Key Role of the CRE Sequence in the <i>Per1</i> Promoter in Mediating the Switch Between Unipolar and Bipolar Depression‐Like Behaviors

The cAMP response element-binding protein (CREB) and Period1 (Per1) have been implicated in depression, but their interactive mechanisms remain unclear. This study investigated the integrative role of CREB and Per1 in depression and explores a potential strategy for rapid antidepressant treatment. Using a chronic unpredictable stress (CUS) model, we conducted behavioral assessments including the sucrose preference test, forced swimming test, elevated plus maze, and open field test. Gene expression was manipulated via stereotaxic surgery and RNA interference (RNAi), while protein levels and viral injection sites were verified through Western blot analysis and immunofluorescence. Additionally, we generated Per1 CRE knockout rats using CRISPR/Cas9, with genotypes confirmed by Sanger sequencing. CUS significantly reduced phosphorylated CREB (pCREB) and PER1 levels in the CA1 region. Both Per1 knockdown in CA1 and CRE sequence knockout induced depression-like behaviors, whereas Per2 knockdown in CA1 produced mania-like behaviors. Notably, CRE knockout in the Per1 promoter increased pCREB binding to the Per2 promoter, upregulating PER2 expression in the CA1 and resulting in depression-like phenotypes that are partially lithium-responsive. Treatment with the adenosine A₁ receptor agonist 2-chloro-N6-cyclopentyladenosine (CCPA) elevated pCREB and PER1 levels in the CA1 and elicited rapid antidepressant effects. These effects were present in heterozygotes but absent in homozygotes with a mutated Per1 CRE sequence. These results revealed the pivotal role of the pCREB-CRE-Per1 pathway in CUS-induced depression and its mediation of rapid antidepressant-like effects via adenosine A₁ receptor activation. Moreover, the CRE sequence in the Per1 promoter may be a critical molecular link to the pathophysiology of bipolar depression.