The regulation of stress-induced changes in the expression of the circadian clock protein PERIOD1, in the mammalian limbic forebrain and hypothalamus

Most organisms have developed internal mechanisms, including the circadian and stress systems, to allow for anticipation of and adaption to regular and unpredictable changes in the environment. The circadian and stress systems communicate constantly with one another; the circadian control of the release of effectors of the stress system, such as glucocorticoid hormones, is well documented, but the processes that govern how stressful events disrupt circadian rhythmicity are less understood. Here, we sought to elucidate these cross-talk mechanisms, by demonstrating that the expression of the circadian clock protein PER1, in the mammalian forebrain is strongly modifiable by stress. Throughout our work, the light-sensitive master pacemaker, the suprachiasmatic nucleus (SCN), remained immune to the effects of all stress manipulations. We first established that categorically different acute stressors distinctively modulate the expression of PER1 and the neuronal activity marker FOS. Systemic stressors increased protein expression in the piriform cortex, paraventricular and dorsomedial nuclei, as well as in the central extended amygdala. Contrastingly, processive stressors increased protein levels in all regions except for in the central extended amygdala, where protein expression was uniquely suppressed. Interestingly, the emotional state of fear, a complex processive stressor, increased PER1 expression in this region, an effect characteristic of systemic stress. Furthermore, we determined that the time of day and modality of stress exposure are vital factors that influence PER1 activity. We then explored the role of glucocorticoids and glucocorticoid receptors (GR) in the modulation of stress-induced PER1, using manipulations that included adrenalectomy and pharmacological blockade of GR. We found that stress-induced PER1 expression in all regions studied, aside from the piriform cortex and SCN, are dependent on glucocorticoid signaling. In summary, the results demonstrate that stress, through the modulatory action of glucocorticoids and GR, can alter circadian clock protein expression in select forebrain and hypothalamic nuclei, possibly leading to their functional dysregulation and subsequent disturbances in circadian physiology and behavior. Our findings allude to a novel functional role for the circadian protein PER1 as an intermediary between the circadian system and systems that dictate emotional states, in the mammalian brain.