Induction of ΔFosB in the periaqueductal gray by stress promotes active coping responses

We analyzed the influence of the transcription factor Delta FosB on learned helplessness, an animal model of affective disorder wherein a subset of mice exposed to inescapable stress (IS) develop a deficit in escape behavior. Repeated IS induces Delta FosB in the ventrolateral periaqueductal gray (vIPAG), and levels of the protein are highly predictive of an individual's subsequent behavorial deficit-with the strongest Delta FosB induction observed in the most resilient animals. Induction of Delta FosB by IS predominates in substance P-positive neurons in the vIPAG, and the substance P gene, a direct target for Delta FosB, is downregulated upon Delta FosB induction. Local overexpression of Delta FosB in the vIPAG using viral-mediated gene transfer dramatically reduces depression-like behaviors and inhibits stress-induced release of substance P. These results indicate that IS-induced accumulation of Delta FosB in the vIPAG desensitizes substance P neurons enriched in this area and opposes behavioral despair by promoting active defense responses.