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Genomic and epigenomic mechanisms of glucocorticoids in the brain

Key Points

  • 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

Abstract

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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Figure 1: Intracellular regulation of the glucocorticoid receptor.
Figure 2: Circadian and ultradian fluctuations in corticosterone.
Figure 3: Stress and allostatic load.
Figure 4: Gene expression profiling of acute and chronic stress compared with cortisol injections.
Figure 5: Genetic polymorphisms can alter stress-induced gene expression.

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Acknowledgements

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.

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All authors contributed equally to researching data for the article, discussion of content, writing the article and reviewing and/or editing the manuscript before submission.

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Correspondence to Bruce S. McEwen.

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Ultradian

Having a period of recurrence shorter than a day but longer than an hour.

Excitotoxicity

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.

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When two different genotypes respond to environmental variation in different ways.

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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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