Synapses and Sleep in Neurodevelopment: A Crucial Interaction at a Critical Time

神经发育中的突触和睡眠：关键时刻的关键相互作用

• 批准号: 8472968
• 负责人: Chiara Cirelli
• 金额: $ 45.89万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-01 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8472968
• 关键词: AMPA Receptors; Acute; Adolescence; Adolescent; Adult; Affect; Animal Model; Animals; Autistic Disorder; Behavior; Behavioral; Birth; Brain; Brain region; Chemosensitization; Child; Childhood; Chronic; Data; Defect; Dendritic Spines; Development; Diagnosis; Drosophila genus; Early Diagnosis; Electroencephalogram; Electroencephalography; Emotional; Enzymes; Foundations; Frequencies; Functional disorder; Goals; Health; Hippocampus (Brain); Homeostasis; Human; Image; Investigation; Lead; Link; Magnetic Resonance Imaging; Measures; Mental Depression; Mental Retardation; Mental disorders; Microscopy; Modeling; Molecular; Monitor; Mood Disorders; Mus; Neurons; Neuropil; Patients; Pattern; Phosphorylation; Physiological; Populations at Risk; Prevention therapy; Preventive; Proteins; Publishing; Rattus; Regulation; Risk; Schizophrenia; Shapes; Sleep; Sleep Deprivation; Slow-Wave Sleep; Structure; Symptoms; Synapses; Synaptosomes; Testing; Therapeutic; Time; Transcranial magnetic stimulation; Transgenic Mice; Vertebral column; Wakefulness; Work; cognitive function; density; early adolescence; frontal lobe; gray matter; human subject; in vivo; indexing; molecular marker; neurodevelopment; neurophysiology; patient population; postsynaptic; presynaptic; response; synaptic function; synaptogenesis; translational study; two-photon

DESCRIPTION (provided by applicant): During development, brain circuits undergo extensive remodeling, involving both synaptogenesis and pruning. Adolescence, in particular, is thought to be a sensitive period for synaptic pruning in cortical circuits involved in cognitive functions and emotional regulation. Adolescence is also a sensitive period for the pathophysiology of many psychiatric disorders, presumably due to this extensive synaptic remodeling. Thus, it would be useful to be able to track changes in the number and efficacy of synapses longitudinally and non-invasively during adolescence. New evidence suggests that changes in sleep slow wave activity (SWA), which can be assessed longitudinally and non-invasively using electroencephalography (EEG), may parallel neurodevelopmental changes in cortical synaptic density. To develop SWA as a potential marker of synaptic function during developmental sensitive periods requires an animal model in which: i) anatomical, molecular, and physiological changes in cortical synapses can be evaluated directly; ii) a point- to-point, intra-subject correlation can be established between sleep SWA and direct measures of synaptic number/molecular composition/efficacy. In Aim 1 of this project, we will pursue these goals by performing both chronic EEG recordings and repeated in vivo imaging with two-photon microscopy in transgenic mice that express yellow fluorescent protein in cortical neurons. Moreover, we will measure molecular and electrophysiological markers of synaptic strength in these mice throughout development. In addition to monitoring synaptic remodeling in vivo, it is important to begin investigating which factors can influence it during the sensitive period of adolescence. Since major changes in synaptogenesis/pruning during development are correlated with major changes in sleep/wake patterns, it has been hypothesized that changes in behavioral state may not only reflect, but also affect synaptic remodeling. Consistent with this notion, new evidence in animals and humans shows that, in the adult brain, waking is associated with a net increase in synaptic strength, and sleep with a net decrease, and that SWA reflects molecular and physiological changes in synaptic function brought about by wake and sleep. Aim 2 of this proposal will test the hypothesis that sleep/wake behavior affect synaptic structure/function also during development. Specifically, we will determine whether sleep and waking differentially affect synaptogenesis and synaptic pruning, consistent with their effects on synaptic strength in adults. If successful, Aim 1 will lead the foundation for EEG monitoring of synaptic efficacy during neurodevelopment in human subjects at risk or patient populations as an essential aid for both diagnosis and therapy. Aim 2 will open the way to preventive/therapeutic approaches for influencing synaptogenesis/pruning by stabilizing/adjusting sleep/wake patterns in children. PUBLIC HEALTH RELEVANCE: Adolescence is a sensitive period during which the brain undergoes massive elimination or "pruning" of synapses - the connections among neurons in the brain. Adolescence is also a sensitive period for the onset and progression of many psychiatric disorders. This project seeks to establish whether the slow waves that can be recorded with the electroencephalogram during sleep in children and adolescents can be used as a sensitive, well-tolerated indicator of the number and strength of synapses. Moreover, this project will establish whether sleep can affect synaptic pruning during development. If so, changes in sleep and waking routines could help both the prevention and the therapy of mental illness.

描述（由申请人提供）：在发育过程中，大脑回路经历广泛的重塑，包括突触发生和修剪。尤其是青春期，被认为是涉及认知功能和情绪调节的皮质回路中突触修剪的敏感时期。青春期也是许多精神疾病病理生理学的敏感时期，大概是由于这种广泛的突触重塑。因此，能够在青春期期间纵向且非侵入性地追踪突触数量和功效的变化将是有用的。新证据表明，睡眠慢波活动（SWA）的变化可以使用脑电图（EEG）进行纵向和非侵入性评估，可能与皮质突触密度的神经发育变化平行。为了将 SWA 开发为发育敏感期突触功能的潜在标志物，需要一个动物模型，其中：i）可以直接评估皮质突触的解剖学、分子和生理变化； ii) 可以在睡眠 SWA 和突触数量/分子组成/功效的直接测量之间建立点对点的受试者内相关性。在该项目的目标 1 中，我们将通过在皮质神经元中表达黄色荧光蛋白的转基因小鼠中进行慢性脑电图记录和双光子显微镜重复体内成像来实现这些目标。此外，我们将测量这些小鼠在整个发育过程中突触强度的分子和电生理标志物。除了监测体内突触重塑之外，开始研究哪些因素可以在青春期敏感期影响突触重塑也很重要。由于发育过程中突触发生/修剪的主要变化与睡眠/觉醒模式的主要变化相关，因此假设行为状态的变化不仅反映而且影响突触重塑。与这一观点相一致的是，动物和人类的新证据表明，在成人大脑中，清醒与突触强度的净增加有关，睡眠与突触强度的净减少有关，而SWA反映了清醒和睡眠带来的突触功能的分子和生理变化。该提案的目标 2 将检验睡眠/觉醒行为在发育过程中也会影响突触结构/功能的假设。具体来说，我们将确定睡眠和清醒是否对突触发生和突触修剪有不同的影响，这与它们对成人突触强度的影响一致。如果成功，目标 1 将为高危人类受试者或患者群体的神经发育过程中的突触功效脑电图监测奠定基础，作为诊断和治疗的重要辅助手段。目标 2 将为通过稳定/调整儿童睡眠/觉醒模式来影响突触发生/修剪的预防/治疗方法开辟道路。 公共健康相关性：青春期是一个敏感时期，在此期间，大脑会经历大量的突触消除或“修剪”，突触是大脑中神经元之间的连接。青春期也是许多精神疾病发生和发展的敏感时期。该项目旨在确定儿童和青少年睡眠期间脑电图记录的慢波是否可以用作突触数量和强度的敏感、耐受性良好的指标。此外，该项目将确定睡眠是否会影响发育过程中的突触修剪。如果是这样，改变睡眠和起床习惯可能有助于预防和治疗精神疾病。