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.

Chronic alcohol remodels prefrontal neurons and disrupts NMDAR-mediated fear extinction encoding

Nature Neuroscience volume 15, pages 1359–1361 (2012)Cite this article

Subjects

Abstract

Alcoholism is frequently co-morbid with post-traumatic stress disorder, but it is unclear how alcohol affects the neural circuits mediating recovery from trauma. We found that chronic intermittent ethanol (CIE) impaired fear extinction and remodeled the dendritic arbor of medial prefrontal cortical (mPFC) neurons in mice. CIE impaired extinction encoding by infralimbic mPFC neurons in vivo and functionally downregulated burst-mediating NMDA GluN1 receptors. These findings suggest that alcohol may increase risk for trauma-related anxiety disorders by disrupting mPFC-mediated extinction of fear.

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

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Learn more

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

Figure 1: CIE impairs fear extinction.
Figure 2: CIE remodels mPFC neurons.
Figure 3: CIE disrupts mPFC extinction encoding and decreases mPFC NMDAR-mediated currents.

References

  1. WHO. World Health Report 2006: Working Together for Health (WHO, Geneva, 2006).

  2. Lattal, K.M. Behav. Neurosci. 121, 1280–1292 (2007).

    Article  CAS  Google Scholar 

  3. Baum, M. J. Comp. Physiol. Psychol. 69, 238–240 (1969).

    Article  CAS  Google Scholar 

  4. Ripley, T.L., O'Shea, M. & Stephens, D.N. Eur. J. Neurosci. 18, 441–448 (2003).

    Article  CAS  Google Scholar 

  5. Bertotto, M.E., Bustos, S.G., Molina, V.A. & Martijena, I.D. Neuroscience 142, 979–990 (2006).

    Article  CAS  Google Scholar 

  6. Milad, M.R. et al. Biol. Psychiatry 66, 1075–1082 (2009).

    Article  Google Scholar 

  7. Sierra-Mercado, D., Padilla-Coreano, N. & Quirk, G.J. Neuropsychopharmacology 36, 529–538 (2011).

    Article  Google Scholar 

  8. Izquierdo, A., Wellman, C.L. & Holmes, A. J. Neurosci. 26, 5733–5738 (2006).

    Article  CAS  Google Scholar 

  9. Burgos-Robles, A., Vidal-Gonzalez, I., Santini, E. & Quirk, G.J. Neuron 53, 871–880 (2007).

    Article  CAS  Google Scholar 

  10. Herry, C., Trifilieff, P., Micheau, J., Luthi, A. & Mons, N. Eur. J. Neurosci. 24, 261–269 (2006).

    Article  Google Scholar 

  11. Burgos-Robles, A., Vidal-Gonzalez, I. & Quirk, G.J. J. Neurosci. 29, 8474–8482 (2009).

    Article  CAS  Google Scholar 

  12. Whittle, N., Hauschild, M., Lubec, G., Holmes, A. & Singewald, N. J. Neurosci. 30, 13586–13596 (2010).

    Article  CAS  Google Scholar 

  13. Goldstein, R.Z. et al. Neuropsychologia 42, 1447–1458 (2004).

    Article  Google Scholar 

  14. Pfefferbaum, A., Sullivan, E.V., Rosenbloom, M.J., Mathalon, D.H. & Lim, K.O. Arch. Gen. Psychiatry 55, 905–912 (1998).

    Article  CAS  Google Scholar 

  15. Holmes, A. & Wellman, C.L. Neurosci. Biobehav. Rev. 33, 773–783 (2009).

    Article  Google Scholar 

  16. Milad, M.R. & Quirk, G.J. Nature 420, 70–74 (2002).

    Article  CAS  Google Scholar 

  17. Martin, K.P. & Wellman, C.L. Cereb. Cortex 21, 2366–2373 (2011).

    Article  Google Scholar 

  18. Becker, H.C. & Lopez, M.F. Alcohol. Clin. Exp. Res. 28, 1829–1838 (2004).

    Article  CAS  Google Scholar 

  19. Wellman, C.L. et al. J. Neurosci. 27, 684–691 (2007).

    Article  CAS  Google Scholar 

  20. Kliethermes, C.L., Cronise, K. & Crabbe, J.C. Physiol. Behav. 85, 479–488 (2005).

    Article  CAS  Google Scholar 

  21. Mozhui, K. et al. J. Neurosci. 30, 5357–5367 (2010).

    Article  CAS  Google Scholar 

  22. Crabbe, J.C., Cameron, A.J., Munn, E., Bunning, M. & Wahlsten, D. Curr. Protoc. Neurosci. 9, 9.26 (2008).

    Google Scholar 

  23. Palachick, B. et al. Alcohol. Clin. Exp. Res. 32, 1479–1492 (2008).

    Article  CAS  Google Scholar 

  24. Daws, L.C. et al. J. Neurosci. 26, 6431–6438 (2006).

    Article  CAS  Google Scholar 

  25. Izquierdo, A., Wellman, C.L. & Holmes, A. J. Neurosci. 26, 5733–5738 (2006).

    Article  CAS  Google Scholar 

  26. Paxinos, K.B.J. & Franklin, G. The Mouse Brain in Stereotaxic Coordinates (Academic Press, London, 2001).

  27. Fiorenza, N.G., Rosa, J., Izquierdo, I. & Myskiw, J.C. Behav. Brain Res. 232, 210–216 (2012).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank Y. Shaham and C. Wellman for valuable comments, and B. Hurd, A. Plitt, D. Fisher and R. Daut for assistance with the CIE procedure. This work was supported by the US Department of Defense in the Center for Neuroscience and Regenerative Medicine (A.H., S.M.F. and O.G.-C.), US National Institutes of Health grants AA019454, AA017668 and AA020911 to T.L.K., C.L. and C.A.M., and AA021043 to K.E.P., US Department of Defense grant PT090344 (T.L.K. and K.E.P.), US National Alliance for Research on Schizophrenia and Depression (T.L.K.), Bowles Center for Alcohol Studies (T.L.K.), and the US National Institute on Alcohol Abuse and Alcoholism Intramural Research Program (A.H., P.J.F., K.P.M., L.D., S.M., G.C., O.G.-C. and M.C.).

Author information

Authors and Affiliations

  1. Laboratory of Behavioral and Genomic Neuroscience, National Institute on Alcohol Abuse and Alcoholism, US National Institutes of Health, Bethesda, Maryland, USA

    Andrew Holmes, Paul J Fitzgerald, Kathryn P MacPherson, Lauren DeBrouse, Giovanni Colacicco, Shaun M Flynn, Sophie Masneuf, Ozge Gunduz-Cinar & Marguerite Camp

  2. Center for Neuroscience and Regenerative Medicine at the Uniformed Services University of the Health Sciences, Bethesda, Maryland, USA

    Shaun M Flynn & Ozge Gunduz-Cinar

  3. Department of Pharmacology, Bowles Center for Alcohol Studies, University of North Carolina, Chapel Hill, North Carolina, USA

    Kristen E Pleil, Chia Li, Catherine A Marcinkiewcz & Thomas L Kash

Authors
  1. Andrew Holmes
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Paul J Fitzgerald
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Kathryn P MacPherson
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Lauren DeBrouse
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Giovanni Colacicco
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Shaun M Flynn
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Sophie Masneuf
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Kristen E Pleil
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Chia Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Catherine A Marcinkiewcz
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Thomas L Kash
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Ozge Gunduz-Cinar
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Marguerite Camp
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

A.H., P.J.F., T.L.K. and M.C. designed the experiments. P.J.F., K.P.M., L.D., G.C., S.M.F., S.M., K.E.P., C.L., C.A.M., T.L.K., O.G.-C. and M.C. collected the data. A.H., P.J.F., K.P.M., L.D., G.C., S.M.F., S.M., K.E.P., C.L., C.A.M., T.L.K., O.G.-C. and M.C. analyzed the data. A.H. wrote the manuscript.

Corresponding author

Correspondence to Andrew Holmes.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–8 (PDF 895 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Holmes, A., Fitzgerald, P., MacPherson, K. et al. Chronic alcohol remodels prefrontal neurons and disrupts NMDAR-mediated fear extinction encoding. Nat Neurosci 15, 1359–1361 (2012). https://doi.org/10.1038/nn.3204

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nn.3204

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