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我们要睡觉。我们至少知道睡眠几乎每个阶段都有助于我们的记忆。 睡眠的特征涉及记忆，包括非快速巩固眼动慢波睡眠 (NREM SWS)、NREM 纺锤体、REM θ节律和睡眠结构连续性的破坏。 所有影响记忆的神经系统疾病（Angelman、自闭症谱系、 酒精中毒、阿尔茨海默病、脆性 X 病、亨廷顿病、帕金森病、雷特病等……）。 人们对这些记忆缺陷知之甚少，并且睡眠在突触中的作用仍然存在很大争议。 突触是支撑记忆和认知的中心生理结构，但每个突触如何睡眠 NREM SWS 和总睡眠与突触重塑的阶段和特征仍不清楚。 参与一般突触降尺度，但 NREM 和纺锤体也参与突触强化； 同样，快速眼动睡眠与突触修剪和维护有关，这是实现这一目标的一个主要障碍。 研究表明，睡眠阶段和特征都是相互关联和整合的。 经常影响其他人在阶段/特征和特定突触功能之间建立关联 通过对神经回路的精确光遗传学控制，我们克服了这一障碍。 连续性和记忆整合可以在不改变整体睡眠架构的情况下被破坏 通过使用下丘脑分泌素神经元刺激每 60 秒引入微唤醒（<2 秒）来提高数量（目标 1）。 通过刺激网状丘脑神经元可以引发 NREM 睡眠纺锤波和记忆巩固 不干扰睡眠（目标 2），Theta 节律和记忆巩固可以通过沉默来破坏。 内侧隔膜 GABA 神经元仅在 REM 发作期间出现，而不影响睡眠结构的完整性（目标 3）。 在完成皮质运动学习任务后，我们将操纵这三个睡眠特征，该任务会快速诱导 运动皮层中突触的形成将重塑这些新形成的突触及其邻居。 使用最先进的体内（双光子）和离体（阵列断层扫描）突触显微镜进行跟踪。 而前者的纵向分析将揭示导致记忆编码的脊柱动力学 整合后，后者的全局突触分析将揭示突触类别（抑制性、兴奋性）、 突触群（取决于层）及其突触下分子成分通过以下方式进行重塑 睡眠连续性（目标 1）、纺锤波（目标 2）和快速眼动睡眠（目标 3）。 在研究突触动力学时操纵不同的睡眠阶段是前所未有的，并且将变得重要 阐明睡眠连续性、NREM 纺锤体和 REM 如何分别影响皮质突触可塑性 这些发现对于未来的策略至关重要。 恢复和治疗神经发育和神经退行性疾病中的记忆和认知缺陷。