Physiology of Regulation of Stress

The Diagram

Overview

1. The Hypothalamic-Pituitary-Adrenal (HPA) axis - the hormonal arm
2. The Sympatho-Adrenomedullary (SAM) axis - the fast neural/catecholamine arm

1. Perception and CNS Integration

"The reaction of the body to stress is integrated in the brain through the hypothalamus. Signals are transmitted downward from the hypothalamus through the brainstem, into the spinal cord and then to organs."

• DiMaio's Forensic Pathology

2. The Fast Arm: Sympatho-Adrenomedullary (SAM) Axis

Stressor → Cortex → Hypothalamus → Brainstem → Spinal cord → Sympathetic ganglia → Target organs + Adrenal medulla

• The hypothalamus triggers widespread sympathetic discharge
• Sympathetic nerve terminals release norepinephrine (NE) at end organs
• The adrenal medulla (a modified sympathetic ganglion) releases both epinephrine (E) and norepinephrine (NE) into the bloodstream

• Increased heart rate and cardiac output
• Vasoconstriction in skin/gut; vasodilation in skeletal muscle
• Bronchodilation
• Pupil dilation
• Mobilization of glucose (glycogenolysis)
• Heightened alertness - the classic "fight-or-flight" response

3. The Sustained Arm: HPA Axis

Step-by-Step Cascade

STRESSOR
    ↓
Cerebral Cortex / Limbic System
    ↓
Hypothalamus (Paraventricular Nucleus)
    ↓  [releases CRH + AVP]
Anterior Pituitary (Corticotrophs)
    ↓  [releases ACTH]
Adrenal Cortex (Zona Fasciculata)
    ↓  [synthesizes and secretes CORTISOL]
Target Tissues (liver, muscle, immune cells, brain)
    ↓
Negative Feedback ← inhibits hypothalamus AND pituitary

CRH (Corticotropin-Releasing Hormone)

• Released by small neurons in the paraventricular nucleus (PVN) of the hypothalamus
• A 41-amino-acid neuropeptide stored in secretory vesicles at the median eminence
• Travels via the hypothalamo-hypophyseal portal venous plexus to the anterior pituitary
• Binds CRH-R1 (a Gαs-coupled GPCR) on corticotroph cells → activates adenylyl cyclase → raises cAMP → activates PKA → opens L-type Ca²⁺ channels → exocytosis of pre-formed ACTH

"The stress response therefore involves the cerebral cortex, specialized neuroendocrine tissue in the hypothalamus, as well as two glands, the pituitary and the adrenal cortex."

• Medical Physiology (Boron & Boulpaep)

AVP (Arginine Vasopressin)

ACTH

• Released from anterior pituitary corticotrophs
• Acts directly on zona fasciculata cells of the adrenal cortex
• Stimulates synthesis and secretion of cortisol from cholesterol
• Has a shorter plasma half-life than cortisol, so its pulsatile secretion appears amplified

Cortisol - The Principal Stress Hormone

4. Negative Feedback - Termination of the Stress Response

1. Short-loop feedback: ACTH inhibits CRH release from the hypothalamus
2. Long-loop feedback: Cortisol inhibits:
   • CRH synthesis/release from the hypothalamus
   • Pituitary corticotroph sensitivity to CRH (directly reducing ACTH release)
3. Hippocampal feedback: The hippocampus contains numerous glucocorticoid receptors - when activated by rising cortisol, it suppresses CRH release from the hypothalamus, helping terminate the response

"Within this CRH-ACTH-cortisol axis, feedback can occur at several levels. Cortisol inhibits the production of CRH by the hypothalamus as well as the sensitivity of the pituitary to a standard dose of CRH."

• Medical Physiology (Boron & Boulpaep)

5. Circadian Modulation

6. Limbic Modulation - Amygdala and Hippocampus

7. Summary Diagram (Conceptual)

         STRESSOR (physical / psychological / biochemical)
                           ↓
         ┌─────────────────────────────────────┐
         │     CEREBRAL CORTEX / AMYGDALA      │
         └─────────────────────────────────────┘
                           ↓ activates
         ┌─────────────────────────────────────┐
         │   HYPOTHALAMUS (paraventricular      │◄── Hippocampus (inhibits)
         │   nucleus) → CRH + AVP              │◄── Cortisol (negative feedback)
         └─────────────────────────────────────┘
           ↓ (portal venous system)        ↓ (spinal cord)
   ┌──────────────────┐          ┌────────────────────────┐
   │ ANTERIOR PITUITARY│          │   SYMPATHETIC NERVOUS  │
   │ → ACTH           │          │   SYSTEM               │
   └──────────────────┘          └────────────────────────┘
           ↓ (blood)                       ↓
   ┌──────────────────┐          ┌────────────────────────┐
   │ ADRENAL CORTEX   │          │ ADRENAL MEDULLA +       │
   │ → CORTISOL       │          │ SYMPATHETIC TERMINALS  │
   └──────────────────┘          │ → EPINEPHRINE + NE     │
           ↓                     └────────────────────────┘
   Metabolic / immune /                    ↓
   cardiovascular effects        Fight-or-flight effects
           ↓
   NEGATIVE FEEDBACK → ↓CRH, ↓ACTH (terminates response)

Key Points Summary

• Two axes: SAM (fast, catecholamines) and HPA (slow, cortisol)
• CRH from hypothalamic PVN is the master stress hormone trigger
• ACTH bridges the pituitary and adrenal cortex
• Cortisol is the effector hormone with wide metabolic, immune, and cardiovascular actions
• Negative feedback at hypothalamic and pituitary levels normally terminates the response
• Amygdala activates, hippocampus inhibits the HPA axis
• Circadian and pulsatile patterns are superimposed on the stress response
• In chronic stress, feedback fails, leading to sustained hypercortisolemia and hippocampal atrophy