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May 09, 20244 min read

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The HPA axis is a pathway in the brain that is active in response to stress. It stands for hypothalamic-pituitary-adrenal axis, with reference to the hypothalamus, pituitary gland, and adrenal cortex

Scheme


The paraventricular nucleus (PVN) is the first site of response to stress. While the amygdala is the sensor for stress, the PVN responds to it. The PVN is located in the hypothalamus and produces corticotropin-releasing hormone (CRH) in response to a stressor.

CRH moves downstream to the anterior pituitary, where it binds to CRH1 and CRH2 receptors and signals the gland to release adrenocorticotropic hormone (ACTH).

ACTH moves through the blood to the adrenal cortex, where it signals the cortex to release cortisol, a glucocorticoid. Cortisol inhibits the HPA axis through binding to the glucocorticoid receptors (GRs) on both the hypothalamus and anterior pituitary, resulting in negative feedback.

Central Regulation

Amygdala

The major area of cortical input for the amygdala is the basal lateral amygdala (BLA), while the central amygdala (CeA) serves as the major output to the lateral hypothalamus, preganglions in brain stem, and spinal cord.

The amygdala, through the CeA, activates the hypothalamus and induces HPA axis activity. Amygdala stimulation has been shown to increase CRF, ACTH, cortisol, and noradrenaline, which is associated with an increase in fear, anxiety, and aggression.

Hippocampus

The hippocampus is involved in the negative feedback loop in the HPA axis. It inhibits the HPA axis from releasing more glucocorticoids through inhibition on the PVN of the hypothalamus. Cortisol binding to the hippocampus results in inhibition of the PVN, and thus lower release of GCs.

In chronic stress, this mechanism is disrupted due to damage to the hippocampus — chronic stress results in excitotoxicity to the hippocampus, degeneration of hippocampal neurons, and impaired ability of the hippocampus to inhibit the HPA axis.

Prefrontal Cortex

The prefrontal cortex is associated with morphological reductions, particularly in the medial PFC, characterized by neuronal atrophy and dendritic retraction, induced by Cortisol and inflammation.

The PFC can function as an inhibitor on the HPA axis, a function which is reduced in MDD patients.

Circadian Rhythm

Basal HPA axis activity adheres to a diurnal cycle. Close to awakening, ACTH is released, which stimulates Cortisol production and results in the CAR, or cortisol awakening response. Cortisol levels peak after 30-60 minutes after awakening, and can be measured by taking saliva samples. Cortisol levels slowly decline over the course of the day, until they rise again the next day.

CAR can be used as an HPA axis proxy for HPA-axis functioning. In MDD patients, CAR is significantly lower than in healthy controls. Desensitization of glucocorticoid receptors leads to decreased sensitivity of the HPA axis.

Pulsatile Release

  • The Pulsatile Release in HPA axis is related to the CAR, which follows a circadian (circa dia) rhythm.

In dysfunction


In depression, the function and structure of the HPA axis is similar to states seen in chronic stress. Impaired sensitivity of glucocorticoid receptors results in disinhibition of CRH release from the hypothalamus and increase in Cortisol levels. Elevated cortisol levels result in desensitization of GRs in the hippocampus and neuronal atrophy in the hippocampus.

High cortisol → desensitization of GR → disinhibition of stress response → increased release of CRH → more cortisol → etc.

  • This is a negative feedback loop

Negative feedback loop may be mediated by several genetic variations, including:

  • NR3C1 (GR) and NR3C2 (MR)
    • Variations in these genes can cause imbalance of GR/MR receptors, impaired sensitivity of GR, reduction of GR, or upregulation of MR.
  • FKBP5 (FKBP51)
    • Disturb ultra-short feedback loop which can lead to susceptibility to stress-related disorders

Cortisol

  • Higher basal CORT throughout day
  • Decreased CORT response to psychosocial stress (Trier Social Stress Test).
  • Increased cortisol in response to DEX/CRH.

Immune Function

  • Glucocorticoids can inhibit immune function through binding to GR receptors on immune cells, which inhibits release of cytokines. In acute stress, this is the way it works.
  • In chronic stress, GR desensitization on immune cells results in impaired ability of GR to inhibit cytokine release, resulting in increased release of cytokines and further stimulation of the HPA axis through pro-inflammatory cytokines, incl. IL-1, activating HPA axis at hypothalamus, anterior pituitary, and adrenal cortex.

GR-TrkB transactivation

  • Stress induced hyperactivity of HPA axis reduces BDNF expression via increased glucocorticoid release
  • Glucocorticoids receptors bind to TrkB and promote BDNF-triggered PLCy signaling for glutamate release.

    Chronic stress → increase in HPA axis & glucocorticoid release → decrease in BDNF functioning → damage → HPA axis feedback → impaired feedback loop

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