Stress regulation of circadian clock gene expression in mammalian forebrain

有相当多的证据表明，压力会破坏昼夜节律，这种破坏会导致身体和行为上的衰弱。然而，人们对压力如何影响昼夜节律知之甚少。虽然已经发现大脑的主生物钟，视交叉上核（SCN），不直接受到压力的影响，但大脑其他地方的时钟的参与还没有系统的研究。在我的实验室之前进行的工作中，我们已经确定了一些前脑区域的生物钟细胞，这些细胞在调节大鼠的动机和情绪以及对压力的反应中起着重要作用。本研究的目的是研究前脑边缘的生理时钟介导应激对生理节律的影响。为此，我提出三条调查思路。首先，我将使用核心时钟蛋白PER1和PER2的表达作为功能标记，详细描述暴露于几种不同质量的压力源（心理、免疫、代谢、社会）对大鼠边缘前脑选定区域生物钟活动的影响。其次，我将研究参与外周组织和SCN（糖皮质激素受体介导的信号传导，哺乳动物雷帕霉素靶（mTOR）信号传导）中PER1和PER2表达调控的选择信号传导机制的贡献。最后，我将研究特定细胞核中PER1和PER2表达的定向扰动如何影响应激诱导的行为昼夜节律变化。总之，这些研究有望揭示压力影响哺乳动物昼夜节律的机制。

There is considerable evidence that stress can disrupt circadian rhythms and that such disruption can have debilitating physiological and behavioral consequences. However, how stress affects circadian rhythms is poorly understood. Although it has been found that the master circadian clock of the brain, the suprachiasmatic nucleus (SCN), is not directly affected by stress, the involvement of clocks elsewhere in the brain has not been systematically investigated. In previous work carried out in my laboratory we have identified circadian clock cells in a number of forebrain regions that play important roles in the regulation of motivation and emotion and the response to stress in rats. The aim of the research proposed in this application is to study the hypothesis that circadian clocks in the limbic forebrain mediate the effect of stress on circadian rhythms. To this end, I propose three lines of investigation. First, I will characterize in detail the effect of exposure to several qualitatively different stressors (psychological, immunological, metabolic, social) on the activity of circadian clocks in select regions of the limbic forebrain in rats, using the expression of the core clock proteins, PER1 and PER2 as functional markers. Second, I will study the contribution of select signaling mechanisms shown to be involved in the regulation of PER1 and PER2 expression in peripheral tissues and in the SCN (glucocorticoid receptor-mediated signaling, mammalian target of rapamycin (mTOR) signaling). Finally, I will study how targeted perturbations of PER1 and PER2 expression within specific nuclei might affect stress-induced changes in behavioral circadian rhythms. Together, these lines of investigation are expected to shed new light on the mechanisms by which stress affects circadian rhythms in mammals.