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.