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.