HPA axis · Grey Matter

The HPA axis is the hormonal chain through which the brain answers stress with cortisol: the hypothalamus signals the pituitary, the pituitary signals the adrenal glands, and the adrenal cortex releases cortisol, which mobilises energy and adjusts the body for a sustained challenge.

HPA axis. The HPA axis is the hormonal chain through which the brain answers stress with cortisol: the hypothalamus signals the pituitary, the pituitary signals the adrenal glands, and the adrenal cortex releases cortisol, which mobilises energy and adjusts the body for a sustained challenge.

The chain has three links. Neurons of the paraventricular nucleus of the hypothalamus release corticotropin-releasing hormone (CRH, helped by vasopressin) into the portal vessels of the pituitary gland. The anterior pituitary answers with ACTH into the general circulation, and ACTH makes the adrenal cortex produce cortisol within minutes. Cortisol raises blood glucose, damps inflammation and changes how the brain processes threat and memory. It also closes the loop: it acts on receptors in the pituitary, the hypothalamus and the hippocampus to switch its own release off.

It is the slow arm of the stress response. The fast arm is the sympathetic system and adrenaline from the adrenal medulla, in seconds; the HPA axis acts over tens of minutes and its effects last hours.

The brain decides what counts as stress. The amygdala drives the axis up, while the hippocampus and the medial prefrontal cortex hold it down, which is why the same event raises cortisol in one person and not in another.

The same three-level pattern runs the thyroid, gonadal and growth axes, each with its own releasing hormone, tropic hormone and feedback.

It has a daily rhythm. Cortisol peaks shortly after waking and falls through the day, set by the suprachiasmatic clock of the hypothalamus.

Questions: How does cortisol switch off its own release, and what is the hippocampus doing in that loop? Cortisol binds glucocorticoid receptors in the pituitary and the hypothalamus, where it suppresses ACTH and CRH, a classic negative feedback. The hippocampus, rich in the same receptors, adds a higher level of brake: it inhibits the paraventricular nucleus through relays, and the medial prefrontal cortex does the same, while the amygdala pushes the axis up. When the brake weakens, cortisol stays high for longer after each stress, which is one reason chronic stress and hippocampal damage are studied together. How does a stressful thought end up raising cortisol in the blood? A situation judged threatening by the cortex and the amygdala excites the paraventricular nucleus of the hypothalamus, which releases CRH into the portal vessels of the pituitary. The anterior pituitary responds with ACTH into the general circulation, and ACTH stimulates the adrenal cortex to make cortisol, which peaks in the blood about 20 to 30 minutes after the stressor. The chain explains why a purely psychological event (an exam, an argument) produces the same hormonal response as a physical one.