Glucocorticoids are essential signalling molecules that bind to the glucocorticoid receptor to regulate the brain's ability to adapt to stress
The glucocorticoid receptor can alter neuronal function through both genomic (transcriptional) and non-genomic (intracellular signalling, epigenetic) effects
Sex hormones, neurotransmitters and neurotrophic factors can modulate the effects of the glucocorticoid receptor
Stress-induced changes resulting from glucocorticoid receptor activation can be persistent and thereby alter future stress reactivity through epigenetic mechanisms
Recovery from stress is not equivalent to reversal: one cannot turn back the clock
Following the discovery of glucocorticoid receptors in the hippocampus and other brain regions, research has focused on understanding the effects of glucocorticoids in the brain and their role in regulating emotion and cognition. Glucocorticoids are essential for adaptation to stressors (allostasis) and in maladaptation resulting from allostatic load and overload. Allostatic overload, which can occur during chronic stress, can reshape the hypothalamic–pituitary–adrenal axis through epigenetic modification of genes in the hippocampus, hypothalamus and other stress-responsive brain regions. Glucocorticoids exert their effects on the brain through genomic mechanisms that involve both glucocorticoid receptors and mineralocorticoid receptors directly binding to DNA, as well as by non-genomic mechanisms. Furthermore, glucocorticoids synergize both genomically and non-genomically with neurotransmitters, neurotrophic factors, sex hormones and other stress mediators to shape an organism's present and future responses to a stressful environment. Here, we discuss the mechanisms of glucocorticoid action in the brain and review how glucocorticoids interact with stress mediators in the context of allostasis, allostatic load and stress-induced neuroplasticity.
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The authors acknowledge the support of NIH/F32 MH102065 to JDG and NIH/RO1 MH41256 and the Hope for Depression Research Foundation grant RGA#13-004 to BSM.
The authors declare no competing financial interests.
Having a period of recurrence shorter than a day but longer than an hour.
Pathological process by which neurons are damaged by overactivation of receptors for glutamate, such as NMDA (N-methyl-D-aspartate) and AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptors.
- Long-term potentiation
Persistent increase in synaptic strength following high-frequency stimulation of a chemical synapse.
- Prime burst potentiation
Specific type of long-term potentiation that combines complex-spike discharge and theta rhythm to produce lasting increases in evoked responses recorded in area CA1.
- Polycomb complexes
A family of proteins that bind to DNA, leading to chromatin remodelling that causes epigenetic silencing of genes.
- Gene–environment interaction
When two different genotypes respond to environmental variation in different ways.
- Neurotrophic hypothesis
This hypothesis states that depression results from decreased neurotrophic support, leading to neuronal atrophy, decreased hippocampal neurogenesis and loss of glia, and that antidepressant treatment blocks or reverses this neurotrophic factor deficit and thereby reverses the atrophy and cell loss.
- Conduct disorder
A mental disorder diagnosed in childhood or adolescence that presents itself through a repetitive and persistent pattern of behaviour in which the basic rights of others or major age-appropriate norms are violated.
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Gray, J., Kogan, J., Marrocco, J. et al. Genomic and epigenomic mechanisms of glucocorticoids in the brain. Nat Rev Endocrinol 13, 661–673 (2017). https://doi.org/10.1038/nrendo.2017.97
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