The brain mineralocorticoid receptor and stress resilience: rise of the underdog. Involvement in Stress, Resilience and the Implications for Treatment

Abstract

The hypothalamic-pituitary-adrenal (HPA) axis is essential in the maintenance of balance in response to stress. It is regulated by the mineralocorticoid (MR) and glucocorticoid receptor (GR) to which cortisol binds. These receptors function in a complementary fashion to successfully adapt to stress and protect an individual from stress-related disorders. Whilst the role of the GR has been extensively researched, the role of MR has received relatively little attention. This is most likely due to the high cortisol binding affinity of the MR, resulting in MR occupation even under basal (non-stressful) conditions. Nevertheless, an increasing body of literature suggests that the MR plays a role in the regulation of basal as well as stress-induced HPA-axis activity and, as such, may be an important contributor to an adaptive stress response. Further, the recent discovery of a membrane-bound MR mediating the rapid effects of cortisol adds to the importance of the MR in the acute phase of the stress response. This review summarizes how the MR affects stress reactivity, fear learning and discusses the subsequent consequences for the development and treatment of psychiatric disorders. Based on the existing literature, increased activity of the MR seems to be associated with a more adaptive stress response and, consequently, helps to protect against the development of psychiatric disorders. MR functionality not only directly affects the endocrine stress response but is also associated with a more adequate appraisal of stressful situations and changes in fear-induced memory formation. Important in light of consistent gender differences in the prevalence of stress-related psychiatric disorders, are the indications that these MR effects occur in a gender-dependent fashion. In conclusion, a relative increase in MR functionality seems to result in both tonic and dynamic changes in HPA-axis activity, giving rise to a more adaptive stress response, and, ultimately, an increased resilience to stress.