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Background  The hypothalamic-pituitary-adrenal (HPA) axis is a neuroendocrine system that regulates numerous physiological processes. Disruptions in the activity of the HPA axis are correlated with stress-related diseases such as post-traumatic stress disorder (PTSD) and major depressive disorder. In this paper, we characterize “normal” and “diseased” states of the HPA axis as basins of attraction of a dynamical system describing the inhibition of peptide hormones such as corticotropin-releasing hormone (CRH) and adrenocorticotropic hormone (ACTH) by circulating glucocorticoids such as cortisol (CORT).    Results  In addition to including key physiological features such as ultradian oscillations in cortisol levels and self-upregulation of CRH neuron activity, our model distinguishes the relatively slow process of cortisol-mediated CRH biosynthesis from rapid trans-synaptic effects that regulate the CRH secretion process. We show that the slow component of the negative feedback allows external stress-induced reversible transitions between “normal” and “diseased” states in novel intensity-, duration-, and timing-dependent ways.    Conclusion  Our two-step negative feedback model suggests a mechanism whereby exposure therapy of stress disorders such as PTSD may act to normalize downstream dysregulation of the HPA axis. Our analysis provides a causative rationale for improving treatments and guiding the design of new protocols.    Reviewers  This article was reviewed by Dr. Daniel Coombs, Dr. Yang Kuang, and Dr. Ha Youn Lee.    Electronic supplementary material  The online version of this article (doi:10.1186/s13062-016-0117-6) contains supplementary material, which is available to authorized users.

Onset, timing, and exposure therapy of stress disorders: mechanistic insight from a mathematical model of oscillating neuroendocrine dynamics