Abstract
The hypothalamic-pituitary-adrenal (HPA) axis is a dynamic oscillatory hormone signalling system that regulates the pulsatile secretion of glucocorticoids from the adrenal glands. In addition to regulation of basal levels of glucocorticoids, the HPA axis provides a rapid hormonal response to stress that is vitally important for homeostasis. Recently it has become clear that glucocorticoid pulses encode an important biological signal that regulates receptor signalling both in the central nervous system and in peripheral tissues. It is therefore important to understand how stressful stimuli disrupt the pulsatile dynamics of this system. Using a computational model that incorporates the crucial feed-forward and feedback components of the axis, we provide novel insight into experimental observations that the size of the stress-induced hormonal response is critically dependent on the timing of the stress. Further, we employ the theory of Phase Response Curves to show that an acute stressor acts as a phase-resetting mechanism for the ultradian rhythm of glucocorticoid secretion. Using our model, we demonstrate that the magnitude of an acute stress is a critical factor in determining whether the system resets via a Type 1 or Type 0 mechanism. By fitting our model to our in vivo stress-response data, we show that the glucocorticoid response to an acute noise stress in rats is governed by a Type 0 phase-resetting curve. Our results provide additional evidence for the concept of a deterministic sub-hypothalamic oscillator regulating the ultradian glucocorticoid rhythm, which constitutes a highly responsive peripheral hormone system that interacts dynamically with hypothalamic inputs to regulate the overall hormonal response to stress.
Highlights
The hypothalamic-pituitary-adrenal (HPA) axis regulates levels of circulating glucocorticoid hormones (CORT–cortisol in humans, corticosterone in rodents), which in turn mediate a wide range of physiological processes, including metabolic, immunological and cognitive function [1]
Basal activity of ultradian glucocorticoid secretion depends on many factors including genetic and epigenetic status as well as the physiological state of the animal [4]
Since dynamic changes in glucocorticoid levels in tissue parallel those in plasma [24], and pulsatile activation of glucocorticoid receptor (GR) has recently been shown to be crucial for normal gene transcription [2,3], any disruptions to the glucocorticoid rhythm will be sensed at target sites and will have significant repercussions at the level of receptor signalling
Summary
The hypothalamic-pituitary-adrenal (HPA) axis regulates levels of circulating glucocorticoid hormones (CORT–cortisol in humans, corticosterone in rodents), which in turn mediate a wide range of physiological processes, including metabolic, immunological and cognitive function [1]. The activity of the HPA axis follows a distinctive circadian pattern of activity with low glucocorticoid levels during the resting period, which increase to a peak around the time of wakening. Underlying this circadian rhythm, is a highly dynamic ultradian rhythm (near hourly oscillations) of glucocorticoid release (Figure 1). Given that many biological systems are regulated by both positive and negative feed-forward and feedback loops, which in turn permits dynamic oscillatory signalling, this makes the HPA axis an interesting model system to explore how exogenous system perturbations interact with endogenous oscillatory activity
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