In the current study, we centered primarily upon the effect of miR-301b on depressive-like behaviors in mouse models and revealed that miR-301b could activate the microglia and facilitate the release of inflammatory factors such as TNF-α, IL-Iβ, and COX-2, thereby aggravating the cognitive impairment and inflammation in mice with depressive-like behaviors. This evidence concerns the gene PTGS2 and Cognitive impairment.