  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 many 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). 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.
Crucially, we find that the slow regulation mechanism mediates external
stress-driven transitions between the stable states in novel, intensity,
duration, and timing-dependent ways. These results indicate that the timing of
traumatic events may be an important factor in determining if and how patients
will exhibit hallmarks of stress disorders. Our model also suggests a mechanism
whereby exposure therapy of stress disorders such as PTSD may act to normalize
downstream dysregulation of the HPA axis.
