title: Characterizing dynamic interactions between ultradian glucocorticoid rhythmicity and acute stress using the phase response curve.
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.
authors.affiliation: Bristol Centre for Applied Nonlinear Mathematics, University of Bristol, Bristol, United Kingdom.
authors.forename: James
authors.initials: J
authors.lastname: Rankin
authors.forename: Jamie J
authors.initials: JJ
authors.lastname: Walker
authors.forename: Richard
authors.initials: R
authors.lastname: Windle
authors.forename: Stafford L
authors.initials: SL
authors.lastname: Lightman
authors.forename: John R
authors.initials: JR
authors.lastname: Terry
mesh_terms: D000204:Activity Cycles / Q000502:physiology*; D000818:Animals; D003345:Corticosterone / Q000378:metabolism; D003346:Corticotropin-Releasing Hormone / Q000378:metabolism; D005260:Female; D005938:Glucocorticoids / Q000378:metabolism*; D007030:Hypothalamo-Hypophyseal System / Q000503:physiopathology; D008297:Male; D008954:Models, Biological; D009991:Oscillometry; D010913:Pituitary-Adrenal System / Q000503:physiopathology; D051381:Rats; D015203:Reproducibility of Results; D013315:Stress, Psychological / Q000503:physiopathology*; D013997:Time Factors
chemical_list: D005938:Glucocorticoids; D003346:Corticotropin-Releasing Hormone; D003345:Corticosterone