The Effect of Sleep on Neural Circuit Connections

睡眠对神经回路连接的影响

• 批准号: 10002309
• 负责人: Noelle D L 'Etoile
• 金额: $ 63.8万
• 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/10002309
• 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.

项目摘要/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 连接以及如何在细胞和分子水平上进行这些变化？我们建议 通过检查紧凑的神经元连接来解决这个问题，完全描述 透明线虫C.秀丽隐杆线虫的神经系统作为其整个大脑活动循环 清醒和睡眠。具体而言，我们建议利用我们的能力调节秀丽隐杆线虫的大脑状态 检查兴奋性以及抑制突触的结构和功能如何随着功能而改变 复发性神经活动。此外，我们将确定实现这一目标的分子机制。在 AIM 1，我们将询问大脑状态如何影响整个动物神经系统的突触建筑 在整个动物中测试不同类型的连接，以应对清醒和睡眠。我们 然后询问连接的数量或大小是否受到影响。我们还将确定分子 大脑状态依赖性突触变化的调节因子，并可视化每个大脑中的突触组件 声明确定突触的方式和何时更改。这些研究将提供第一个证据的证据 秀丽隐杆线虫中的广泛睡眠依赖性突触重塑。在AIM 2中，我们将表征活动钙 瞬态（GCAMP6/7），CGMP通量（WINCG）和神经肽驱动的GPCR配体结合（D-Lite适应D 秀丽隐杆线虫的整个大脑的记者都可以睡觉，并将其与觉醒的动物进行比较。使用此 信息我们将评估这些变化的模式，并将其与突触的结构相关联 单位内最大变化的组件。我们将尝试了解突触更改是否 大脑范围内分散以及这些连接是否负责稳定睡眠依赖性变化 行为。然后，我们将使用CHR，ARCH，我们的CGMP-Sponge的光学操纵来改变大脑活动 WINCD和细胞和计时在睡眠期间对神经肽处理的特定调节以测试需求 为了导致我们观察到的连接的直接变化。这样，我们将开始理解 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大脑 了解任何动物的连接活动与结构之间的相互作用。这 理解将为旨在减轻活动驱动的疗法的新方法提供见解 人类脑活动的变化，促进对活动的不良适应反应，例如成瘾和邮政 创伤性应激障碍。