Genomic and epigenomic mechanisms of glucocorticoids in the brain

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.

Selective vulnerability of dorsal raphe‐medial prefrontal cortex projection neurons to corticosterone‐induced hypofunction

“…A caveat to the interpretation of our findings is that while exogenous CORT administration models a prominent component of the stress response, it is not equivalent to the experience of stress. The uniform decreases in DR 5‐HT neuronal activity described in the above reports may be due to the additive effects of multiple neuroendocrine responses to behavioral stressors (Gray et al., ), while the selective decrease in firing frequency that we observed in mPFC‐projecting neurons may reflect a more specific role of glucocorticoid signaling pathways.…”

“…Excess cortisol and disruption of its normal circadian rhythm are some of the most commonly observed clinical features in depressed patients (Juruena, Bocharova, Agustini, & Young, ; Pariante & Lightman, ). The enormous public health burden of MDD (Ferrari et al., ) and the widespread use of high‐dose glucocorticoid therapies in the US (Gray, Kogan, Marrocco, & McEwen, ) indicate that the identification and characterization of specific neural pathways underlying the associations between glucocorticoid abnormalities and depressive symptoms may have significant clinical impact.…”

Prenatal maternal distress associates with a blunted cortisol response in rhinovirus-positive infants

“…This association was more clearly seen in boys than in girls. Sex differences in HPA axis functioning have been reported previously (Gray et al, 2017;Giesbrecht et al, 2017). While human-based studies with a design similar to ours are lacking, so far, our results are in line with a mouse model study reporting that stressexposed male mice had a blunted corticosterone response to influenza A virus compared to females (Avitsur et al, 2006).…”

Brain Differences in the Prefrontal Cortex, Amygdala, and Hippocampus in Youth with Congenital Adrenal Hyperplasia

“…Inadequate production of cortisol and aldosterone, and overproduction of adrenal androgens, starting in the first trimester in utero can manifest in female newborns with the severe, classical forms of CAH as masculinized external genitalia (2,3). Given widespread expression of androgen and glucocorticoid receptors throughout the brain (4,5), there has been interest in understanding how hormonal imbalances related to CAH may impact distinct subregions of the developing brain (6). Several studies have begun to examine brain and behavioral alterations associated with CAH, with reported differences in emotional and memory processes in CAH patients.…”