Chronic methamphetamine disrupts sleep-dependent molecular/energetic homeostasis

说明（由申请人提供）：甲基苯丙胺滥用和成瘾对心理和身体健康的负面影响是一个主要的公共卫生问题。迄今为止，很多研究都集中在大脑奖赏回路在调解甲基苯丙胺的行为和心理影响中的作用上。虽然这些研究对甲基苯丙胺成瘾的机制有了重要的认识，但戒断的甲基苯丙胺滥用者的复发率仍然很高。嗜睡症，以白天过度嗜睡为特征，是早期戒断甲基苯丙胺使用者的典型症状。正常人的睡眠伴随着大脑葡萄糖代谢的降低。在早期戒断甲基苯丙胺使用者中，嗜睡与大脑中葡萄糖的过度利用是平行的。甲基苯丙胺改变睡眠和大脑代谢的神经生物学机制尚不清楚。我们假设先前记录的甲基苯丙胺对大脑中突触连接相关基因网络（包括转录调节因子Egr3及其靶标，活动调节的细胞骨架相关蛋白Arc）的抑制会破坏睡眠的神经能量功能。我们的主要假设是，甲基苯丙胺破坏睡眠/清醒依赖的Egr3和Arc表达的动态，可以阻止葡萄糖代谢和脑电图慢波动力学的睡眠依赖变化。在缺乏Egr3的小鼠身上进行实验，其中Arc表达以类似于慢性甲基安非他明暴露的方式被抑制，这将使我们能够解决我们提出的实验的工作假设：Egr3/Arc转录调控途径的睡眠/觉醒周期依赖动力学对于定义正常睡眠/觉醒周期的脑葡萄糖代谢和睡眠慢波活动的下降至关重要。我们提出了两个具体目标，我们将确定egr3缺乏是否会改变1)睡眠/觉醒周期依赖的睡眠慢波活动和脑葡萄糖代谢的变化，2)甲基甲醚诱导的睡眠/觉醒周期依赖的Arc表达的抑制。预期的结果将通过证明Egr3/Arc表达变化与睡眠依赖性代谢事件之间的机制联系，为未来的工作建立一个概念和实验框架。在我们看来，拟议中的实验是创新的，因为它们有可能确定以前未被认识到的滥用甲基苯丙胺对基本大脑功能的影响。研究结果表明，长期接触甲基苯丙胺会破坏睡眠的神经能量功能。

DESCRIPTION (provided by applicant): The negative effects of methamphetamine abuse and addiction on psychological and physical well-being are a major public health concern. Much effort to date has rightfully focused on the role of the brain's reward circuitry in mediating the behavioral and psychological effects of methamphetamine. While such studies have led to important insights into the mechanisms of methamphetamine addiction, the rate of relapse among abstinent methamphetamine abusers remains high. Hypersomnolence, characterized by excessive daytime sleepiness, is typical of early abstinent methamphetamine users. In normal individuals sleep is coupled to reduced cerebral glucose metabolism. In early abstinent methamphetamine users, hypersomnolence is paralleled by excessive glucose utilization in the brain. The neurobiological mechanism whereby methamphetamine alters sleep and cerebral metabolism is unknown. We posit that the previously documented suppression of a synaptic connectivity-related gene network in the brain (including the transcriptional regulator Egr3 and its target, the activity-regulated cytoskeleton-associated protein, Arc) by methamphetamine disrupts the neuroenergetic function of sleep. Our overarching hypothesis is that disruption of the sleep/wake- dependent dynamics of Egr3 and Arc expression by methamphetamine prevents sleep-dependent changes in glucose metabolism and electroencephalographic slow wave dynamics. Experimentation on Egr3-deficient mice, in which Arc expression is suppressed in a manner similar to chronic methamphetamine exposure, will allow us to address our working hypothesis for the proposed experiments: sleep/wake cycle-dependent dynamics of the Egr3/Arc transcriptional regulatory pathway is essential for the decline of cerebral glucose metabolism and sleep slow wave activity that define normal sleep/wake cycles. We propose two specific aims in which we will determine whether Egr3-deficiency modifies 1) sleep/wake cycle-dependent changes in sleep slow wave activity and cerebral glucose metabolism and 2) METH-induced suppression of sleep/wake cycle- dependent Arc expression. The anticipated results will establish a conceptual and experimental framework for future work by demonstrating a mechanistic link between changes in Egr3/Arc expression and sleep- dependent metabolic events. The proposed experiments are innovative, in our opinion, because they have the potential to identify a previously unrecognized impact of methamphetamine abuse on a fundamental brain function. The results are expected to collectively establish that chronic methamphetamine exposure disrupts the neuroenergetic function of sleep.