title: Onset, timing, and exposure therapy of stress disorders: mechanistic insight from a mathematical model of oscillating neuroendocrine dynamics.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Biomathematics, Univ of California, Los Angeles, 5109 Life Sciences 621 Charles E. Young Dr. South, Los Angeles, USA.
authors.forename: Lae U
authors.initials: LU
authors.lastname: Kim
authors.affiliation: Department of Mathematics, CalState-Northridge, 18111 Nordhoff St., Los Angeles, USA.
authors.forename: Maria R
authors.initials: MR
authors.lastname: D'Orsogna
authors.affiliation: Department of Biomathematics and Department of Mathematics, University of California, Los Angeles, 5209 Life Sciences 621 Charles E. Young Dr. South, Los Angeles, USA. tomchou@ucla.edu.
authors.forename: Tom
authors.initials: T
authors.lastname: Chou
mesh_terms: D000324:Adrenocorticotropic Hormone / Q000378:metabolism; D000818:Animals; D003346:Corticotropin-Releasing Hormone / Q000378:metabolism; D006801:Humans; D007030:Hypothalamo-Hypophyseal System / Q000378:metabolism; D008962:Models, Theoretical; D010913:Pituitary-Adrenal System / Q000378:metabolism; D013312:Stress, Physiological / Q000502:physiology
chemical_list: D000324:Adrenocorticotropic Hormone; D003346:Corticotropin-Releasing Hormone
keywords: Dynamical system; HPA-axis; PTSD; Stress disorders