Stress regulation of circadian clock gene expression in mammalian forebrain

有相当多的证据表明，压力会扰乱昼夜节律，这种扰乱可能会产生令人衰弱的生理和行为后果。然而，人们对压力如何影响昼夜节律知之甚少。尽管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，但大脑其他部位的生物钟的参与还没有得到系统的研究。在我的实验室之前开展的工作中，我们已经在一些前脑区域发现了生物钟细胞，这些细胞在大鼠的动机和情绪调节以及对压力的反应中发挥着重要作用。在这项申请中提出的研究的目的是研究边缘前脑中的昼夜节律调节压力对昼夜节律的影响的假说。为此，我提出了三条调查路线。首先，我将以核心时钟蛋白PER1和PER2的表达为功能标记物，详细描述暴露于几种不同的应激源(心理、免疫、代谢、社会)对大鼠边缘前脑特定区域生物钟活动的影响。其次，我将研究选择性信号机制在外周组织中调节PER1和PER2表达以及在SCN(糖皮质激素受体介导的信号，哺乳动物雷帕霉素靶标(MTOR)信号)中的作用。最后，我将研究特定核团中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的变化。总而言之，这些研究有望为应激影响哺乳动物昼夜节律的机制提供新的线索。

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.