Glucocorticoids and Stress-Induced Changes in the Expression of PERIOD1 in the Rat Forebrain

Abstract

The secretion of glucocorticoids in mammals is under circadian control, but glucocorticoids themselves are also implicated in modulating circadian clock gene expression. We have shown that the expression of the circadian clock protein PER1 in the forebrain is modulated by stress, and that this effect is associated with changes in plasma corticosterone levels, suggesting a possible role for glucocorticoids in the mediation of stress-induced changes in the expression of PER1 in the brain. To study this, we assessed the effects of adrenalectomy and of pretreatment with the glucocorticoid receptor antagonist, mifepristone, on the expression of PER1 in select limbic and hypothalamic regions following acute exposure to a neurogenic stressor, restraint, or a systemic stressor, 2-Deoxy-D-glucose (2DG) in rats. Acute restraint suppressed PER1 expression in the oval nucleus of the bed nucleus of the stria terminalis (BNSTov) and the central nucleus of the amygdala (CEAl), whereas 2DG increased PER1 in both regions. Both stressors increased PER1 expression in the paraventricular (PVN) and dorsomedial (DMH) nuclei of the hypothalamus, and the piriform cortex (Pi). Adrenalectomy and pretreatment with mifepristone reversed the effects of both stressors on PER1 expression in the BNSTov and CEAl, and blocked their effects in the DMH. In contrast, both treatments enhanced the effects of restraint and 2DG on PER1 levels in the PVN. Stress-induced PER1 expression in the Pi was unaffected by either treatment. PER1 expression in the suprachiasmatic nucleus, the master circadian clock, was not altered by either exposure to stress or by the glucocorticoid manipulations. Together, the results demonstrate a key role for glucocorticoid signaling in stress-induced changes in PER1 expression in the brain.

Performing a hepatic timing signal: glucocorticoids induce gper1a and gper1b expression and repress gclock1a and gbmal1a in the liver of goldfish

“…In addition, a recent report demonstrates that stress modifies per gene expression in a tissue-specific manner in mammals (Al-Safadi et al 2015). Present results in a teleost evidence modifications in the hepatic oscillator by a stress-signaling hormone.…”

“…Stress is responsible of a transient misalignment of different oscillators in mammals, where the SCN lacks glucocorticoid receptors (Akashi and Nishida 2000;Segall and Amir 2010;Al-Safadi et al 2015) and therefore is unresponsive to the effect of these hormones (Balsalobre et al 2000;Al-Safadi et al 2015). In addition, a recent report demonstrates that stress modifies per gene expression in a tissue-specific manner in mammals (Al-Safadi et al 2015).…”

“…Moreover, the circadian system is also regulated by different endogenous inputs, as metabolic signals and hormones (Mendoza et al 2011;Nisembaum et al 2014a, b). Glucocorticoids are one of the best studied signals that modulates mainly the peripheral oscillators in mammals (Albrecht 2012;Tsang et al 2014;Al-Safadi et al 2015), but this subject remains to be explored in other vertebrates.…”

Rhythmic Release of Corticosterone Induces Circadian Clock Gene Expression in the Cerebellum

“…This study also represents methodological advances in investigations of the interplay between glucocorticoids and extra-hypothalamic circadian clock gene expression. In previous studies, the endogenous rhythm in corticosterone was abolished by ADX and exogenous glucocorticoids were administered in the drinking water with daily rhythm dependent on nocturnal drinking behavior [22,24,27,58] or by use of time-specific intraperitoneal injections [21,26,28,30,59]. By lesioning the SCN, we abolished not only the daily rhythm in corticosterone, but all SCN-dependent physiological circadian rhythms that could potentially influence extra-hypothalamic circadian oscillators.…”

“…The endogenous secretion of glucocorticoids exhibits a prominent circadian rhythm [15][16][17][18], and the glucocorticoid receptor is highly expressed in the cerebellar cortex [19,20]. Furthermore, studies based on acute administration of hormone or adrenalectomy (ADX) suggest that glucocorticoids may entrain molecular circadian oscillators in both peripheral tissues [21][22][23] and in various parts of the forebrain, including the paraventricular nucleus [24,25], the amygdala [26,27], the bed nucleus of the stria terminalis [26,27], the hippocampus [28,29], and prefrontal cortex [30]; however, the possible role of glucocorticoids in the regulation of the cerebellar circadian oscillator has not been investigated.…”