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

Abstract

This study reports that the induction of the transcription factor ΔFosB is critical for mice to show resilience to the effects of chronic social defeat stress and for antidepressant responses in susceptible mice. ΔFosB acts to promote resilience by the induction of the GluR2 AMPA glutamate subunit, which decreases the responsiveness of nucleus accumbens neurons to glutamate. 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.