Abstract
Strong psychologically stressful events are known to have a long-lasting impact on behavior. The consolidation of such, largely adaptive, behavioral responses to stressful events involves changes in gene expression in limbic brain regions such as the hippocampus and amygdala. However, the underlying molecular mechanisms were until recently unresolved. More than a decade ago, we started to investigate the role of glucocorticoid hormones in signaling and epigenetic mechanisms participating in the effects of stress on gene transcription in hippocampal neurons. We discovered a novel, rapid non-genomic mechanism in which glucocorticoids via glucocorticoid receptors facilitate signaling of the ERK-MAPK signaling pathway to the downstream nuclear kinases MSK1 and Elk-1 in dentate gyrus granule neurons. Activation of this signaling pathway results in serine10 (S10) phosphorylation and lysine14 (K14) acetylation at histone H3 (H3S10p-K14ac), leading to the induction of the immediate-early genes c-Fos and Egr-1. In addition, we found a role of the DNA methylation status of gene promoters. A series of studies showed that these molecular mechanisms play a critical role in the long-lasting consolidation of behavioral responses in the forced swim test and Morris water maze. Furthermore, an important role of GABA was found in controlling the epigenetic and gene transcriptional responses to psychological stress. Thus, psychologically stressful events evoke a long-term impact on behavior through changes in hippocampal function brought about by distinct glutamatergic and glucocorticoid-driven changes in epigenetic regulation of gene transcription, which are modulated by (local) GABAergic interneurons and limbic afferent inputs. These epigenetic processes may play an important role in the etiology of stress-related mental disorders such as major depressive and anxiety disorders like post-traumatic stress disorder.
Highlights
The mnemonic function of the brain is one of its most important cognitive attributes
Some people develop an anxiety disorder like post-traumatic stress disorder (PTSD), which seriously compromises their quality of life for a long time, often life-long
To obtain insight into the identity of the neuroanatomical substrate of the glucocorticoid receptor (GR)-mediated glucocorticoid effect on the behavioral immobility response, De Kloet et al infused RU38486 into the dentate gyrus (DG), parafascicular nucleus, or paraventricular nucleus of the hypothalamus before the initial swim test [23]. They found a significantly impaired behavioral immobility response if the drug had been infused into the DG but not into any of the other nuclei [23]. These findings indicated that GRs in the DG are important for the consolidation of this behavioral response
Summary
The mnemonic function of the brain is one of its most important cognitive attributes. We found sparsely distributed c-Fos and Egr-1 immuno-positive neurons in DG of rats and mice, which increased in numbers after exposure to psychological stressors such forced swimming, novelty, and Morris water maze training [9, 18, 25, 32] (Carter et al, unpublished observation).
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