Synaptic Microcircuits Controlling Sleep

控制睡眠的突触微电路

• 批准号: 8857985
• 负责人: Michael Nitabach
• 金额: $ 41.51万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-30 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8857985
• 关键词: Animals; Arousal; Behavioral; Biological Models; Biological Neural Networks; Biological Process; Brain; Brain region; Cells; Circadian Rhythms; Clinical; Communication; Disease; Dissection; Drosophila genus; Drosophila melanogaster; Economics; Electrophysiology (science); Exhibits; Feedback; Functional Imaging; Genetic; Goals; Human; Image; Individual; Interneurons; Jet Lag Syndrome; Label; Libraries; Mammals; Measures; Mediating; Membrane Potentials; Mental Depression; Modeling; Molecular; Morbidity - disease rate; Mushroom Bodies; Narcolepsy; Neuromodulator; Neurons; Output; Peptides; Phase; Physiological; Population; Process; Regulation; Relative (related person); Sensory; Signal Transduction; Sleep; Sleep Deprivation; Source; Structure; Synapses; Testing; Time; Transgenic Organisms; cell type; dopaminergic neuron; fly; in vivo; mind control; mortality; neurogenetics; neuroregulation; optogenetics; patch clamp; prevent; public health relevance; relating to nervous system; response; sensory stimulus; shift work; sleep regulation; small molecule; tool

 DESCRIPTION (provided by applicant): Neural networks in the brain control sleep and circadian rhythms, key interacting processes that regulate numerous physiological and behavioral outputs. Human disorders caused or exacerbated by impaired regulation of sleep and circadian rhythms - such as narcolepsy, genetic sleep phase disturbances, jet lag, shift work, sleep deprivation, depression, etc. - are a major source of morbidity, mortality, and economic hardship. Their amelioration will be facilitated by understanding how sleep and circadian rhythm control circuits function in vivo, importantly including intercellular synaptic signaling and homeostatic plasticity. One of the key features of sleep-wake regulation is the ability to rapidly transition from one state to the other, such as to wake up upon receipt of sensory stimuli signaling danger. Current models of rapid sleep state switching in mammals involve mutually inhibitory feedback loops between sleep-promoting and wake-promoting populations of neurons to implement a bistable "flip-flop". Sleep flip-flop and circadian regulator circuits rely on classical, rapid synaptic signaling, as well as small molecule and peptide neuromodulators. Our long-term goal is mechanistic dissection of synaptic communication, neuromodulation, and their interaction in sleep and circadian control circuits of the intact animal In pursuit of this goal we combine the cell-specific neurogenetic manipulability of the Drosophila model system with whole-cell patch-clamp and functional imaging. We will combine neurogenetic manipulation of classical synaptic release, optogenetic neuronal stimulation, whole-cell patch-clamp, and fluorescent imaging of intracellular Ca2+ and membrane potential to analyze the functional relationships within and between the sleep-promoting and wake-promoting neurons of the mushroom body to determine how the mushroom body controls sleep bidirectionally and whether it behaves as a bistable flip-flop. We will combine neurogenetic manipulation of classical synaptic release, optogenetic neuronal stimulation, and whole-cell patch-clamp in intact fly brain to determine the synaptic connections that underlie the functional network. We will also test the hypothesis that one or more of the sleep- and/or wake-promoting mushroom body neuron classes encodes homeostatic sleep drive that biases the network to one or the other state.

 描述（由申请人提供）：大脑中的神经网络控制睡眠和昼夜节律，调节许多生理和行为输出的关键相互作用过程。由睡眠和昼夜节律的调节受损引起或加剧的人类疾病--例如发作性睡病、遗传性睡眠阶段紊乱、时差反应、轮班工作、睡眠剥夺、抑郁症等--是发病率、死亡率和经济困难的主要来源。通过了解睡眠和昼夜节律控制回路在体内的功能，包括细胞间突触信号传导和稳态可塑性，将有助于改善它们。睡眠-觉醒调节的关键特征之一是从一种状态快速转换到另一种状态的能力，例如在接收到发出危险信号的感官刺激时醒来。目前哺乳动物快速睡眠状态转换的模型涉及促进睡眠和促进唤醒的神经元群体之间的相互抑制反馈回路，以实现一个快速的“触发器”。睡眠触发器和昼夜节律调节器电路依赖于经典的快速突触信号传导以及小分子和肽神经调节剂。我们的长期目标是机械解剖突触通信，神经调节，以及它们在睡眠和昼夜节律控制电路的完整动物的相互作用在追求这一目标，我们联合收割机了果蝇模型系统的细胞特异性神经遗传操作与全细胞膜片钳和功能成像。我们将结合联合收割机的经典突触释放，光遗传神经元刺激，全细胞膜片钳，和细胞内钙离子和膜电位的荧光成像，分析蘑菇体的睡眠促进和唤醒促进神经元内和之间的功能关系，以确定蘑菇体如何双向控制睡眠，它是否表现为一个双稳态触发器。我们将结合联合收割机的经典突触释放，光遗传神经元刺激，和完整的苍蝇大脑的全细胞膜片钳神经遗传操作，以确定突触连接的功能网络的基础。我们还将测试一个假设，即一个或多个促进睡眠和/或唤醒的蘑菇体神经元类编码稳态睡眠驱动，使网络偏向一种或另一种状态。