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Chronic stress is one of the major causes that lead to major depressive disorder (MDD), which is a prevalent mood disorder worldwide. Lots of MDD patients could not benefit from available medication due to the complex etiology of MDD. Recently, long non-coding RNAs (lncRNAs), molecular switches of downstream genes expression, have been reported to be involved in the pathogenesis of MDD. LncRNA TCONS_00019174 has been implicated in MDD risk and antidepressant effects, However, the effect of lncRNA TCONS_00019174 on antidepressant responses has not been investigated. This study is designed to determine whether altered expression of lncRNA TCONS_00019174 contributes to the depression-like behaviors associated with chronic stress. We found that mice exposed to chronic ultra-mild stress (CUMS) displayed apparent depression-like behaviors and decreased expression of lncRNA TCONS_00019174 in hippocampus. Both changed behaviors and lncRNA TCONS_00019174 expression level were rescued by chronic treatment of imipramine (IMI). Viral-mediated lncRNA TCONS_00019174 overexpression in hippocampal neurons improved behaviors of mice exposed to CUMS. Further, we found lncRNA TCONS_00019174 overexpression upregulated phosphorylated-GSK3β (p-GSK3β) protein and β-catenin in the hippocampus. These findings suggest that lncRNA TCONS_00019174 exerts antidepressant-like effect in mice by activating Wnt/β-catenin pathway, proposing that lncRNAs may serve as a potential therapeutic target for MDD in the clinical application. [ABSTRACT FROM AUTHOR]