The Effect of Sleep on Neural Circuit Connections

项目摘要/摘要 神经科学和人类健康中的一个基本问题是不同的大脑状态如何改变神经元 连接以及这些变化是如何在细胞和分子水平上进行的？我们建议 通过检查完整描述的紧凑结构中的神经元连接来解决这个问题 透明线虫的神经系统在其整个大脑活动周期之间 清醒和睡眠。具体地说，我们建议利用我们调节线虫大脑状态的能力来 研究兴奋性突触和抑制性突触的结构和功能是如何作为一种功能改变的 反复出现的神经活动。此外，我们将确定实现这一目标的分子机制。在……里面 目标1，我们将询问大脑状态如何通过以下方式影响动物神经系统的突触结构 测试动物体内不同类型的连接，以了解它们对清醒和睡眠的反应。我们 然后会询问连接的数量或大小是否受到影响。我们还将鉴定分子 调节大脑状态依赖的突触变化，并可视化每个大脑中的突触组件 状态以确定如何以及何时更改突触。这些研究将提供第一个证据 线虫广泛的睡眠依赖性突触重构。在目标2中，我们将表征活性钙 瞬时(GCaMP6/7)、cGMP通量(WincG)和神经肽驱动的GPCR配体结合(D-Lite适应 记者)观察线虫睡眠时的整个大脑，并与清醒的动物进行比较。使用这个 我们将评估这些变化的模式，并将它们与突触的结构联系起来 单位内变化最大的组件。我们将尝试理解突触的变化是否 以及这些连接是否对稳定睡眠依赖的变化负责 在行为上。然后，我们将通过光学操作cGMP海绵Chr，Arch来改变大脑活动 WincD与细胞和时间特异性调节睡眠中神经肽的处理以测试这一要求 让模式化的活动引导我们观察到的联系的变化。通过这种方式，我们将开始了解 大脑状态如何影响影响行为的结构性变化。这些研究将提供第一个全脑范围的 理解任何动物的连接的活动和结构之间的相互作用。这 理解将提供对旨在缓解活动驱动的治疗的新方法的洞察 人类大脑活动的变化，促进对活动的适应不良反应，如成瘾和后 创伤性应激障碍。

Project Summary/Abstract A fundamental question in neuroscience and human health is how do different brain states alter neuronal connections and how are these changes carried out at the cellular and molecular levels? We propose to address this question by examining neuronal connections through out the compact, completely described nervous system of the transparent nematode C. elegans as its whole brain activity cycles between wakefulness and sleep. Specifically, we propose to use our ability to modulate the C. elegans brain state to examine how the structure and function of excitatory as well as inhibitory synapses are changed as a function of recurrent neural activity. Further, we will identify the molecular mechanisms by which this is achieved. In Aim 1, We will ask how the brain states affect synaptic architecture across the animal's nervous system by testing different types of connections throughout the animals for their response to wakefulness and sleep. We will then ask whether the number or size of connections is affected. We will also identify the molecular regulators of the brain state-dependent synaptic changes, and visualize synaptic components in each brain state to determine how and when synapses are altered. These studies would provide the first evidence of broad sleep-dependent synaptic remodeling in C. elegans. In Aim 2, We will characterize the activity calcium transients (GCaMP6/7), cGMP fluxes (WincG) and neuropeptide-driven GPCR ligand binding (D-lite adapted reporters) of the entire brain of C. elegans as it sleeps and compare that to the wakeful animal. Using this information we will assess the pattern of these changes and relate them to the structure of synaptic components within the units that change most. We will attempt to understand if the synaptic changes are dispersed brain-wide and whether these connections are responsible for stabilizing sleep dependent changes in behavior. We will then alter the brain activity using optical manipulation of ChR, Arch, our cGMP-sponge WincD and cell and timing specific regulation of neuropeptide processing during sleep to test the requirement for patterned activity to direct changes in connections that we observe. In this way, we will begin to understand how brain state effects structural changes that affect behavior. These studies would provide the first brain wide understanding of the interplay between the activity and structure of connections in any animal. This understanding will provide insights into novel approaches to therapies aimed at mitigating activity-driven changes in human brain activity that promote maladaptive responses to activity such as addiction and post traumatic stress disorder.