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ΔFosB in brain reward circuits mediates resilience to stress and antidepressant responses

Abstract

In contrast with the many studies of stress effects on the brain, relatively little is known about the molecular mechanisms of resilience, the ability of some individuals to escape the deleterious effects of stress. We found that the transcription factor ΔFosB mediates an essential mechanism of resilience in mice. Induction of ΔFosB in the nucleus accumbens, an important brain reward-associated region, in response to chronic social defeat stress was both necessary and sufficient for resilience. ΔFosB induction was also required for the standard antidepressant fluoxetine to reverse behavioral pathology induced by social defeat. ΔFosB produced these effects through induction of the GluR2 AMPA glutamate receptor subunit, which decreased the responsiveness of nucleus accumbens neurons to glutamate, and through other synaptic proteins. Together, these findings establish a previously unknown molecular pathway underlying both resilience and antidepressant action.

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Figure 1: ΔFosB induction in NAc by social defeat mediates resilience.
Figure 2: Effect of social isolation on ΔFosB and on susceptibility to social defeat.
Figure 3: ΔFosB induction in NAc mediates the antidepressant effect of fluoxetine.
Figure 4: GluR2 has a pro-resilience, antidepressant-like effect in NAc.
Figure 5: AMPA receptor composition is differentially regulated in susceptible and resilient mice.
Figure 6: SC1 has pro-resilience, antidepressant-like effects in NAc.

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Acknowledgements

This work was supported by grants from the National Institute of Mental Health and by a research alliance with AstraZeneca. We thank P. McKinnon and H. Russell for the SC1 cDNA; and I. Maze, R. Oosting, S. Gautron and D. Vialou for discussion and comments on the manuscript.

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Authors and Affiliations

Authors

Contributions

V.V. and E.J.N. were responsible for overall study design. Q.C.L. and V.V. designed, conducted and analyzed the RNA and ChIP experiments. A.J. Robison designed, conducted and analyzed the electrophysiological studies. H.E.C. and V.V. designed and conducted the NBQX pharmacological experiments. Q.C.L., D.M.D., E.L.W. and V.V. performed the stereotaxic surgeries. Y.N.O. cloned SC1 cDNA into the HSV vector. Y.H.O. performed the AP1 luciferase assay. Q.C.L., D.M.D., D.L.W. and V.V. designed and conducted the social isolation experiments. V.V., E.L.W. and A.J. Rush performed the social defeat tests and immunohistochemical quantification. S.D.I., Q.C.L., B.L.W., C.A.B. and V.V. performed and analyzed rat surgery and the forced swim test. E.M. and R.L.N. provided the viral vectors for viral transgenesis. M.A.S., V.K. and O.B. trained V.V. in social defeat and biochemical analysis, and provided quality control over the social defeat data. S.G. and C.A.T. provided the human postmortem brain tissue. V.V. and E.J.N. wrote the paper with the help of the other authors.

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Correspondence to Eric J Nestler.

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The authors declare no competing financial interests.

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Vialou, V., Robison, A., LaPlant, Q. et al. ΔFosB in brain reward circuits mediates resilience to stress and antidepressant responses. Nat Neurosci 13, 745–752 (2010). https://doi.org/10.1038/nn.2551

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