Glucocorticoids, epigenetic control and stress resilience

Abstract

Glucocorticoid hormones play a pivotal role in the response to stressful challenges. The surge in glucocorticoid hormone secretion after stress needs to be tightly controlled with characteristics like peak height, curvature and duration depending on the nature and severity of the challenge. This is important as chronic hyper- or hypo-responses are detrimental to health due to increasing the risk for developing a stress-related mental disorder. Proper glucocorticoid responses to stress are critical for adaptation. Therefore, the tight control of baseline and stress-evoked glucocorticoid secretion are important constituents of an organism's resilience. Here, we address a number of mechanisms that illustrate the multitude and complexity of measures safeguarding the control of glucocorticoid function. These mechanisms include the control of mineralocorticoid (MR) and glucocorticoid receptor (GR) occupancy and concentration, the dynamic control of free glucocorticoid hormone availability by corticosteroid-binding globulin (CBG), and the control exerted by glucocorticoids at the signaling, epigenetic and genomic level on gene transcriptional responses to stress. We review the beneficial effects of regular exercise on HPA axis and sleep physiology, and cognitive and anxiety-related behavior. Furthermore, we describe that, possibly through changes in the GABAergic system, exercise reduces the impact of stress on a signaling pathway specifically in the dentate gyrus that is strongly implicated in the behavioral response to that stressor. These observations underline the impact of life style on stress resilience. Finally, we address how single nucleotide polymorphisms (SNPs) affecting glucocorticoid action can compromise stress resilience, which becomes most apparent under conditions of childhood abuse.

Mineralocorticoid and glucocorticoid receptor-mediated control of genomic responses to stress in the brain

“…Traditionally, GR has been thought to be the primary mediator of the genomic effects of elevated cort levels after stress as it only becomes substantially occupied after such GC levels due to its lower binding affinity for cort compared with MR (Reul et al, , 2015Trollope, Mifsud, Saunderson, & Reul, 2017;Zalachoras, Houtman, & Meijer, 2013). Evidence does exist, however, showing that MRs and GRs can form heterodimers, in addition to the respective homodimers, in cell-free systems and in cells in vitro (Liu, Wang, Sauter, & Pearce, 1995;Savory et al, 2001;Trapp, Rupprecht, Castren, Reul, & Holsboer, 1994).…”

Rapid Down-Regulation of Glucocorticoid Receptor Gene Expression in the Dentate Gyrus after Acute Stress in vivo: Role of DNA Methylation and MicroRNA Activity

“…GCs act on areas of the brain, like the hippocampus, to evoke a number of biochemical, physiological, and behavioural responses [1,2]. The hippocampus is a key area of the brain involved in the formation of contextual memories and is essential for appropriate adaptation to stress [3].…”

Epigenetic programming of the neuroendocrine stress response by adult life stress

“…The NMDA receptor was later identified as a co-activator of the MAPK pathway, whose synchronised activation is necessary for formation of H3S10p-K14ac and IEG induction ). For an extensive review describing this glucocorticoid control over epigenetic modifications, Reul et al (2015). exposure (Plotsky & Meaney 1993, Chen et al 2012, Mironova et al 2013, Xu et al 2014, Eraslan et al 2015, and epigenetic mechanisms may underlie these changes.…”