Lifetime achievement from a brain-adrenal perspective: On the CRF–urocortin–glucocorticoid balance

This contribution dedicated to Wylie Vale is focused on the action of the glucocorticoid hormone aimed to counterbalance the stress response orchestrated by the corticotrophin releasing factor (CRF) and urocortin (Ucn) family of peptides. It appears that the release and action of these stress hormones themselves are subjected to intrinsic self-regulatory feedback loops that operate as checks and balances in stress adaptation. One of these feedback loops is operated by the mineralocorticoid (MR) and glucocorticoid receptors (GR) that mediate in complementary fashion the action of endogenous cortisol/corticosterone in brain circuits underlying the onset and termination of the stress response. By affecting appraisal processes MR has an important role in coordinating emotional expression and cognitive flexibility with the onset of the stress response, while GR's role is prominent in the management of behavioral and physiological adaptations during the recovery phase. Genetic variation in interaction with environmental input and experience-related factors can modulate this balance between susceptibility and recovery governed by a balanced MR:GR signaling. Thanks to the Wylie Vale School of scientists a parallel balanced regulation between the CRF/CRF-1 and Ucn/CRF-2 receptor systems is being uncovered, leading inexorably to the question: how do the CRF/Ucn and glucocorticoid systems interact in multiple brain sites to maintain homeostasis and health?