The hypothalamic-pituitary-adrenal (HPA) axis regulates circulating levels of vital glucocorticoid hormones, and is the major neuroendocrine system in mammals that provides a rapid response and defence against stress. The dynamics of this system is characterized by an ultradian pulsatile pattern of hormone secretion, which becomes disrupted in different physiological and pathological conditions. The biological basis for these hormone oscillations is not known, but a neuronal "pulse generator" within the hypothalamus has remained a popular hypothesis. Using a mathematical model, we show that the combination of delay with negative feedback in the pituitary-adrenal system provides a mechanism for generating systems-level ultradian hormone oscillations, independent of pulsatile stimulation from the hypothalamus. Our model also predicts that these oscillations become disrupted for higher levels of hypothalamic drive. Testing these predictions in vivo, we show that a constant infusion of CRH and/or AVP induces ultradian oscillations in ACTH and glucocorti- coids, and confirm that higher constant levels of hypothalamic drive disrupt the oscillatory dynamics of the system. We also use our mathematical model to investigate how stressful stimuli perturb the pulsatile dynamics of the system. Using the theory of phase re- sponse curves, we demonstrate that an acute stress acts as a phase-resetting mechanism of the ultradian glucocorticoid oscillation. Our results demonstrate that pulsatile hypothalamic activity is not re- quired for generating ultradian glucocorticoid oscillations, and suggest that these oscillations emerge from a sub-hypothalamic pituitary-adrenal system, which functions as a deterministic peripheral hormone oscillator with a char- acteristic ultradian frequency. This constitutes a novel mechanism by which the level, rather than the pattern, of hypothalamic stimulation determines the dynamics of glucocorticoid hormone secretion. These findings could be important for our understanding of glucocorticoid signalling dynamics in both health and disease.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:571276 |
| Date | January 2012 |
| Creators | Walker, Jamie John |
| Publisher | University of Bristol |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
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