Chronic methamphetamine disrupts sleep-dependent molecular/energetic homeostasis

描述（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，许多努力都集中在大脑的奖励回路在介导甲基苯丙胺的行为和心理影响中的作用上。虽然这类研究使人们对甲基苯丙胺成瘾的机制有了重要的了解，但戒断的甲基苯丙胺滥用者的复吸率仍然很高。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。在正常人中，睡眠与大脑葡萄糖代谢降低有关。在早期戒断的甲基苯丙胺使用者中，过度睡眠是由于大脑中葡萄糖的过度利用。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。我们认为，以前记录的抑制突触连接相关的基因网络在大脑中（包括转录调节因子Egr 3和它的目标，活性调节的细胞因子相关蛋白，弧）的甲基苯丙胺破坏睡眠的神经能量功能。我们的首要假设是，甲基苯丙胺对Egr 3和Arc表达的睡眠/觉醒依赖性动力学的破坏阻止了葡萄糖代谢和脑电图慢波动力学的睡眠依赖性变化。Egr 3缺陷小鼠的实验，其中Arc表达以类似于慢性甲基苯丙胺暴露的方式被抑制，将使我们能够解决我们对所提出的实验的工作假设：Egr 3/Arc转录调控途径的睡眠/觉醒周期依赖性动力学对于大脑葡萄糖代谢和睡眠慢波活动的下降是必不可少的，这些活动定义了正常的睡眠/觉醒周期。我们提出了两个具体的目标，其中我们将确定Egr 3缺乏是否改变1）睡眠慢波活动和脑葡萄糖代谢的睡眠/觉醒周期依赖性变化和2）METH诱导的睡眠/觉醒周期依赖性Arc表达的抑制。预期的结果将通过证明Egr 3/Arc表达变化与睡眠依赖性代谢事件之间的机制联系，为未来的工作建立概念和实验框架。在我们看来，拟议的实验是创新的，因为它们有可能确定甲基苯丙胺滥用对基本大脑功能的以前未被认识的影响。这些结果有望共同确定慢性甲基苯丙胺暴露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.