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.

Keywords: CBG; Exercise; Glucocorticoid receptor; HPA axis; Mineralocorticoid receptor; PTSD.

Fig. 1

Forced swimming results in significantly enhanced binding of GRs to a GRE sequence within the Per1 gene promoter. In an xChIP assay, cross-linked chromatin samples prepared from neocortex tissue of baseline (Bs) and forced swim (FS) rats were incubated with anti-GR antibody (Santa Cruz, CA). Bound and Input GRE-containing Per1 gene promoter DNA were quantified using qPCR. Data are expressed as the ratio of Bound/Input; mean ± SEM, n = 5. ∗, P < 0.001, Student's t-test.

Fig. 2

Effect of long-term voluntary exercise on forced swimming-induced MSK1/2 and ERK1/2 phosphorylation and c-Fos induction in rat dentate gyrus neurons. Male Sprague Dawley rats had 4 weeks access to a running wheel in their home cages after which they were either killed under baseline conditions (Bs) or at 15 min (pMSK, pERK) or at 60 min after start of forced swimming (FS; 15 min, 25 C water). Sacrifice and immunohistochemical procedures (including used antibodies) were exactly performed as described in Gutierrez-Mecinas et al. (2011). A–F: representative images of the dorsal blade of the dentate gyrus of baseline (A–C) and stressed (D–F) sedentary control rats. G–I: Quantitation of immuno-positive neurons in the dentate gyrus of sedentary and exercised rats killed at baseline or after forced swimming. Data are expressed as the average counts in a coronal 50 μm section (for details, see Gutierrez-Mecinas et al., 2011); mean ± SEM, n = 4 rats. ∗, P < 0.05, significantly different from the respective baseline group; ⁺, P < 0.05, significantly different from the sedentary FS group, post-hoc Bonferroni test after two-way ANOVA. Scale bar is 100 µm.