Fig. 1From: Onset, timing, and exposure therapy of stress disorders: mechanistic insight from a mathematical model of oscillating neuroendocrine dynamicsSchematic of HPA axis. a Stress is processed in the central nervous system (CNS) and a signal is relayed to the PVN in the hypothalamus to activate CRH secretion into the hypophyseal portal system. b CRH diffuses to the pituitary gland and activates ACTH secretion. ACTH travels down to the adrenal cortex to activate cortisol (CORT) release. Cortisol inhibits both CRH and ACTH secretion to down-regulate its own production, forming a closed loop. In the pituitary gland, cortisol binds to glucocorticoid receptors (GR) (yellow box) to inhibit ACTH and self-upregulate GR production. This part of the axis comprises the PA subsystem. c Negative feedback of cortisol affects the synthesis process in the hypothalamus, which indirectly suppresses the release of CRH. External inputs such as stressors and circadian inputs also directly affect the release rate of CRHBack to article page