Brain Plasticity and Local Sleep Homeostasis: A Molecular Perspective

睡眠脑电图中的慢波活动（SWA; 0.5-4.0 Hz）是睡眠需要的标志， 随着先前清醒的持续时间而增加，并且在睡眠期间呈指数下降。生物 然而，作为先前觉醒的函数，负责SWA增加的过程仍然未知。 根据最近的一个假说-睡眠功能的突触稳态假说-可塑性过程 在清醒期间发生的这种变化导致许多皮层回路中突触强度的净增加。作为 因此，当皮层神经元在睡眠期间开始以低频率振荡时， 同步，导致高振幅的慢波，从而增加SWA。这些慢波，在 反过来，负责突触强度的重新正常化，并对能量产生有益的影响 代谢和性能。最近的研究表明，与这一假设一致，觉醒是 与参与突触增强的基因的诱导相关，如Arc、BDNF、P-CREB和 NGFI-A，而睡眠与参与突触抑制的基因的更高表达相关，如 钙调磷酸酶和NSF。在这些结果的基础上，该项目将研究特定的分子标记， 突触增强/抑制与自由行为中SWA的局部场电位记录平行 大鼠目的1将量化清醒和睡眠时突触AMPA受体的数量和磷酸化状态 为了证实前者与突触增强有关，后者与突触增强有关的预测， 萧条目标2将测试睡眠SWA将更高的预测，对于相同的觉醒量， 如果通过增加探索活动在更高水平诱导突触增强的标记物。目标3 我将采用一个受项目II、III和IV中人类学习任务启发的前肢运动学习任务 为了测试与突触增强相关的局部分子变化与突触增强相关的预测， 大鼠对侧运动皮层中SWA稳态的局部增加。因此，本项目将提供 整个提案的分子/电生理学基础。

Slow wave activity (SWA; 0.5-4.0 Hz) in the sleep electroencephalogram is a marker of sleep need, increasing with the duration of prior wakefulness and decreasing exponentially during sleep. The biological process responsible for the increase of SWA as a function of prior wakefulness, however, remains unknown. According to a recent hypothesis - the synaptic homeostasis hypothesis of sleep function - plastic processes occurring during wakefulness result in a net increase in synaptic strength in many cortical circuits. As a consequence, when cortical neurons begin oscillating at low frequencies during sleep, they become strongly synchronized, leading to slow waves of high amplitude and thereby to increased SWA. These slow waves, in turn, are responsible for the renormalization of synaptic strength and have beneficial effects on energy metabolism and performance. Recent work has shown that, consistent with the hypothesis, wakefulness is associated with the induction of genes involved in synaptic potentiation, such as Arc, BDNF, P-CREB, and NGFI-A, while sleep is associated with higher expression of genes involved in synaptic depression, such as calcineurin and NSF. Building upon these results, this Project will examine specific molecular markers of synaptic potentiation/depression in parallel with local field potential recordings of SWA in freely behaving rats. Aim 1 will quantify synaptic AMPA receptor number and phosphorylation state in wakefulness and sleep to confirm the prediction that the former is associated with synaptic potentiation and the latter with synaptic depression. Aim 2 will test the prediction that sleep SWA will be higher, for the same amount of wakefulness, if markers of synaptic potentiation are induced at higher levels through increased exploratory activity. Aim 3 will employ a forelimb motor learning task inspired by the human learning task used in Projects II, III, and IV to test the prediction that local molecular changes associated with synaptic potentiation are associated with a local increase in SWA homeostasis in rat contralateral motor cortex. Thus, this Project will provide the molecular / electrophysiological underpinning for the entire proposal.