Abstract
Stressful events can disrupt circadian rhythms in mammals but mechanisms underlying this disruption remain largely unknown. One hypothesis is that stress alters circadian protein expression in the forebrain, leading to functional dysregulation of the brain circadian network and consequent disruption of circadian physiological and behavioral rhythms. Here we characterized the effects of several different stressors on the expression of the core clock protein, PER1 and the activity marker, FOS in select forebrain and hypothalamic nuclei in rats. We found that acute exposure to processive stressors, restraint and forced swim, elevated PER1 and FOS expression in the paraventricular and dorsomedial hypothalamic nuclei and piriform cortex but suppressed PER1 and FOS levels exclusively in the central nucleus of the amygdala (CEAl) and oval nucleus of the bed nucleus of the stria terminalis (BNSTov). Conversely, systemic stressors, interleukin-1β and 2-Deoxy-D-glucose, increased PER1 and FOS levels in all regions studied, including the CEAl and BNSTov. PER1 levels in the suprachiasmatic nucleus (SCN), the master pacemaker, were unaffected by any of the stress manipulations. The effect of stress on PER1 and FOS was modulated by time of day and, in the case of daily restraint, by predictability. These results demonstrate that the expression of PER1 in the forebrain is modulated by stress, consistent with the hypothesis that PER1 serves as a link between stress and the brain circadian network. Furthermore, the results show that the mechanisms that control PER1 and FOS expression in CEAl and BNSTov are uniquely sensitive to differences in the type of stressor. Finally, the finding that the effect of stress on PER1 parallels its effect on FOS supports the idea that Per1 functions as an immediate-early gene. Our observations point to a novel role for PER1 as a key player in the interface between stress and circadian rhythms.
Highlights
There is considerable evidence that stress can disrupt circadian behavioral and physiological rhythms in mammals, including humans, but the underlying mechanisms are poorly understood
To identify extra-suprachiasmatic nucleus (SCN) nodes of interaction between the circadian and stress systems, we investigated the effect of stress on PER1 expression in select limbic forebrain and hypothalamic structures, including the oval nucleus of the bed nucleus of the stria terminalis (BNSTov), the lateral division of the central nucleus of the amygdala (CEAl), the paraventricular nucleus (PVN), the dorsomedial hypothalamus (DMH), and piriform cortex (Pi)
PER1 and FOS levels in the SCN were unaffected by restraint at all 3 time points (Fig. 3A), consistent with previous findings [4]
Summary
There is considerable evidence that stress can disrupt circadian behavioral and physiological rhythms in mammals, including humans, but the underlying mechanisms are poorly understood. Circadian clock proteins, which form the core of the mammalian circadian oscillator [5,6,7], are expressed rhythmically in multiple brain regions outside the SCN, including forebrain and hypothalamic structures that play important roles in stress, motivation and emotion regulation [6,8,9,10,11]. It has been previously shown that the expression of clock proteins in many of these brain regions can be altered by manipulations that affect energy balance, such as restricted feeding, by treatment with drugs of abuse, and by various hormonal manipulations that affect behavioral state, including changes in circulating levels of the adrenal glucocorticoid stress hormone, corticosterone (CORT) [12,13,14,15,16,17,18,19]. Per has been implicated in behavioral processes such as cocaine sensitization [26,27] and alcohol drinking behavior in mice [28], demonstrating that it can play a role outside of the clock machinery
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