Summary: New findings indicate that textbook concepts about how stress hormones act in the brain may need revision.
Source: University of Bristol
Stress is widespread and can contribute to poor physical health and mental disorders. New research shows that commonly held ideas about how stress hormones interact with receptors in the brain—particularly in the hippocampus—should be reconsidered.
Disruption in the signaling of stress hormones is implicated in conditions such as major depression and post-traumatic stress disorder (PTSD). Coping with stressful events requires changes in gene expression in the hippocampus, a brain region essential for learning and memory. These gene expression changes are driven in part by glucocorticoid hormones acting through two receptor types that bind DNA and regulate transcription: mineralocorticoid receptors (MRs) and glucocorticoid receptors (GRs).
A study funded by the BBSRC and published in the journal PNAS reports that MR action at the neuronal genome cannot be predicted simply from how much hormone occupies the receptor. This challenges the longstanding textbook model that MRs provide a steady, tonic influence while GRs are only engaged during stress to mediate negative feedback and support learning after an event.
Researchers Professor Hans Reul and Dr. Karen Mifsud from the University of Bristol’s School of Clinical Sciences directly examined MR and GR binding to genes in the hippocampus following stress. Contrary to expectations, MR binding at target gene sites was not consistently high at baseline. Instead, MR binding was relatively low under non-stress conditions and increased substantially after acute stress. GR binding behaved as predicted: minimal at baseline and rising markedly after stress. The team used chromatin immunoprecipitation (ChIP) and gene expression analysis to document these changes in vivo.
Importantly, the study provides the first strong in vivo evidence that MRs and GRs can form heterodimers and co-bind the same glucocorticoid response elements (GREs) within target genes after stress. This co-binding appears to be gene-dependent: for some genes the receptors bind together, while for others they do not. The results suggest that GR binding after stress can facilitate MR cobinding at specific sites, adding a layer of complexity to how glucocorticoids regulate hippocampal gene expression.
Professor Reul commented that these findings represent a significant advance in understanding how glucocorticoid hormones act on the brain following stress. By identifying hippocampal genes directly affected by GR/MR binding after stress, the work opens new avenues for investigating the molecular basis of stress-related psychiatric disorders and for developing targeted therapies.
The research used acute stress models—including forced swim, novelty exposure, and restraint—to measure glucocorticoid responses, hippocampal gene expression, and receptor binding at GREs within key glucocorticoid-responsive genes such as Fkbp5, Per1, and Sgk1. Acute stress increased RNA expression of these genes and produced substantial, gene-dependent increases in GR binding and, unexpectedly, in MR binding. Sequential and tandem ChIP analyses revealed that MRs and GRs can bind concurrently to the same GREs in Fkbp5 and Per1 after stress, but not in Sgk1, indicating selective heterodimerization and cobinding behavior.
These results show that MR binding at GREs is more restricted at baseline than previously assumed, and that stress-driven GR binding can promote MR recruitment to particular genomic sites. The interaction between MRs and GRs at the genome level therefore represents an additional level of regulatory complexity beyond predictions based solely on receptor–ligand affinity.
Funding: The study was supported by BBSRC grants. Professor Reul and Dr. Mifsud received further funding exceeding £1 million to continue this stress research programme.
Publication: Karen R. Mifsud and Johannes M. H. M. Reul, “Acute stress enhances heterodimerization and binding of corticosteroid receptors at glucocorticoid target genes in the hippocampus,” PNAS, published online September 21, 2016. DOI: 10.1073/pnas.1605246113.
Source: University of Bristol. Image adapted from the University of Bristol press release.
Abstract (concise)
Acute stress triggers glucocorticoid secretion that binds MRs and GRs in the hippocampus to regulate cognitive and emotional responses. While MRs have high affinity for glucocorticoids and were thought to be continually occupied, and GRs to be activated mainly during stress, the in vivo pattern of receptor binding at GREs was unclear. This study shows that forced-swim and other acute stressors increase hippocampal expression of glucocorticoid-responsive genes and cause gene-specific increases in both GR and, unexpectedly, MR binding at GREs. Sequential ChIP indicates that MRs and GRs can bind simultaneously to the same GREs for some genes, implying stress-enhanced heterodimerization and cobinding. These findings reveal added complexity in the genomic action of corticosteroid receptors in the hippocampus beyond expectations based solely on ligand–receptor affinities.