Based on these results, we hypothesized that the increased anxiety- and depression-like behavior displayed by defeated rats with knock-down of S1PR3 was due to increased expression of TNFα in the mPFC and that knocking down TNFα, but not IL1β, would rescue the anxiogenic and pro-depressive phenotype of rats with reduced S1PR3 in the mPFC. This evidence concerns the gene TNF and major depressive disorder.