Impact of sleep-wake circuits on cortical synapse plasticity during motor learning

睡眠-觉醒回路对运动学习过程中皮质突触可塑性的影响

• 批准号: 10349518
• 负责人: Philippe Mourrain
• 金额: $ 49.71万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-03-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10349518
• 关键词: Affect; Aging; Alcoholism; Alzheimer' s Disease; Arousal; Array tomography; Brain; Charge; Cognition; Cognitive deficits; Defect; Excitatory Synapse; Fragile X Syndrome; Frequencies; Future; Huntington Disease; Image; In Vitro; Individual; Learning; Light; Logic; Long-Term Potentiation; Maintenance; Medial; Memory; Memory impairment; Microscopy; Molecular; Motor Cortex; Neurodegenerative Disorders; Neurodevelopmental Disorder; Neurons; Neurosciences; Opsin; Outcome; Parkinson Disease; Parvalbumins; Performance; Physiological; Population; Procedures; Process; Publishing; REM Sleep; Research; Role; Science; Sleep; Sleep Architecture; Sleep Deprivation; Sleep Fragmentations; Sleep Stages; Sleep disturbances; Slow-Wave Sleep; Structure; Synapses; Synaptic plasticity; System; Testing; Thalamic structure; Theta Rhythm; Time; Vertebral column; Virus; autism spectrum disorder; base; deprivation; gamma-Aminobutyric Acid; hypocretin; in vivo; inhibitory neuron; longitudinal analysis; memory consolidation; memory encoding; memory process; memory retention; motor learning; neocortical; nervous system disorder; neuronal circuitry; neuroregulation; non rapid eye movement; optogenetics; postsynaptic; response; sleep abnormalities; sleep quantity; sleep regulation; sleep spindle; synaptic function; synaptogenesis; theories; tool; two-photon

Abstract We still wonder why we sleep. We know at least that sleep helps our memory. Almost every stages and features of sleep are involved memory consolidation, including non-rapid eye movement slow wave sleep (NREM SWS), NREM spindles, REM theta rhythm and sleep architecture continuity. Disruption of these stages and features are found in all neurological disorders afflicting memory (Angelman, autism spectrum, alcoholism, Alzheimer's, fragile X, Huntington's, Parkinson's, Rett etc…). The mechanisms underpinning these memory deficits are poorly understood and the role of sleep at the synapse is still highly debated. Synpases are the central physiological structures underpinning memory and cognition, but how each sleep stages and features remodels synapses remains unclear. NREM SWS and total sleep have been implicated in general synaptic downscaling, but NREM and spindles have also been involved in synaptic strengthening; similarly REM has been associated to both synapse pruning and maintenance. One major obstacle to such study has been that sleep stages and features are all interconnected and integrated. The disruption of one often impacts the others making the association between a stage/feature and a specific synaptic function challenging. Using precise optogenetic control of neuronal circuits, we have overcome this obstacle. Sleep continuity and memory consolidation can be disrupted without changing overall sleep architecture and quantity by introducing micro-arousals (<2sec) every 60 sec using hypocretin neuron stimulation (Aim 1). NREM sleep spindles and memory consolidation can be elicited by stimulating reticular thalamus neurons without disturbing sleep (Aim 2). Theta rhythms and memory consolidation can be disrupted by silencing medial septum GABA neurons during REM bouts only without affecting sleep architecture integrity (Aim 3). We will manipulate these three sleep features after a cortical motor learning task which rapidly induces synapse formation in the motor cortex. Remodeling of these newly formed synapses and their neighbors will be followed using state-of-the-art in vivo (two-photon) and ex vivo (array tomography) synapse microscopy. While the former longitudinal analysis will uncover the spine dynamics leading to memory encoding consolidation, the latter global synapse analysis will reveal how synapse classes (inhibitory, excitatory), synapse populations (depending on layers) and their subsynaptic molecular components are remodeled by sleep continuity (Aim 1), spindles (Aim 2) and REM specifically (Aim 3). The specific use of optogenetics to manipulate different sleep stages as synaptic dynamics are studied is unprecedented and will shed important light on how sleep continuity, NREM spindles, and REM can each influence cortical synaptic plasticity underpinning memory consolidation after motor learning. These discoveries are crucial for future strategies to recover and treat memory and cognitive deficits in neurodevelopmental and neurodegenerative disorders.

抽象的 我们仍然想知道为什么要睡觉。我们至少知道睡眠有助于我们的记忆。几乎每个阶段 睡眠的特征涉及记忆巩固，包括非比型眼运动慢波睡眠 （NREM SWS），NREM纺锤，REM Theta节奏和睡眠结构连续性。这些破坏 阶段和特征都在所有困扰记忆的神经系统疾病中都发现（Angelman，自闭症谱系， 酒精中毒，阿尔茨海默氏症，脆弱的X，亨廷顿，帕金森氏症，雷特等...）。支撑的机制 这些记忆的定义很鲜为人知，睡眠在突触中的作用仍然是高度争议的。 synpases是基于记忆和认知的基础生理结构，但每个人如何睡觉 阶段和功能重塑突触尚不清楚。 NREM SW和全部睡眠已被牵涉 总的来说，突触的降尺度，但是NREM和纺锤体也参与了突触增强。 同样，REM也与突触修剪和维护既有联系。这样的主要障碍 研究一直是睡眠阶段和特征都是相互联系和整合的。一个人的破坏 通常会影响其他人，使阶段/特征与特定突触功能之间的关联 具有挑战性的。使用对神经元电路的精确光遗传控制，我们克服了这一障碍。睡觉 连续性和记忆整合可以破坏而无需改变整体睡眠体系结构和 通过使用低封素神经刺激每60秒引入每60秒的微型序列（<2sec）来数量（AIM 1）。 NREM睡眠纺锤体和记忆合并可以通过刺激网状丘脑神经元引起 不打扰睡眠（目标2）。 theta节奏和记忆巩固可以通过沉默来破坏 内侧隔膜GABA神经元在REM回合过程中仅不影响睡眠结构完整性（AIM 3）。 我们将在一项皮层运动学习任务后操纵这三个睡眠功能，这会迅速引起 运动皮层中的突触形成。这些新成立的突触的重塑，他们的邻居将 随后使用最新的体内（两光子）和Ex Vivo（阵列断层扫描）突触显微镜。 而以前的纵向分析将发现脊柱动力学，导致记忆编码 合并，后一种全球突触分析将揭示突触类别（抑制性，兴奋性）如何， 突触种群（取决于层）及其突触后分子成分被重塑 睡眠连续性（AIM 1），主轴（AIM 2）和REM（AIM 3）。光遗传学的特定用途 操纵不同的睡眠阶段，因为综合动力学是前所未有的，并且将变得重要 阐明睡眠连续性，NREM纺锤体和REM如何影响皮层突触可塑性 运动学习后的记忆合并基础。这些发现对于未来的策略至关重要 在神经发育和神经退行性疾病中恢复和治疗记忆和认知缺陷。