Our recent studies have also demonstrated that exposure to chronic restraint stress (CRS) triggered the significant activation of microglia and neuroinflammation induced by high mobility group box-1 (HMGB1), and induced depression-like behaviors in rats subjected to CRS [19], which indicated that stress-activated neuroinflammation might be the key pathway linking stress and depression. This evidence concerns the gene HMGB1 and major depressive disorder.