Chronic methamphetamine disrupts sleep-dependent molecular/energetic homeostasis

描述(申请人提供)：滥用甲基苯丙胺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。到目前为止，许多研究都恰如其分地集中在大脑奖赏回路在调节甲基苯丙胺的行为和心理影响方面所起的作用。虽然这些研究对甲基苯丙胺成瘾的机制有了重要的见解，但戒断性甲基苯丙胺滥用者的复发率仍然很高。睡眠过度，以白天过度嗜睡为特征，是早期戒除甲基苯丙胺使用者的典型特征。在正常人中，睡眠与大脑葡萄糖代谢降低有关。在早期戒除甲基苯丙胺的使用者中，睡眠亢进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，先前报道的甲基苯丙胺对大脑中突触连接相关基因网络(包括转录调控因子Egr3及其靶标、活性调节细胞骨架相关蛋白Arc)的抑制作用扰乱了睡眠的神经能量功能。我们的主要假设是，甲基苯丙胺破坏了Egr3和Arc表达的睡眠/清醒依赖动力学，阻止了葡萄糖代谢和脑电慢波动力学的睡眠依赖性变化。在Egr3基因缺陷小鼠上进行的实验，其中Arc表达被抑制的方式类似于慢性甲基苯丙胺暴露，将使我们能够解决我们对拟议实验的工作假说：Egr3/Arc转录调控通路的依赖于睡眠/清醒周期的动力学对于定义正常睡眠/唤醒周期的大脑葡萄糖代谢和睡眠慢波活动的下降至关重要。我们提出了两个特定的目标，以确定Egr3缺乏是否改变了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，以及2)冰毒诱导的睡眠/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表达的变化和睡眠依赖的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。我们认为，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甲基苯丙胺滥用对基本大脑功能的影响。这些结果有望共同证实，长期接触甲基苯丙胺会扰乱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.