Abstract
In this paper we report differential decoding of the ultradian corticosterone signal by glucocorticoid target tissues. Pulsatile corticosterone replacement in adrenalectomised rats resulted in different dynamics of Sgk1 mRNA production, with a distinct pulsatile mRNA induction profile observed in the pituitary in contrast to a non-pulsatile induction in the prefrontal cortex (PFC). We further report the first evidence for pulsatile transcriptional repression of a glucocorticoid-target gene in vivo, with pulsatile regulation of Pomc transcription in pituitary. We have explored a potential mechanism for differences in the induction dynamics of the same transcript (Sgk1) between the PFC and pituitary. Glucocorticoid receptor (GR) activation profiles were strikingly different in pituitary and prefrontal cortex, with a significantly greater dynamic range and shorter duration of GR activity detected in the pituitary, consistent with the more pronounced gene pulsing effect observed. In the prefrontal cortex, expression of Gilz mRNA was also non-pulsatile and exhibited a significantly delayed timecourse of increase and decrease when compared to Sgk1, additionally highlighting gene-specific regulatory dynamics during ultradian glucocorticoid treatment.
Highlights
The secretion of glucocorticoid hormones from the adrenal glands of mammals is regulated by the hypothalamic-pituitaryadrenal (HPA) axis and fluctuates greatly over the course of a day
This profile temporally models the hourly intervals observed with endogenous ultradian glucocorticoid secretion (Windle et al, 1998a, 1998b; Stavreva et al, 2009; Conway-Campbell et al, 2010), and will be the model used throughout the present study for downstream assessment of transcriptional rhythmic responsiveness in the prefrontal cortex (PFC) and pituitary
Glucocorticoid-induced leucine zipper (Gilz) mRNA (Fig. 2a) levels remained at a low plateau during the first three corticosterone pulses, only increasing significantly above basal levels at 150 min (M 1⁄4 1.65 ± 0.08 fold induction, P < 0.01), suggesting at least three consecutive corticosterone pulses were required to induce an increase in expression of this transcript
Summary
The secretion of glucocorticoid hormones from the adrenal glands of mammals is regulated by the hypothalamic-pituitaryadrenal (HPA) axis and fluctuates greatly over the course of a day. In healthy unstressed individuals with glucocorticoid levels rising prior to waking and decreasing prior to sleep (Lightman and Conway-Campbell, 2010; Biddie et al, 2012) Underlying these circadian fluctuations exists a highly conserved ultradian glucocorticoid secretion pattern with pulses of endogenous glucocorticoid secreted at regular intervals (approximately 60 min in rats (Windle et al, 1998a, 1998b) and 60e90 min in humans (Veldhuis et al, 1989)) that arise due to an intrinsic positive feed-forward and negative feedback loop in the HPA axis (Walker et al, 2010, 2012). Using our established rat model of pulsatile corticosterone administration (Stavreva et al, 2009; Conway-Campbell et al, 2010) and a candidate gene approach, the following questions were explored: 1) Can ultradian corticosterone exposure direct unique and gene-specific regulation within the same tissue? 2) What are the dynamics of a glucocorticoid-repressible gene during ultradian corticosterone exposure? 3) Will the same gene exhibit similar or different expression profile dynamics in different tissues?
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