依靠内耳发出的信号，在那里，被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，这些信息由大脑中的中央前庭神经元处理。脑干通过向脊髓的投射转化为体位性输出。虽然对切片的研究准备工作表明，前庭神经元对其输入进行线性计算，这一概念没有在体内进行测试。这项建议的目的是确定前庭脊髓神经元是如何执行感官输入的计算。克服检查突触和细胞的技术挑战这条线路的特性，我建议用斑马鱼幼体。斑马鱼是这一系列的绝佳系统研究是因为它们的可及性、透明度和与其他脊椎动物的同源性。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制分析。这项技术进步允许我们记录感官- 在姿势行为发展的一段时间内，完整大脑中的诱发活动。此外，我们可以利用突变的鱼线，其中耳石发育延迟两周，实际上提供了很高的前庭回路的选择性感觉剥夺。因此，拟议中的实验将揭示出无论是在正常情况下还是在感觉延迟的情况下，信息都是在发育过程中编码的。在AIM 1，我们将使用行为、成像和生理学的组合来定义解剖学、感觉反应、以及前庭脊髓神经元在体内的功能作用。这些实验将定义两者之间的同源性斑马鱼和哺乳动物的前庭脊髓核。在目标2中，我们将量化感觉传入如何汇聚到产生中央调谐。我们将进一步询问这种趋同在以下时间段中是如何发展的动物开始在地心引力作用下保持自如。在这里，我们将使用两种超微结构重建前庭中枢前庭脊髓神经元的传入及其发育的生理学分析感官编码。最后，在目标3中，我们将检验抑制对感觉的功能贡献。调整和开发一个高度受限的前庭计算模型。总而言之，建议的实验将提供一个严格和定量的分析，以了解感觉调谐是如何在中枢前庭神经元。