Dysregulation of CRY1 impairs brain thyroid hormone pathway and promotes anxiety-like behavior in male mice

Background: The circadian clock system plays a crucial role in influencing mood and behavior, with the clock gene Cry1 serving as a core component of the molecular circadian clock. However, the role of CRY1 in anxiety-related behaviors and their underlying mechanisms are poorly understood.

Methods and results: In this study, we investigated the role of CRY1 in anxiety-related behaviors through various behavioral approaches, and assessed potential molecular alterations in key brain regions involved in behavioral responses. We found that male Cry1^-/- (Cry1 knockout) mice developed anxiety-like behavior in both stressed and non-stressed conditions. Administration of CRY1 stabilizer KL201 significantly alleviated anxiety-like behavior in male mice. Further studies suggested involvement of the brain thyroid hormone signaling in CRY1 regulation of anxiety-like behavior, evidenced by markedly reduced brain T3 levels relation to down-regulation of OATP1C1 and DIO2 mediated by CRY1, which underlies neurogenesis deficits and contributes to anxiety. Subsequent in vivo and cell-based experiments confirmed that CRY1 positively regulates the expression of OATP1C1 and DIO2. Mechanistically, CRY1 regulates OATP1C1 and DIO2 through regulating the transcriptional activity of E4BP4. E4BP4 trans-inactivates OATP1C1 and DIO2 via direct binding to its specific response element in the gene promoters.

Conclusion: These findings underscore the critical role of CRY1 in regulating thyroid hormone and anxiety, providing insight into the underlying pathogenesis and potential treatment strategies for mood disorders.