Bipolar disorder (BD) is a severe psychiatric disorder characterized by alternating manic/hypomanic and depressive episodes. However, the molecular mechanism of transition between both states is unknown yet. Our study reveals that knockdown of the circadian clock gene Per2 in the hippocampal CA1 induces mania-like behaviors in rats. In contrast, overexpression of Per2 in the same region results in depression-like behaviors, indicating that Per2 expression levels may mediate the manic/depressive phenotype switch. In addition, we found that phosphorylation of the transcriptional factor CREB regulates the expression of Per2 and CREB-Per2 pathway forms a positive feedback loop which underlies the manic/depressive phase transformation.