SYNAPTIC COMPUTATIONS IN CENTRAL VESTIBULAR NEURONS

项目摘要 动物在环境中行走时必须科普无处不在的重力。去感知和回应 脊椎动物依靠内耳发出的信号来抵抗这种力量，内耳中的重力惯性传感器称为耳石， 外周前庭回路的活动。这些信息然后由大脑中的前庭神经元处理。 脑干，并通过投射到脊髓转化为姿势输出。尽管切片研究 准备表明前庭神经元对其输入进行线性计算，这一概念 未在体内进行测试。这项建议的目的是确定前庭脊髓神经元如何执行 感觉输入的计算。为了克服检查突触和细胞的技术挑战 这个电路的属性，我建议使用斑马鱼幼虫。斑马鱼是一个很好的系统， 因为它们的可获得性，透明度和与其他脊椎动物的同源性，所以可以进行研究。此外，我们可以 进行许多在哺乳动物模型中不可行的实验，包括体内全细胞贴片， 对感觉刺激的突触反应的钳位分析。这项技术的进步使我们能够记录感官- 诱发活动在完整的大脑，在这段时间内，姿势行为的发展。另外我们 可以利用一种耳石发育延迟两周的突变鱼， 选择性感觉剥夺前庭回路。因此，拟议中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。在Aim中 1，我们将使用行为，成像和生理学的组合来定义解剖，感觉反应， 和前庭脊髓神经元的功能作用。这些实验将确定 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收敛到 产生中央调谐。我们将进一步询问这种趋同在以下时间段内是如何发展的： 动物开始自我纠正重力。在这里，我们将使用两种超微结构重建 前庭神经传入中枢前庭脊髓神经元以及发育的生理分析 感觉编码的。最后，在目标3中，我们将研究抑制对感觉的功能贡献。 调整和发展一个高度受限的前庭计算模型。在一起，拟议的 实验将提供一个严格的和定量的分析如何感官调谐是在中央构造 前庭神经元

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.