Stress regulation of circadian clock gene expression in mammalian forebrain

哺乳动物前脑生物钟基因表达的应激调节

• 批准号: 37358-2013
• 负责人: Amir, Shimon
• 金额: $ 2.4万
• 依托单位: Concordia University
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2017
• 资助国家: 加拿大
• 起止时间: 2017-01-01 至 2018-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=631410
• 关键词: Stress; regulation; circadian; clock; gene

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.

有相当多的证据表明，压力可以扰乱昼夜节律，这种破坏可以使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。虽然已经发现大脑的主生物钟，视交叉上核（SCN），并不直接受到压力的影响，但大脑其他地方的生物钟的参与还没有得到系统的研究。在我的实验室以前进行的工作中，我们已经确定了一些前脑区域中的昼夜节律钟细胞，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重要作用。本申请中提出的研究的目的是研究边缘前脑中的昼夜节律钟介导压力对昼夜节律的影响的假设。为此，我建议进行三方面的调查。首先，我将详细描述暴露于几种不同性质的压力源（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，使用核心时钟蛋白PER 1和PER 2作为功能标记。其次，我将研究选择信号机制的贡献，这些信号机制被证明参与外周组织和SCN（糖皮质激素受体介导的信号传导，哺乳动物雷帕霉素靶蛋白（mTOR）信号传导）中PER 1和PER 2表达的调节。最后，我将研究如何有针对性的PER1和PER2的表达在特定的核扰动可能会影响压力引起的行为昼夜节律的变化。总之，这些调查路线有望揭示压力影响哺乳动物昼夜节律的机制。