Regulation of circadian behavioral and molecular functioning by chronic social isolation stress

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There is considerable evidence that physically or emotionally stressful events disrupt circadian behavioral and physiological rhythms. Importantly, animal studies have shown that the master circadian clock, the suprachiasmatic nucleus (SCN), is not directly affected by stress and that circadian clocks elsewhere in the brain are likely involved in the interface between stress and circadian functioning. Using the rhythmic expression of the core clock protein, PER2 as a clock marker, we identified circadian clock cells in multiple forebrain regions that are known to play important roles in the regulation of cognition, motivation, and emotion. Furthermore, we found that the PER2 oscillations outside the SCN are altered, in a region-specific manner by various hormonal (corticosterone, estrogen) and behavioral (restricted feeding) perturbations that directly affect motivational and emotional state. Importantly, we also found that the expression of the core clock protein, PER1 in some of these regions is acutely and differentially sensitive to different forms of stress and to manipulations of brain glucocorticoid signaling. Social isolation has profound effects on behavioral and physiological functioning in humans and has been used extensively as a model of chronic non-invasive stress in laboratory rodents. Currently, the effect of social isolation stress (SIS) on circadian functioning remains poorly studied. A recent study in male rats has shown that prolonged post-weaning SIS alters the expression of the clock protein, CLOCK in the dorsomedial hypothalamus. However, the effect of SIS on the core molecular circadian gene network of the brain and on circadian behavioral and endocrine functioning remains largely unknown. The aim of the proposed research is to elucidate the effect of SIS on circadian behavioral and physiological functioning and on the functioning of the brain circadian gene network. To this end, I will first characterize the circadian behavioral (locomotor activity) and hormonal (melatonin, corticosterone) phenotypes of isolated vs. grouped-housed male and female mice kept under different lighting conditions. Next, I will analyze the effect of SIS on the rhythmic expression of the mRNA (qPCR) and proteins (Western blotting, immunohistochemistry) of the core clock genes, Per1, Per2 and Bmal1, and the clock-controlled gene, Dbp, in forebrain structures implicated in social, motivation and emotion regulation. Lastly, to identify links between SIS and circadian functioning I will use pharmacological and genetic approaches to investigate the involvement of two signaling mechanisms, glucocorticoids and mammalian/mechanistic target of rapamycin (mTOR). Together, these lines of research are expected to define the impact of social isolation on behavioral and molecular circadian functioning and to elucidate the involvement of two key signaling mechanisms shown to play a key role in the regulation of circadian clock gene expression in the brain.