Speaker: Ioannis (Yannis) P. Androulakis, Rutgers University

Title: Allostatic Adaptation to Stress and Personalized Physiological Trade-Offs in the Circadian Regulation of the HPA Axis

Abstract: Endocrine disruption activates the hypothalamic-pituitary-adrenal (HPA) axis – a key component of the stress response – leading to increased levels of cortisol initiating systemic adverse effects. Evidence suggests that endocrine disruptors  perturb circadian rhythms. The HPA exhibits complex dynamics resulting in robust circadian patterns driving the dynamics of glucocorticoid hormones. Persistent disruption of homeostatic glucocorticoid circadian rhythmicity due to chronic exposure is correlated with the incidence of a range of pathological conditions. A hallmark of HPA dynamics is its stress response diversity mediated by regulatory plasticity in its activity. Sex differences in HPA activity are prominent and thought to contribute to sex-specific disparity in the prevalence of stress disorders. We discuss mathematical models characterizing differences in regulatory properties controlling the circadian dynamics of the HPA axis contributing to sex-specific and inter-individual variability and stress-responsive functioning. We focus on understanding sex-dependent sensitivities in the dynamics of the HPA, hypothesizing that regulatory plasticity enables HPA adjustments to maintain homeostasis under stress and demonstrating that adaptation comes at a cost (allostatic load). We identify distinct sex-specific parameter spaces of greater adrenal sensitivity and weaker negative feedback in females indicative of the inter-individual variability in the HPA regulatory mechanisms. Allostatic habituation of HPA regulation provides fitness advantages by preventing the sustained dysregulation of glucocorticoid-responsive signaling pathways. Allostatic adaptation results in physiological cost impairing the homeostatic stress-responsive and synchronizing functions of the HPA in the form of trade-off between the two objectives. Finally, the allostatic regulatory adaptations are predicted to cause time-of-day dependent sensitization of the acute stress response and impair the entrainability of the HPA. Our HPA model capturing individual variability provides a basis for a mechanistic tool that will allow health risk assessment of endocrine disruptors.