Stress regulation of circadian clock gene expression in mammalian forebrain

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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.