From ligands to behavioral outcomes: understanding the role of mineralocorticoid receptors in brain function

Stress is a normal response to situational pressures or demands. Exposure to stress activates the hypothalamic-pituitary-adrenal (HPA) axis and leads to the release of corticosteroids, which act in the brain via two distinct receptors: mineralocorticoid receptors (MR) and glucocorticoid receptors (GR). Persistent HPA axis overactivation or dysregulation can disrupt an individual's homeostasis, thereby contributing to an increased risk for mental illness. On the other hand, successful coping with stressful events involves adaptive and cognitive processes in the brain that render individuals more resilient to similar stressors in the future. Here we review the role of the MR in these processes, starting with an overview of the physiological structure, ligand binding, and expression of MR, and further summarizing its role in the brain, its relevance to psychiatric disorders, and related rodent studies. Given the central role of MR in cognitive and emotional functioning, and its importance as a target for promoting resilience, future research should investigate how MR modulation can be used to alleviate disturbances in emotion and behavior, as well as cognitive impairment, in patients with stress-related psychiatric disorders.