The cortisol switch between vulnerability and resilience

In concert with neuropeptides and transmitters, the end products of the hypothalamus-pituitary-adrenal (HPA) axis, the glucocorticoid hormones cortisol and corticosterone (CORT), promote resilience: i.e., the ability to cope with threats, adversity, and trauma. To exert this protective action, CORT activates mineralocorticoid receptors (MR) and glucocorticoid receptors (GR) that operate in a complementary manner -as an on/off switch- to coordinate circadian events, stress-coping, and adaptation. The evolutionary older limbic MR facilitates contextual memory retrieval and supports an on-switch in the selection of stress-coping styles at a low cost. The rise in circulating CORT concentration after stress subsequently activates a GR-mediated off-switch underlying recovery of homeostasis by providing the energy for restraining the primary stress reactions and promoting cognitive control over emotional reactivity. GR activation facilitates contextual memory storage of the experience to enable future stress-coping. Such complementary MR-GR-mediated actions involve rapid non-genomic and slower gene-mediated mechanisms; they are time-dependent, conditional, and sexually dimorphic, and depend on genetic background and prior experience. If coping fails, GR activation impairs cognitive control and promotes emotional arousal which eventually may compromise resilience. Such breakdown of resilience involves a transition to a chronic stress construct, where information processing is crashed; it leads to an imbalanced MR-GR switch and hence increased vulnerability. Novel MR-GR modulators are becoming available that may reset a dysregulated stress response system to reinstate the cognitive flexibility required for resilience.

Automated summary

The glucocorticoid hormones cortisol and corticosterone play a role in promoting resilience by activating mineralocorticoid receptors (MR) and glucocorticoid receptors (GR) of the hypothalamus-pituitary-adrenal (HPA) axis. MR facilitates memory retrieval and stress-coping selection, while GR promotes recovery and cognitive control over emotional reactivity. The balance between MR and GR activation is important for resilience, and disruptions in this balance may lead to chronic stress and increased vulnerability. Novel modulators of MR and GR may help reinstate cognitive flexibility required for resilience.