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

描述（由申请人提供）：在发育过程中，脑回路经历广泛的重塑，涉及突触发生和修剪。特别是青春期，被认为是涉及认知功能和情绪调节的皮层回路中突触修剪的敏感时期。青春期也是许多精神疾病的病理生理学的敏感时期，可能是由于这种广泛的突触重塑。因此，在青春期能够纵向和非侵入性地跟踪突触的数量和功效的变化将是有用的。新的证据表明，睡眠慢波活动（SWA）的变化，这可以纵向和非侵入性地使用脑电图（EEG）进行评估，可能会平行皮质突触密度的神经发育变化。为了开发SWA作为发育敏感期期间突触功能的潜在标志物，需要动物模型，其中：i）可以直接评估皮质突触中的解剖学、分子和生理学变化; 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。在本项目的目标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EEG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。除了在体内监测突触重塑外，重要的是开始调查在青春期的敏感期哪些因素可以影响它。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，动物和人类的新证据表明，在成年人的大脑中，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，SWA反映了清醒和睡眠带来的突触功能的分子和生理变化。本提案的目标2将检验睡眠/觉醒行为在发育过程中也影响突触结构/功能的假设。具体来说，我们将确定睡眠和清醒是否会不同程度地影响突触发生和突触修剪，这与它们对成年人突触强度的影响一致。如果成功，Aim 1将为EEG监测处于风险中的人类受试者或患者群体的神经发育期间的突触功效奠定基础，作为诊断和治疗的重要辅助手段。目标2将为通过稳定/调整儿童的睡眠/觉醒模式来影响突触发生/修剪的预防/治疗方法开辟道路。

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.