Acute stress enhances heterodimerization and binding of corticosteroid receptors at glucocorticoid target genes in the hippocampus

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A stressful event results in secretion of glucocorticoid hormones (GCs), which bind to mineralocorticoid (MRs) and glucocorticoid receptors (GRs) in the hippocampus to regulate cognitive and affective responses to the challenge. MRs are already highly occupied by low GC levels under baseline conditions, whereas GRs only become substantially occupied by stress- or circadian-driven GC levels. Currently, however, the binding of MRs and GRs to GC responsive elements (GREs) within hippocampal GC target genes under such physiological conditions in vivo is unknown. We found that forced swim (FS) stress evoked increased hippocampal RNA expression levels of the GC-responsive genes Fkbp5, Per1 and Sgk1. Chromatin immuno-precipitation (ChIP) analysis showed that this stressor caused substantial gene-dependent increases in GR binding and, surprisingly, also in MR binding to GREs within these genes. Different acute challenges, including novelty, restraint and FS stress, produced distinct GC responses but resulted in largely similar MR and GR binding to GREs. Sequential and Tandem ChIP analyses showed that after FS stress MRs and GRs bind concomitantly to the same GRE sites within Fkbp5 and Per1, but not Sgk1. Thus, after stress MRs and GRs appear to bind to GREs as homo- and/or heterodimers in a gene-dependent manner. MR binding to GREs at baseline appears to be restricted, whilst after stress GR binding may facilitate co-binding of MR. This study reveals that the interaction of MRs and GRs with GREs within the genome constitutes an additional level of complexity in hippocampal GC action beyond expectancies based on ligand-receptor interactions.
Original languageEnglish
Pages (from-to)11336-11341
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number40
Early online date21 Sep 2016
Publication statusPublished - 4 Oct 2016


  • stress
  • mineralocorticoid receptor
  • glucocorticoid receptor
  • hippocampus
  • heterodimerization


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