Allostatic adaptation and personalized physiological trade-offs in the circadian regulation of the HPA axis: A mathematical modeling approach

Rohit Rao,Ioannis P Androulakis

doi:10.1038/s41598-019-47605-7

Rohit Rao, Ioannis P Androulakis

Open Access

https://doi.org/10.1038/s41598-019-47605-7

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Journal: Scientific Reports	Publication Date: Aug 1, 2019
Citations: 31	License type: open-access

Affiliation: Rutgers, The State University of New Jersey

Abstract

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.

Highlights

The hypothalamic-pituitary-adrenal (HPA) axis integrates environmental information and calibrates the internal milieu, through an intricate network of glucocorticoid (GC)-sensitive pathways, adapting to predictable and unpredictable environmental variations[1]
A parametric analysis of our model indicates that homeostatic glucocorticoid rhythms[23,32] (Fig. 2a) are attained within a well-defined region of parameter values of the three key regulatory arms (Fig. 2b)
Our model predicts that this regulatory variability inextricably links the sensitivity of the HPA axis to external stressors with its ability to integrate and be entrained by environmental cues such as light and temperature

Summary

Introduction

The hypothalamic-pituitary-adrenal (HPA) axis integrates environmental information and calibrates the internal milieu, through an intricate network of glucocorticoid (GC)-sensitive pathways, adapting to predictable and unpredictable environmental variations[1]. The HPA axis is a central player in the response to unpredictable environmental stressors[2] leading to release of GCs and enabling the host to actively re-establish homeostasis[3]. Successful habituation to chronic stress requires the activation of further adaptive allostatic regulatory mechanisms, which can alter the homeostatic functioning of related physiological systems when the host is exposed to novel environments or stressors. The observation of apparently nominal levels of glucocorticoids upon chronic stress habituation might conceal underlying regulatory changes in the HPA axis that could impair its homeostatic functioning. In such cases, a modeling-based approach can be a useful tool for generating and evaluating experimentally verifiable hypotheses[21]

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