The Effect of Sleep on Neural Circuit Connections

睡眠对神经回路连接的影响

• 批准号: 10201755
• 负责人: Noelle D L 'Etoile
• 金额: $ 62.7万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-02-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10201755
• 关键词: Activity Cycles; Address; Affect; Alzheimer' s Disease; Animals; Architecture; Behavior; Brain; Brain imaging; Buffers; Butanones; Caenorhabditis elegans; Calcium; Cells; Cognition; Coupled; Cyclic GMP; Development; Excitatory Synapse; G-Protein-Coupled Receptors; Health; Hour; Human; Image; Inhibitory Synapse; Ligand Binding; Major Depressive Disorder; Mammals; Memory; Molecular; Nematoda; Nervous system structure; Neurons; Neuropeptides; Neurosciences; Optics; Pattern; Porifera; Post-Traumatic Stress Disorders; Process; Recurrence; Regulation; Reporter; Role; Sensory; Sleep; Structure; Synapses; System; Testing; Training; Wakefulness; addiction; insight; nervous system disorder; neural circuit; novel strategies; opioid use; optogenetics; relating to nervous system; response; traumatic event

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.

项目概要/摘要 神经科学和人类健康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 通过检查整个紧凑的、完整描述的神经元连接来解决这个问题 透明线虫的神经系统。秀丽隐杆线虫的整个大脑活动在 清醒和睡眠。具体来说，我们建议利用我们调节线虫大脑状态的能力 检查兴奋性和抑制性突触的结构和功能如何变化 反复发生的神经活动。此外，我们将确定实现这一目标的分子机制。在 目标 1，我们将询问大脑状态如何影响动物神经系统的突触结构： 测试动物不同类型的连接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 大脑状态依赖性突触变化的调节器，并可视化每个大脑中的突触成分 状态来确定突触如何以及何时改变。这些研究将提供第一个证据 秀丽隐杆线虫中广泛的睡眠依赖性突触重塑。在目标 2 中，我们将表征活性钙 瞬态 (GCaMP6/7)、cGMP 通量 (WincG) 和神经肽驱动的 GPCR 配体结合（D-lite 适应 记者）观察了秀丽隐杆线虫睡眠时的整个大脑，并将其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 变化最大的单元内的组件。我们将尝试了解突触变化是否是 分散在大脑范围内，以及这些连接是否负责稳定睡眠依赖性变化 在行为上。然后，我们将使用 ChR、Arch（我们的 cGMP 海绵）的光学操作来改变大脑活动 WincD 和睡眠期间神经肽处理的细胞和计时特定调节以测试要求 模式化的活动来指导我们观察到的联系的变化。这样我们就会开始明白 大脑状态如何影响影响行为的结构变化。这些研究将提供第一个全脑 了解任何动物的活动和连接结构之间的相互作用。这 理解将为旨在减轻活动驱动的新疗法提供见解 人类大脑活动的变化会促进对成瘾和后遗症等活动的适应不良反应 创伤性应激障碍。