Abstract
Many of the behavioral consequences of stress are mediated by the activation of the glucocorticoid receptor by stress-induced high levels of glucocorticoid hormones. To explore the molecular mechanisms of these effects, we combined in vivo and in vitro approaches. We analyzed mice carrying a brain-specific mutation (GRNesCre) in the glucocorticoid receptor gene (GR, also called Nr3c1) and cell lines that either express endogenous glucocorticoid receptor or carry a constitutively active form of the receptor (ΔGR) that can be transiently induced. In the hippocampus of the mutant mice after stress, as well as in the cell lines, activation of glucocorticoid receptors greatly increased the expression and enzymatic activity of proteins in the MAPK signaling pathway and led to an increase in the levels of both Egr-1 mRNA and protein. In parallel, inhibition of the MAPK pathway within the hippocampus abolished the increase in contextual fear conditioning induced by glucocorticoids. The present results provide a molecular mechanism for the stress-related effects of glucocorticoids on fear memories.
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Acknowledgements
We are grateful to Y. Shaham for comments on the manuscript and to M. Petit and A. Le Roux for technical help. This work was supported by INSERM, Bordeaux Institute for Neurosciences (IFR8), the Université Victor Segalen–Bordeaux 2 and Conseil Régional d'Aquitaine.
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Supplementary Fig. 1
Schematic representation of the proposed molecular mechanism by which stress-activated GRs mediate some of the behavioral effects of stress. Following stress, activation of the GR by glucocorticoids rapidly increases (within 30 min) the levels of Egr-1 via a MAPK-independent pathway potentially acting on the Egr-1 promoter either directly or through the modulation of other transcription factors (grey circle). In parallel, stress-activated GR also rapidly increases the expression of proteins up-stream in MAPK pathway (Ras and Raf-1). This effect is followed by a delayed activation of Erk1/2 (maximal at 2 hours), which in turn results in sustained increased expression of Egr-1, even when the glucocorticoid signal has been turned off. This increase in Egr-1 expression can mediate some of the behavioral effects of stress, such as the enhanced memory of emotionally charged experience. (PDF 1306 kb)
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Revest, JM., Di Blasi, F., Kitchener, P. et al. The MAPK pathway and Egr-1 mediate stress-related behavioral effects of glucocorticoids. Nat Neurosci 8, 664–672 (2005). https://doi.org/10.1038/nn1441
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DOI: https://doi.org/10.1038/nn1441
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