Corticosteroids: way upstream

Studies into the mechanisms of corticosteroid action continue to be a rich bed of research, spanning the fields of neuroscience and endocrinology through to immunology and metabolism. However, the vast literature generated, in particular with respect to corticosteroid actions in the brain, tends to be contentious, with some aspects suffering from loose definitions, poorly-defined models, and appropriate dissection kits. Here, rather than presenting a comprehensive review of the subject, we aim to present a critique of key concepts that have emerged over the years so as to stimulate new thoughts in the field by identifying apparent shortcomings. This article will draw on experience and knowledge derived from studies of the neural actions of other steroid hormones, in particular estrogens, not only because there are many parallels but also because 'learning from differences' can be a fruitful approach. The core purpose of this review is to consider the mechanisms through which corticosteroids might act rapidly to alter neural signaling

Methylation at the CpG island shore region upregulates Nr3c1 promoter activity after early-life stress

Early-life stress (ELS) induces long-lasting changes in gene expression conferring an increased risk for the development of stress-related mental disorders. Glucocorticoid receptors (GR) mediate the negative feedback actions of glucocorticoids (GC) in the paraventricular nucleus (PVN) of the hypothalamus and anterior pituitary and therefore play a key role in the regulation of the hypothalamic-pituitary-adrenal (HPA) axis and the endocrine response to stress. We here show that ELS programs the expression of the GR gene (Nr3c1) by site-specific hypermethylation at the CpG island (CGI) shore in hypothalamic neurons that produce corticotropin-releasing hormone (Crh), thus preventing Crh upregulation under conditions of chronic stress. CpGs mapping to the Nr3c1 CGI shore region are dynamically regulated by ELS and underpin methylation-sensitive control of this region's insulation-like function via Ying Yang 1 (YY1) binding. Our results provide new insight into how a genomic element integrates experience-dependent epigenetic programming of the composite proximal Nr3c1 promoter, and assigns an insulating role to the CGI shore.European Union Directorate General for Research & Innovation through the CRESCENDO Consortium (O.F.X.A. and D.S) and the NINA Initial Training Program (D.S. and O.F.X.A

Methylation at the CpG island shore region upregulates <i>Nr3c1</i> promoter activity after early-life stress

<div><p>Early-life stress (ELS) induces long-lasting changes in gene expression conferring an increased risk for the development of stress-related mental disorders. Glucocorticoid receptors (GR) mediate the negative feedback actions of glucocorticoids (GC) in the paraventricular nucleus (PVN) of the hypothalamus and anterior pituitary and therefore play a key role in the regulation of the hypothalamic-pituitary-adrenal (HPA) axis and the endocrine response to stress. We here show that ELS programs the expression of the GR gene (<i>Nr3c1</i>) by site-specific hypermethylation at the CpG island (CGI) shore in hypothalamic neurons that produce corticotropin-releasing hormone (Crh), thus preventing Crh upregulation under conditions of chronic stress. CpGs mapping to the <i>Nr3c1</i> CGI shore region are dynamically regulated by ELS and underpin methylation-sensitive control of this region's insulation-like function via Ying Yang 1 (YY1) binding. Our results provide new insight into how a genomic element integrates experience-dependent epigenetic programming of the composite proximal <i>Nr3c1</i> promoter, and assigns an insulating role to the CGI shore.</p></div

Glucocorticoids and neuro- and behavioural development

Epidemiological evidence links exposure to stress hormones during fetal or early postnatal development with lifetime prevalence of cardiac, metabolic, auto-immune, neurological and psychiatric disorders. This has led to the concept of 'developmental programming through stress'. Importantly, these effects (specifically, hypertension, hyperglycaemia and neurodevelopmental and behavioural abnormalities) can be reproduced by exposure to high glucocorticoid levels, indicating a crucial role of glucocorticoids in their causation. However, there can be important differences in outcome, depending on the exact time of exposure, as well as duration and receptor selectivity of the glucocorticoid applied. The mechanisms underlying programming by stress are still unclear but it appears that these environmental perturbations exploit epigenetic modifications of DNA and/or histones to induce stable modifications of gene expression. Programming of neuro- and behavioural development by glucocorticoids and stress are important determinants of lifetime health and should be a consideration when choosing treatments in obstetric and neonatal medicine.The authors’ own studies were recently supported through grants from German Academic Exchange Service (DAAD)/Portuguese Universities Rectors’ Conference (CRUP), and the European Commission (FP 7 – CRESCENDO – Contract LSHM-CT-2005-018652)