Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

The MAPK pathway and Egr-1 mediate stress-related behavioral effects of glucocorticoids

Nature Neuroscience volume 8, pages 664–672 (2005)Cite this article

An Erratum to this article was published on 01 June 2005

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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Differences under basal condition in the expression of proteins in the MAPK pathway and Egr-1 in wild-type (WT) and GRNesCre mice in which the glucocorticoid receptor (GR) was selectively deleted in neurons.
Figure 2: Stimulation of the MAPK pathway and Egr-1 after glucocorticoid receptor (GR) activation by corticosterone in AtT20 cells.
Figure 3: Functional characterization of a constitutively active form (ΔGR) of the glucocorticoid receptor (GR).
Figure 4: Stimulation of the MAPK pathway and Egr-1 by ΔGR in CHO-K1 Tet-ON cells.
Figure 5: Influence of the glucocorticoid receptor (GR) on the activation of the MAPK pathway and Egr-1 induced by stress in the hippocampus.
Figure 6: Activation of Egr-1 expression by the glucocorticoid receptor (GR) through both a MAPK-independent and a MAPK-dependent mechanism.
Figure 7: Influence of ERK activation on glucocorticoid-mediated enhancement of contextual fear conditioning.

Similar content being viewed by others

References

  1. De Kloet, E.R. Hormones, brain and stress. Endocr. Regul. 37, 51–68 (2003).

    CAS  PubMed  Google Scholar 

  2. McEwen, B.S., De Kloet, E.R. & Rostene, W. Adrenal steroid receptors and actions in the nervous system. Physiol. Rev. 66, 1121–1188 (1986).

    Article  CAS  Google Scholar 

  3. McEwen, B.S. The neurobiology of stress: from serendipity to clinical relevance. Brain Res. 886, 172–189 (2000).

    Article  CAS  Google Scholar 

  4. Piazza, P.V. & Le Moal, M. Glucocorticoids as a biological substrate of reward: physiological and pathophysiological implications. Brain Res. Brain Res. Rev. 25, 359–372 (1997).

    Article  CAS  Google Scholar 

  5. Sapolsky, R.M. Glucocorticoids and hippocampal atrophy in neuropsychiatric disorders. Arch. Gen. Psychiatry 57, 925–935 (2000).

    Article  CAS  Google Scholar 

  6. De Kloet, E.R., Oitzl, M.S. & Joels, M. Stress and cognition: are corticosteroids good or bad guys? Trends Neurosci. 22, 422–426 (1999).

    Article  CAS  Google Scholar 

  7. McGaugh, J.L. & Roozendaal, B. Role of adrenal stress hormones in forming lasting memories in the brain. Curr. Opin. Neurobiol. 12, 205–210 (2002).

    Article  CAS  Google Scholar 

  8. Holsboer, F. The corticosteroid receptor hypothesis of depression. Neuropsychopharmacology 23, 477–501 (2000).

    Article  CAS  Google Scholar 

  9. Wei, Q. et al. Glucocorticoid receptor overexpression in forebrain: a mouse model of increased emotional lability. Proc. Natl. Acad. Sci. USA 101, 11851–11856 (2004).

    Article  CAS  Google Scholar 

  10. Funder, J.W. Glucocorticoid receptors. J. Steroid Biochem. Mol. Biol. 43, 389–394 (1992).

    Article  CAS  Google Scholar 

  11. Miner, J.N. & Yamamoto, K.R. Regulatory crosstalk at composite response elements. Trends Biochem. Sci. 16, 423–426 (1991).

    Article  CAS  Google Scholar 

  12. Tronche, F., Kellendonk, C., Reichardt, H.M. & Schutz, G. Genetic dissection of glucocorticoid receptor function in mice. Curr. Opin. Genet. Dev. 8, 532–538 (1998).

    Article  CAS  Google Scholar 

  13. Chang, L. & Karin, M. Mammalian MAP kinase signalling cascades. Nature 410, 37–40 (2001).

    Article  CAS  Google Scholar 

  14. Marais, R. & Marshall, C.J. Control of the ERK MAP kinase cascade by Ras and Raf. Cancer Surv. 27, 101–125 (1996).

    CAS  PubMed  Google Scholar 

  15. O'Donovan, K.J., Tourtellotte, W.G., Millbrandt, J. & Baraban, J.M. The EGR family of transcription-regulatory factors: progress at the interface of molecular and systems neuroscience. Trends Neurosci. 22, 167–173 (1999).

    Article  CAS  Google Scholar 

  16. Meller, E. et al. Region-specific effects of acute and repeated restraint stress on the phosphorylation of mitogen-activated protein kinases. Brain Res. 979, 57–64 (2003).

    Article  CAS  Google Scholar 

  17. Sananbenesi, F., Fischer, A., Schrick, C., Spiess, J. & Radulovic, J. Mitogen-activated protein kinase signaling in the hippocampus and its modulation by corticotropin-releasing factor receptor 2: a possible link between stress and fear memory. J. Neurosci. 23, 11436–11443 (2003).

    Article  CAS  Google Scholar 

  18. Guzowski, J.F., Setlow, B., Wagner, E.K. & McGaugh, J.L. Experience-dependent gene expression in the rat hippocampus after spatial learning: a comparison of the immediate-early genes Arc, c-fos, and zif268. J. Neurosci. 21, 5089–5098 (2001).

    Article  CAS  Google Scholar 

  19. Hall, J., Thomas, K.L. & Everitt, B.J. Cellular imaging of zif268 expression in the hippocampus and amygdala during contextual and cued fear memory retrieval: selective activation of hippocampal CA1 neurons during the recall of contextual memories. J. Neurosci. 21, 2186–2193 (2001).

    Article  CAS  Google Scholar 

  20. Jouvert, P., Dietrich, J.B., Aunis, D. & Zwiller, J. Differential rat brain expression of EGR proteins and of the transcriptional corepressor NAB in response to acute or chronic cocaine administration. Neuromolecular Med. 1, 137–151 (2002).

    Article  CAS  Google Scholar 

  21. Moratalla, R., Robertson, H.A. & Graybiel, A.M. Dynamic regulation of NGFI-A (zif268, egr1) gene expression in the striatum. J. Neurosci. 12, 2609–2622 (1992).

    Article  CAS  Google Scholar 

  22. Valjent, E., Pages, C., Herve, D., Girault, J.A. & Caboche, J. Addictive and non-addictive drugs induce distinct and specific patterns of ERK activation in mouse brain. Eur. J. Neurosci. 19, 1826–1836 (2004).

    Article  Google Scholar 

  23. Atkins, C.M., Selcher, J.C., Petraitis, J.J., Trzaskos, J.M. & Sweatt, J.D. The MAPK cascade is required for mammalian associative learning. Nat. Neurosci. 1, 602–609 (1998).

    Article  CAS  Google Scholar 

  24. Blum, S., Moore, A.N., Adams, F. & Dash, P.K. A mitogen-activated protein kinase cascade in the CA1/CA2 subfield of the dorsal hippocampus is essential for long-term spatial memory. J. Neurosci. 19, 3535–3544 (1999).

    Article  CAS  Google Scholar 

  25. Bozon, B., Davis, S. & Laroche, S. A requirement for the immediate early gene zif268 in reconsolidation of recognition memory after retrieval. Neuron 40, 695–701 (2003).

    Article  CAS  Google Scholar 

  26. Jones, M.W. et al. A requirement for the immediate early gene Zif268 in the expression of late LTP and long-term memories. Nat. Neurosci. 4, 289–296 (2001).

    Article  CAS  Google Scholar 

  27. Kelly, A., Laroche, S. & Davis, S. Activation of mitogen-activated protein kinase/extracellular signal-regulated kinase in hippocampal circuitry is required for consolidation and reconsolidation of recognition memory. J. Neurosci. 23, 5354–5360 (2003).

    Article  CAS  Google Scholar 

  28. Tronche, F. et al. Disruption of the glucocorticoid receptor gene in the nervous system results in reduced anxiety. Nat. Genet. 23, 99–103 (1999).

    Article  CAS  Google Scholar 

  29. Storm, S.M., Cleveland, J.L. & Rapp, U.R. Expression of raf family proto-oncogenes in normal mouse tissues. Oncogene 5, 345–351 (1990).

    CAS  PubMed  Google Scholar 

  30. Kitchener, P., Di Blasi, F., Borrelli, E. & Piazza, P.V. Differences between brain structures in nuclear translocation and DNA binding of the glucocorticoid receptor during stress and the circadian cycle. Eur. J. Neurosci. 19, 1837–1846 (2004).

    Article  Google Scholar 

  31. Gossen, M. et al. Transcriptional activation by tetracyclines in mammalian cells. Science 268, 1766–1769 (1995).

    Article  CAS  Google Scholar 

  32. Yuryev, A. & Wennogle, L.P. The RAF family: an expanding network of post-translational controls and protein-protein interactions. Cell Res. 8, 81–98 (1998).

    Article  CAS  Google Scholar 

  33. Favata, M.F. et al. Identification of a novel inhibitor of mitogen-activated protein kinase kinase. J. Biol. Chem. 273, 18623–18632 (1998).

    Article  CAS  Google Scholar 

  34. Strawhecker, J.M., Betz, N.A., Neades, R.Y., Houser, W. & Pelling, J.C. Binding of the 97 kDa glucocorticoid receptor to the 5′ upstream flanking region of the mouse c-Ha-ras oncogene. Oncogene 4, 1317–1322 (1989).

    CAS  PubMed  Google Scholar 

  35. Lee, J.E., Beck, T.W., Wojnowski, L. & Rapp, U.R. Regulation of A-raf expression. Oncogene 12, 1669–1677 (1996).

    CAS  PubMed  Google Scholar 

  36. Beato, M., Herrlich, P. & Schutz, G. Steroid hormone receptors: many actors in search of a plot. Cell 83, 851–857 (1995).

    Article  CAS  Google Scholar 

  37. Cella, N., Groner, B. & Hynes, N.E. Characterization of Stat5a and Stat5b homodimers and heterodimers and their association with the glucocortiocoid receptor in mammary cells. Mol. Cell. Biol. 18, 1783–1792 (1998).

    Article  CAS  Google Scholar 

  38. Widen, C., Zilliacus, J., Gustafsson, J.A. & Wikstrom, A.C. Glucocorticoid receptor interaction with 14–3-3 and Raf-1, a proposed mechanism for cross-talk of two signal transduction pathways. J. Biol. Chem. 275, 39296–39301 (2000).

    Article  CAS  Google Scholar 

  39. Qiu, J. et al. Rapid activation of ERK1/2 mitogen-activated protein kinase by corticosterone in PC12 cells. Biochem. Biophys. Res. Commun. 287, 1017–1024 (2001).

    Article  CAS  Google Scholar 

  40. Richter-Levin, G. & Akirav, I. Amygdala-hippocampus dynamic interaction in relation to memory. Mol. Neurobiol. 22, 11–20 (2000).

    Article  CAS  Google Scholar 

  41. Oitzl, M.S., Reichardt, H.M., Joels, M. & De Kloet, E.R. Point mutation in the mouse glucocorticoid receptor preventing DNA binding impairs spatial memory. Proc. Natl. Acad. Sci. USA 98, 12790–12795 (2001).

    Article  CAS  Google Scholar 

  42. Impey, S., Obrietan, K. & Storm, D.R. Making new connections: role of ERK/MAP kinase signaling in neuronal plasticity. Neuron 23, 11–14 (1999).

    Article  CAS  Google Scholar 

  43. Kelleher, R.J., III, Govindarajan, A., Jung, H.Y., Kang, H. & Tonegawa, S. Translational control by MAPK signaling in long-term synaptic plasticity and memory. Cell 116, 467–479 (2004).

    Article  CAS  Google Scholar 

  44. Lee, J.L., Everitt, B.J. & Thomas, K.L. Independent cellular processes for hippocampal memory consolidation and reconsolidation. Science 304, 839–843 (2004).

    Article  CAS  Google Scholar 

  45. Marinelli, M. & Piazza, P.V. Interaction between glucocorticoid hormones, stress and psychostimulant drugs. Eur. J. Neurosci. 16, 387–394 (2002).

    Article  Google Scholar 

  46. Deroche-Gamonet, V. et al. The glucocorticoid receptor as a potential target to reduce cocaine abuse. J. Neurosci. 23, 4785–4790 (2003).

    Article  CAS  Google Scholar 

  47. Piazza, P.V. & Le Moal, M. The role of stress in drug self-administration. Trends Pharmacol. Sci. 19, 67–74 (1998).

    Article  CAS  Google Scholar 

  48. Lu, L., Dempsey, J., Liu, S.Y., Bossert, J.M. & Shaham, Y. A single infusion of brain-derived neurotrophic factor into the ventral tegmental area induces long-lasting potentiation of cocaine seeking after withdrawal. J. Neurosci. 24, 1604–1611 (2004).

    Article  CAS  Google Scholar 

  49. Godowski, P.J., Rusconi, S., Miesfeld, R. & Yamamoto, K.R. Glucocorticoid receptor mutants that are constitutive activators of transcriptional enhancement. Nature 325, 365–368 (1987).

    Article  CAS  Google Scholar 

  50. Desmedt, A., Garcia, R. & Jaffard, R. Differential modulation of changes in hippocampal-septal synaptic excitability by the amygdala as a function of either elemental or contextual fear conditioning in mice. J. Neurosci. 18, 480–487 (1998).

    Article  CAS  Google Scholar 

Download references

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.

Author information

Authors and Affiliations

  1. INSERM U588, Laboratoire de Physiopathologie du Comportement, Bordeaux Institute for Neurosciences, University Victor Segalen–Bordeaux 2, Domaine de Carreire, 146 Rue Léo Saignat, Bordeaux, 33077, Cedex, France

    Jean-Michel Revest, Francesco Di Blasi, Pierre Kitchener, Françoise Rougé-Pont & Pier Vincenzo Piazza

  2. CNRS UMR5106, Laboratoire de Neurosciences Cognitives, Avenue des Facultés, Talence, 33405, France

    Aline Desmedt

  3. CNRS FRE2401, Molecular Genetics, Neurophysiology and Behavior, Institute of Biology, College de France, 11 place Marcelin Berthelot, Paris, 75231, Cedex 5, France

    Marc Turiault & François Tronche

Authors
  1. Jean-Michel Revest
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Francesco Di Blasi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Pierre Kitchener
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Françoise Rougé-Pont
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Aline Desmedt
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Marc Turiault
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. François Tronche
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Pier Vincenzo Piazza
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Pier Vincenzo Piazza.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

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)

Supplementary Methods (PDF 94 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nn1441

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing