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.

项目摘要 动物必须在环境导航时应对重力的普遍力。感知和回应 在这种力量上，脊椎动物依靠内耳的信号，在该信号中 外围前庭电路的活性。然后，中央前庭神经元处理此信息 脑干并通过投影到脊髓变成姿势输出。尽管在切片中进行研究 准备工作表明前庭神经元对其输入进行线性计算，此概念具有 未在体内进行测试。该提案的目的是确定前庭脊髓神经元如何进行 感觉输入的计算。克服检查突触和细胞的技术挑战 该电路的性质，我建议使用幼虫斑马鱼。斑马鱼是这条线的绝佳系统 研究由于其可及性，透明度和与其他脊椎动物的同源性。此外，我们可以 进行许多在哺乳动物模型中不可行的实验，包括体内全细胞斑块 - 对感觉刺激的突触反应的夹具分析。这种技术进步使我们能够记录感官 - 在姿势行为发展的时期内，完整大脑中的活动诱发了活动。另外，我们 可以利用一条突变的鱼类线，其中耳石发育延迟了两周，实际上提供了高度的 选择性感觉剥夺前庭电路。因此，提出的实验将揭示感觉如何 在开发过程中，在正常条件下和感觉延迟的信息都进行了编码。目标 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， 前庭脊髓神经元在体内的功能作用。这些实验将定义 斑马鱼和哺乳动物的前庭脊髓核。在AIM 2中，我们将量化感官传统如何融合到 产生中央调节。我们将进一步询问这种融合如何在此期间发展 动物在重力方面开始自我权利。在这里，我们将使用两种超微结构重建 前庭前庭神经元的前庭传入以及开发的生理分析 感官编码。最后，在AIM 3中，我们将检查抑制对感觉的功能贡献 调整和开发一个高度约束的前庭计算模型。一起，提议 实验将对中央中的感觉调整进行严格和定量分析 前庭神经元。