Introduction
Corticosteroid hormones affect the brain via the Mineralocorticoid Receptor (MR) and Glucocorticoid Receptor (GR), controlling development, metabolism, homeostasis, cognition, and mood. Both receptor types can exert rapid non-genomic effects on neuronal activity, but they are best known as ligand activated transcription factors that regulate gene transcription. Both receptors, with differing affinities to corticosteroids and specific expression patterns throughout the brain, can bind at the same regulatory target sequences of genes. However, they also control distinct transcriptional networks to differentially regulate broadly defined neuronal processes from cell differentiation and survival to cognitive and emotional functions (de Kloet, Joëls and Holsboer, 2005).
Corticosteroids include both glucocorticoids like cortisol and corticosterone, and mineralocorticoids such as aldosterone and the less potent deoxycorticosterone (DOC). Glucocorticoids are the main ligands for both MR and GR in the brain. They are synthesized and released in a circadian and ultradian rhythm from the zona fasciculata of the adrenal cortex, regulated by the hypothalamic-pituitary-adrenal (HPA) axis, which in conjunction with the sympathetic nervous system coordinates the response to stress (figure 1). The HPA axis is critical for life and operates by feed-back loops to regulate glucocorticoid concentrations to maintain a dynamic and allostatic system homeostasis (Lightman, Birnie and Conway-Campbell, 2020). In addition, brain aldosterone-preferring MRs regulate salt and water balance, including their associated behaviours (de Kloet and Joëls, 2017).
Corticosteroid signaling becomes dysregulated in certain disease states or by chronic exposure to synthetic glucocorticoids used in treatment and replacement strategies, and this can enhance vulnerability to disease (Lightman, Birnie and Conway-Campbell, 2020). Furthermore, MR and GR may contribute to (brain) disease in conditions that are not typically associated with high hormone levels. Here, we focus on the specific role of MR (inevitably in concert with GR) in mediating the effects of corticosteroids in the brain on gene transcription, cellular processes, and control of cognitive and emotional function.