Corticosteroid receptor signalling modes and stress adaptation in the brain

Adrenal glucocorticoid hormones modulate neuronal activity to support an adaptive response to stress. They modulate brain circuitry mediating physiological responses, emotion and cognitive processing. Chronically elevated glucocorticoid exposure is however linked to the development of mental disease. Glucocorticoid effects depend on mineralo- and glucocorticoid receptors, which are powerful transcription factors, but also can act via a diversity of non-genomic mechanisms. Here, I review generic factors that determine neuronal glucocorticoid sensitivity, in relation to brain function. First, pre-receptor mechanisms determine ligand availability. Second, there may be considerable variation in the receptor splice-and translation variants. Third, other transcription factors and many transcriptional coregulators interact with steroid receptors, determining nature and magnitude of steroid responses, in part through epigenetic regulation of DNA accessibility. Which factors underlie adaptive and pathogenic effects of stress hormones is largely unknown. Genome-wide identification of the receptor-DNA interactions in specific behavioural and physiological contexts provides a way of assessing the complete genomic range of glucocorticoid modes of action. Novel ligands that induce selective activation of particular receptor signalling modes will aid our understanding of receptor signalling and may allow selective targeting of glucocorticoid effects in emotional or cognitive domains, in research and, hopefully, in clinical settings.