Transcriptional implications of ultradian glucocorticoid secretion in homeostasis and in the acute stress response

Abstract

Glucocorticoids exert significant downstream effects, including the regulation of many inflammatory genes. The HPA axis functions such that glucocorticoids are released in a pulsatile manner, producing ultradian rhythms in plasma glucocorticoid levels. It is becoming increasingly evident that this ultradian pulsatility is important in maintaining proper homeostatic regulation and responsiveness to stress. This is particularly interesting from a clinical perspective given that pathological dysfunctions of the HPA axis produce altered ultradian patterns. Modeling this system facilitates the understanding of how glucocorticoid pulsatility arises, how it can be lost, and the transcriptional implications of ultradian rhythms. To approach these questions, we developed a mathematical model that integrates the cyclic production of glucocorticoids by the HPA axis and their downstream effects by integrating existing models of the HPA axis and glucocorticoid pharmacodynamics. This combined model allowed us to evaluate the implications of pulsatility in homeostasis as well as in response to acute stress. The presence of ultradian rhythms allows the system to maintain a lower response to homeostatic levels of glucocorticoids, but diminished feedback within the HPA axis leads to a loss of glucocorticoid rhythmicity. Furthermore, the loss of HPA pulsatility in homeostasis correlates with a decrease in the peak output in response to an acute stressor. These results are important in understanding how cyclic glucocorticoid secretion helps maintain the responsiveness of the HPA axis.hypothalamic-pituitary-adrenal axis; modeling; pharmacodynamics; biological rhythms GLUCOCORTICOID HORMONES, CORTICOSTERONE in rats and cortisol in humans, are released from the adrenal cortex as a general response to stress. The secretion of glucocorticoids is regulated by the hypothalamic-pituitary-adrenal (HPA) axis: corticotrophin-releasing hormone (CRH) released from the hypothalamus stimulates adrenocorticotropic hormone (ACTH) secretion in the pituitary gland, which provokes the production of glucocorticoids by the adrenal gland. Glucocorticoids then complete feedback loops by inhibiting the release of both CRH and ACTH. Circadian rhythms in CRH, ultimately originating from exogenous cues of light and feeding (38), drive circadian rhythms in plasma glucocorticoid levels. Feedback between glucocorticoids and ACTH production leads to ultradian (roughly hourly) rhythms in glucocorticoid release (50).Experimentally, discrete ultradian bursts of glucocorticoid release can be determined, and the amplitude, timing, and regularity of these bursts can be assessed (47, 48). These pulse properties can be differentially regulated in disease (26), motivating interest in understanding the origins of HPA pulsatility, the relationship between pulsatility and stress responsiveness, the modulation of ultradian rhythms, and the mechanisms of downstream effects.Several experiments have shown the importance of glucocorticoid pulsatility in regulating the transcripti...

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