The hypothalamic-pituitary-adrenal (HPA) axis orchestrates the physiological response to unpredictable acute stressors. Moreover, the HPA axis exhibits prominent circadian activity and synchronizes peripheral circadian clocks to daily environmental cycles, thereby promoting homeostasis. Persistent disruption of homeostatic glucocorticoid circadian rhythmicity due to chronic stress exposure is correlated with the incidence of various pathological conditions including depression, diabetes and cancer. Allostatic habituation of the HPA axis, such that glucocorticoid levels retain homeostatic levels upon chronic exposure to stress, can therefore confer fitness advantages by preventing the sustained dysregulation of glucocorticoid-responsive signaling pathways. However, such allostatic adaptation results in a physiological cost (allostatic load) that might impair the homeostatic stress-responsive and synchronizing functions of the HPA axis. We use mathematical modeling to characterize specific chronic stress-induced allostatic adaptations in the HPA network. We predict the existence of multiple individualized regulatory strategies enabling the maintenance of homeostatic glucocorticoid rhythms, while allowing for flexible HPA response characteristics. We show that this regulatory variability produces a trade-off between the stress-responsive and time-keeping properties of the HPA axis. Finally, allostatic regulatory adaptations are predicted to cause a time-of-day dependent sensitization of the acute stress response and impair the entrainability of the HPA axis.
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