Figure 2.

The hypothalamic-pituitary-adrenal axis integrates and mediates the stress response to early life and later on adversity. The perception of real and/or presumed physical and social threats causes activation of the hypothalamic-pituitary-adrenal axis. Anxious states arise from activation of the amygdala and magnify the stress response via neuronal projections to the paraventricular nucleus (PVN). The hippocampus plays an important role in the assessment of stressors and as a site of glucocorticoid receptor (GR) mediated negative feedback regulation. Release of the hypothalamic neuropeptides corticotrophin-releasing hormone (CRH) and arginine vasopressin (AVP) promotes the synthesis and secretion of adrenocorticotrophin (ACTH), a posttranslational cleavage product of anterior pituitary pro-opiomelanocortin mRNA (POMC). ACTH in turn stimulates the release of glucocorticoids from the adrenal glands. These hormones circulate throughout the whole body and the brain and bind to intracellular nuclear steroid receptors. Hippocampal mineralocorticoid (MR) receptors act to the onset of the stress response, while GR at the hippocampus, PVN, and anterior pituitary terminates the stress response. The GR further transactivates FKBP51 encoding a chaperon protein which curtails GR activity through a fast intracellular negative feedback loop.