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

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.Comment: 30 pages, 16 figures, submitted to BMC Biology Direc

Mathematical models of stress disorders: Neuroendocrine dynamics and response

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 dissertation, 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. In addition to including key physiological features such as circadian and 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 use the developed dynamical systems model of the HPA axis to understand the mechanisms underlying clinical protocols used to probe patient stress response. Specifically, we address dexamethasone and ACTH challenge tests, which probe pituitary and adrenal gland responses, respectively. We show that some previously observed features and experimental observations can arise from the dynamics intrinsic to our bistable model, rather than relying on specific and permanent parameter changes due to physiological disruption.Importantly, we find that the slow regulation mechanism mediates external stress-driven transitions between the stable states in intensity, duration, and timing-dependent ways. These results indicate that the timing of traumatic events may be a significant factor in determining if and how patients will exhibit hallmarks of stress disorders.Motivated by the importance of the timing, we develop a preliminary model that includes the interaction between the HPA axis and the endocannabinoid system, which regulates the initiation and termination process of the stress response. The preliminary model exhibited habituation of the stress response to a repeated stressor. We investigate the general mechanism shared in different levels of the sensory system that establishes and stores the information of a repeating stimulus pattern and propose a possible form of building blocks of such systems

Perturbing the Hypothalamic–Pituitary–Adrenal Axis: A Mathematical Model for Interpreting PTSD Assessment Tests

We use a dynamical systems model of the hypothalamic–pituitary–adrenal (HPA) axis to understand the mechanisms underlying clinical protocols used to probe patient stress response. Specifically, we address dexamethasone (DEX) and ACTH challenge tests, which probe pituitary and adrenal gland responses, respectively. We show that some previously observed features and experimental responses can arise from a bistable mathematical model containing two steady-states, rather than relying on specific and permanent parameter changes due to physiological disruption. Moreover, we show that the timing of a perturbation relative to the intrinsic oscillation of the HPA axis can affect challenge test responses. Conventional mechanistic hypotheses supported and refuted by the challenge tests are reexamined by varying parameters in our mathematical model associated with these hypotheses. We show that (a) adrenal hyposensitivity can give rise to the responses seen in ACTH challenge tests and (b) enhanced cortisol-mediated suppression of the pituitary in subjects with PTSD is not necessary to explain the responses observed in DEX stress tests. We propose a new two-stage DEX/external stressor protocol to more clearly distinguish between the conventional hypothesis of enhanced suppression of the pituitary and bistable dynamics hypothesized in our model