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

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.

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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.

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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.).

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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.

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Correspondence to Andrew Holmes.

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The authors declare no competing financial interests.

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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

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