Stress-Induced Changes in the Expression of the Clock Protein PERIOD1 in the Rat Limbic Forebrain and Hypothalamus: Role of Stress Type, Time of Day, and Predictability

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.

Altered Expression Pattern of Clock Genes in a Rat Model of Depression

“…Further, studies have been published investigating the effect of stress on the expression of clock genes in rodents. However, different stressors were applied, such as post-traumatic stress disorder (Koresh et al, 2012), severe stressors (chronic unpredictable stress; Jiang et al, 2013), and systemic glucocorticoid administration and restraint stress (Al-Safadi et al, 2014). Furthermore, the use of different strains of animals (Erburu et al, 2015; Schaufler et al, 2016) and time points of day for decapitation makes it difficult to compare our results with these studies.…”

Temporal variations in presynaptic release probability in the lateral habenula

“…One shared symptom observed in patients with schizophrenia and depression is the presence of aberrant circadian rhythms4950, including insomnia350. Several studies employing different stressors observed impaired circadian rhythms of molecular clock proteins including Per1, Clock, and Cry2 in the amygdala, the limbic forebrain and the hypothalamus5152. These studies suggest that stress can disrupt circadian rhythms of brain areas related to emotional processing.…”

Circadian Rhythms and Psychopathology: From Models of Depression to Rhythms in Clock Gene Expression and Back Again

“…For example, the environmental light-dark cycle is a powerful zeitgeber that adjusts rhythms of period circadian clock gene expression in the SCN. In contrast, daily rhythms in period circadian clock gene expression outside of the SCN tend to be sensitive to diverse behavioral and physiologic factors, including changes in feeding schedules, body temperature, glucocorticoid release, and stress (5)(6)(7)(8). By identifying zeitgebers that act in a region-specific manner, it is possible to gain insight into the functional importance of extra-SCN rhythms.…”

“…This daily rhythm of adrenal glucocorticoid release-corticosterone in rodents-is also important for the synchronization or entrainment of daily oscillations of PER2 expression in the limbic forebrain (6). PER1 expression in the same brain areas also responds to acute stressors, and these effects depend on whether a processive stressor (forced swim, restraint) or a systemic stressor (interleukin-1β or 2-deoxy-D-glucose injection) is used (7). Most of these manipulations failed to adjust PER1 and PER2 expression rhythms in the SCN (6,7).…”

“…However, although acute manipulations have generally failed to adjust PER1 and PER2 rhythms in the SCN, the UCMS manipulation used by Logan et al (1) seems to be able to modulate rhythms in the master circadian clock. Therefore, the effects of stress and glucocorticoids would seem to exhibit a complex interaction that depends heavily on the nature (e.g., chronic or acute) and type (e.g., processive or systemic) of stressor, clock gene of interest (e.g., PER1 or PER2), and brain area (6,7).…”