Importance of the brain corticosteroid receptor balance in metaplasticity, cognitive performance and neuro-inflammation

• Published in: Frontiers in neuroendocrinology Vol. 49; pp. 124 - 145
• Main Authors: de Kloet, E.R., Meijer, O.C., de Nicola, A.F., de Rijk, R.H., Joëls, M.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.04.2018
• Subjects: Amygdala; Amygdala - metabolism; Animals; Brain; Cognitive Dysfunction - etiology; Cognitive Dysfunction - metabolism; Cognitive Dysfunction - physiopathology; Coregulators; Cortisol; Glucocorticoid receptors; Hippocampus; Hippocampus - metabolism; Inflammation; Inflammation - metabolism; Memory; Metaplasticity; Mineralocorticoid receptors; NeuroD transcription factor; Neuronal Plasticity - physiology; Receptors, Glucocorticoid - metabolism; Receptors, Mineralocorticoid - metabolism; Stress; Stress, Psychological - complications; Stress, Psychological - metabolism; Stress, Psychological - physiopathology; Brain; NeuroD transcription factor; Amygdala; Memory; Metaplasticity; Mineralocorticoid receptors; Coregulators; Inflammation; Cortisol; Glucocorticoid receptors; Stress; Hippocampus
• ISSN: 0091-3022; 1095-6808
• DOI: 10.1016/j.yfrne.2018.02.003

•Resilience depends on balanced MR- and GR-mediated actions.•Brain MR promotes appraisal processes, choice of coping style, learning and memory retrieval.•Brain GR promotes recovery, rational decisions and contextual memory.•Corticosterone-induced amygdala metaplasticity tunes emotional memory.•Transcription factor and coregulators confer specificity to MR- and GR-mediated actions. Bruce McEwen’s discovery of receptors for corticosterone in the rat hippocampus introduced higher brain circuits in the neuroendocrinology of stress. Subsequently, these receptors were identified as mineralocorticoid receptors (MRs) that are involved in appraisal processes, choice of coping style, encoding and retrieval. The MR-mediated actions on cognition are complemented by slower actions via glucocorticoid receptors (GRs) on contextualization, rationalization and memory storage of the experience. These sequential phases in cognitive performance depend on synaptic metaplasticity that is regulated by coordinate MR- and GR activation. The receptor activation includes recruitment of coregulators and transcription factors as determinants of context-dependent specificity in steroid action; they can be modulated by genetic variation and (early) experience. Interestingly, inflammatory responses to damage seem to be governed by a similarly balanced MR:GR-mediated action as the initiating, terminating and priming mechanisms involved in stress-adaptation. We conclude with five questions challenging the MR:GR balance hypothesis.