The relationship between the circadian protein PER and adolescent depression: the mediating effect of aberrant functional connectivity of suprachiasmatic nucleus-orbitofrontal cortex

BACKGROUND: As a major contributor to the development of major depressive disorder (MDD) in adolescents, circadian rhythm disruption has been linked with aberrant circadian protein levels and suprachiasmatic nucleus (SCN) activity. However, it remains unclear how the function of SCN underlies the association between circadian rhythm disruption and depression among adolescents. METHODS: We recruited 165 subjects, including 114 first-episode drug-naïve adolescents with MDD and 51 healthy controls (HC). All completed clinical assessments, venous blood sampling for detecting circadian proteins (CLOCK, BMAL-1, CRY, PER, CIART, and TIMELESS), and brain magnetic resonance imaging (MRI). We first ascertained group differences in levels of circadian proteins. Then, we examined whole-brain, voxel-wise functional connectivity (FC) differences between groups, using seeds of the bilateral SCN. Correlation analysis and mediation assay were further conducted to investigate the effect of FC in the association between circadian proteins and MDD. RESULTS: The MDD group showed weak rhythmic flexibility and greater rhythmic amplitudes. Concurrently, the MDD group exhibited reduced CRY, CIART, and PER levels but elevated TIMELESS levels. Neuroimaging analyses demonstrated significantly reduced FC between the left SCN and the left medial orbitofrontal cortex (OFC) in the MDD group. Moreover, PER levels were positively correlated with SCN-OFC FC, while negatively correlated with depressive symptoms. Additionally, SCN-OFC FC was found to have a negative correlation with depressive severity. Mediation analysis revealed that SCN-OFC FC mediated the association between altered PER levels and depression symptoms. CONCLUSION: Our study revealed that depression severity in adolescents correlates with circadian desynchronization. These findings reveal the potential value of PER and SCN-OFC connectivity as biomarkers for MDD in adolescents.