Fig. 2: Hypothalamic-Pituitary-Adrenal (HPA) axis and Autonomic Nervous System interactions.

HPA is activated in response to physical, emotional, or environmental stressors. The hypothalamus detects stress through sensory inputs and integrates signals from the limbic system (emotional processing). It releases CRH (corticotropin-releasing hormone) and AVP (arginine vasopressin) into the hypophyseal portal system. CRH and AVP stimulate the anterior pituitary to secrete ACTH (adrenocorticotropic hormone) into the bloodstream. ACTH targets the adrenal cortex, prompting the release of glucocorticoids (e.g., cortisol in humans). Cortisol helps mobilize energy by increasing glucose availability, suppressing non-essential functions (like digestion and immunity), and facilitating adaptation to stress. The ANS (Autonomic Nervous System), particularly the SNS (Sympathetic Nervous System), is the body’s rapid-response system during stress. It closely interacts with the HPA axis. Stress triggers the hypothalamus to activate the SNS. The SNS stimulates the adrenal medulla to release catecholamines (e.g., adrenaline and noradrenaline). Catecholamines cause immediate physiological changes: increased heart rate, blood pressure, pupil dilation, and energy mobilization (the “fight or flight” response). Catecholamines can modulate hypothalamic activity, influencing CRH release. Similarly, glucocorticoids can enhance or suppress SNS activity depending on the context. The SNS provides a quick response, while the HPA axis sustains the stress response over minutes to hours. After the stressor is resolved, the PNS (Parasympathetic Nervous System) counteracts the SNS, promoting “rest and digest” functions. Glucocorticoid feedback to the hypothalamus and pituitary inhibits the HPA axis, facilitating recovery. The prefrontal cortex, involved in stress regulation, also responds to endocannabinoid signaling to modulate HPA axis activity, enhancing adaptive responses to stress.