Brain glucocorticoid receptors are necessary for the rhythmic expression of the clock protein, PERIOD2, in the central extended amygdala in mice

Abstract

The adrenal glucocorticoid, corticosterone, induces changes in gene expression in both neural and non-neural tissues. The rhythmic release of corticosterone has been shown in rats to be necessary for the rhythmic expression of the clock protein PERIOD2 (PER2) in select regions of the limbic forebrain. The mechanisms mediating the effects of glucocorticoids on changes in gene expression have been linked to the transcriptional activity of the low affinity glucocorticoid receptor, GR. We examined the patterns of PER2 expression in the brains of mice containing an inactivation of GR gene restricted to neural tissues (GR(NesCre) mice). We found that central deletion of the GR gene blunts the daily pattern of PER2 expression in the oval nucleus of the bed nucleus of the stria terminalis (BNSTov) and central nucleus of the amygdala (CEA) both of which make up the central extended amygdala, but not in the suprachiasmatic nucleus (SCN), basolateral amygdala (BLA) or dentate gyrus of the hippocampus (DG). These results implicate brain GR receptors in the regulation of PER2 expression in the BNSTov and CEA and are consistent with our previous findings that the rhythmic expression of PER2 in these areas is selectively sensitive to fluctuations in circulating corticosterone.

Exogenous Corticosterone Induces the Expression of the Clock Protein, PERIOD2, in the Oval Nucleus of the Bed Nucleus of the Stria Terminalis and the Central Nucleus of the Amygdala of Adrenalectomized and Intact Rats

“…Ligand-activated GRs act as transcription factors that regulate the expression of target genes by binding to specific DNA sequences in their promoter region (Robin-Jagerschmidt et al 2000;Kellendonk et al 2002). We found that the conditional inactivation of brain GRs attenuated PER2 rhythms in the BNSTov and CEA in the mouse (Segall et al 2009). Together with findings that the transactivation and binding of GRs to DNA in the brain is dose-dependent with respect to glucocorticoid levels (Spiga and Lightman 2009), these results suggest that the modulation of PER2 expression by corticosterone may occur at the level of the low-affinity receptor.…”

Glucocorticoid Regulation of Clock Gene Expression in the Mammalian Limbic Forebrain

“…The mutation is generated using the CreloxP system and is a reliable and valid way to achieve spatial and temporal control over select genes (Tronche et al 1999). Looking at two time points representing the onset and offset of activity, we found that PER2 expression in the BNSTov and CEAl of mice bearing the mutation was blunted such that the rhythm was attenuated, much like the PER2 immunoreactivity observed in those regions after ADX (Segall et al 2009). Our findings are consistent with previous results linking the up-regulation of clock genes to the GR in peripheral tissues.…”

Circadian clock gene Period2 regulates a time-of-day–dependent variation in cutaneous anaphylactic reaction

“…[28][29][30] Therefore, regarding the inhibitory effects of dexamethasone on the degranulation response and passive cutaneous anaphylactic reaction, it remains unclear whether dexamethasone directly inhibited those responses or indirectly suppressed them by resetting mast cell clock gene expression.…”