Department of Chemical and Biochemical Engineering, Rutgers, the State University of New Jersey, Piscataway, USA.
Department of Biomedical Engineering, Rutgers, the State University of New Jersey, Piscataway, NJ, 08854, USA.
Sci Rep. 2019 Aug 1;9(1):11212. doi: 10.1038/s41598-019-47605-7.
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.
下丘脑-垂体-肾上腺 (HPA) 轴协调对不可预测的急性应激源的生理反应。此外，HPA 轴表现出明显的昼夜节律活动，并使外周昼夜节律时钟与日常环境周期同步，从而促进体内平衡。由于慢性应激暴露导致稳态糖皮质激素昼夜节律性持续破坏，与各种病理状况的发生相关，包括抑郁症、糖尿病和癌症。HPA 轴的适应耗竭，即糖皮质激素水平在慢性应激暴露下保持稳态水平，因此可以通过防止糖皮质激素反应信号通路的持续失调来带来适应性优势。然而，这种适应耗竭会导致生理代价（适应负荷），可能会损害 HPA 轴的稳态应激反应和同步功能。我们使用数学模型来描述 HPA 网络中特定的慢性应激诱导的适应耗竭。我们预测存在多种个体化的调节策略，使稳态糖皮质激素节律得以维持，同时允许 HPA 反应特征具有灵活性。我们表明，这种调节变异性在 HPA 轴的应激反应和计时特性之间产生了权衡。最后，预测适应耗竭会导致急性应激反应的昼夜依赖性敏感化，并损害 HPA 轴的同步性。
