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. 2020 May 15;11:443. doi: 10.3389/fpsyt.2020.00443

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Copyright © 2020 Tafet and Nemeroff

This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

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Graphic representation of the hypothalamic-pituitary-adrenal (HPA) axis. The hypothalamic paraventricular nucleus (PVN) releases corticotropin releasing hormone (CRH) to the hypophyseal portal blood, to reach the pituitary (P), where adrenocorticotropic hormone (ACTH) is synthesized and released to systemic blood to reach the adrenal cortex (AC), where in turn cortisol is synthesized and released to the main bloodstream. The HPA is regulated by stimulatory projections from the amygdala and inhibitory projections from the hippocampus. In addition, the PVN receives noradrenergic projections from the locus coeruleus (LC) and serotonergic projections from the raphe nuclei (RN). Stimulatory and inhibitory feedback loops are also represented, where cortisol is able to regulate its own synthesis and release by inhibiting ACTH and CRH synthesis in the pituitary and PVN respectively, and stimulating the hippocampus, which in turn may inhibit the PVN. Under repeated uncontrollable stress these feedback mechanisms result abolished, with the consequent hypercortisolism, alongside with increased reactivity of the amygdala and decreased activity of the hippocampus. Successful treatment is translated into recovery of these feedback mechanisms, with the consequent normalization of cortisol, decreased amygdala reactivity, increased hippocampal function, and normalization of noradrenergic and serotonergic systems.