Coping with the multifaceted and multifunctional role of cortisol in the brain

Glucocorticoid hormones cortisol and corticosterone (collectively called CORT), secreted as the end products of the hypothalamus-pituitary-adrenal (HPA)-axis, coordinate body and brain function over the circadian cycle and during adaptation to stress. For this purpose, the hormones bind to the mineralocorticoid receptors (MR) with the highest expression in the hippocampus/lateral septum neurons and a 10-fold lower affinity to the widely distributed glucocorticoid receptors (GR). MR and GR mediate opposing rapid non-genomic actions of CORT on neuronal excitability. MR and GR also mediate in a slower complementary manner the genomic actions on neuronal excitability, the management of energy resources, the control of defense reactions, and emotional, motivational, social, and valuation processes to gain control and adapt. The glucocorticoids perform this life-sustaining pleiotropic action in interaction with the neuropeptides of the HPA-axis, the central and autonomic nervous systems, and the immune system. Here, the progress is discussed in (i) detecting dysregulation and recovery in glucocorticoid secretion patterns, (ii) unraveling the complementary function of MR and GR in the mechanism underlying stress-coping and adaptation, and (iii) applying selective CORT receptor modulators for attenuating neurodegeneration and enhancing resilience.