Stress and Depression: a Crucial Role of the Mineralocorticoid Receptor

Abstract

Cortisol and corticosterone act on the appraisal process, which comprises the selection of an appropriate coping style and the encoding of the experience for storage in the memory. This action exerted by the stress hormones is mediated by mineralocorticoid receptors (MRs), which are expressed abundantly in the limbic circuitry, particularly in the hippocampus. Limbic MR is down-regulated by chronic stress and during depression but induced by antidepressants. Increased MR activity inhibits hypothalamic-pituitary-adrenal axis activity, promotes slow wave sleep, reduces anxiety and switches circuit connectivity to support coping. Cortisol and emotioncognition are affected by MR gene haplotypes based on rs5522 and rs2070951. Haplotype 1 (GA) moderates the effects of (early) life stressors, reproductive cycle and oral contraceptives. MR haplotype 2 (CA) is a gain of function variant that protects females against depression by association with an optimistic, resilient phenotype. Activation of MR therefore may offer a target for alleviating depression and cognitive dysfunction. Accordingly, the MR agonist fludrocortisone was found to enhance the efficacy of antidepressants and to improve memory and executive functions in young depressed patients. In conclusion, CORT coordinates via MR the networks underlying how an individual copes with stress, and this action is complemented by the widely distributed lower affinity glucocorticoid receptor (GR) involved in the subsequent management of stress adaptation. In this MR:GR regulation, the MR is an important target for promoting resilience.

30 YEARS OF THE MINERALOCORTICOID RECEPTOR: Evolution of the mineralocorticoid receptor: sequence, structure and function

“…The insight that the MR and GR were kin has been important for applying information about each receptor to understanding mineralocorticoid and glucocorticoid responses in normal physiology and in treatment of endocrine-dependent diseases. With the current explosive increase in genomic sequences, in which thousands of human genomes can be studied for mutations, we can expect new insights into the molecular basis for diseases dependent on the MR, GR and their ligands (Markov et al 2009, Hawkins et al 2012, Nelson et al 2013, de Kloet 2014, Gomez-Sanchez & Gomez-Sanchez 2014, Fuller 2015, Rossier et al 2015, de Kloet et al 2016, Jaisser & Farman 2016.…”

Aldosterone-sensitive HSD2 neurons in mice

“…All psychiatric symptoms result from changing neural circuit activity, but the specific mechanisms linking hyperaldosteronism to mood circuits in the brain remain unknown. Prior work on corticosteroids and mood focused largely on glucocorticoids acting on MR in the hippocampus and other limbic regions lacking HSD2 (de Kloet et al, 2016). For hyperaldosteronism, our work predicts a simple, testable model where aldosterone boosts the activity of HSD2 neurons, their axons excite FoxP2+ relay neurons in pLC/PBcL, and their projections to the diencephalon activate a stress-associated network of forebrain regions that produce anorexia, anhedonia, and other dysphoric symptoms.…”

Heart and brain interaction in patients with heart failure: overview and proposal for a taxonomy. A position paper from the Study Group on Heart and Brain Interaction of the Heart Failure Association

“…Mineralocorticoid receptor antagonists did not change the incidence of stroke, nervous system or psychiatric disorders in RALES and EPHESUS trials. The brain mineralocorticoid receptors mediate the actions of corticosteroids in patients with stress and depression, however the role of mineralocorticoid receptor antagonists in depression are controversial and more studies are required to thoroughly elucidate their role in the management of these patients …”