Unfixed light pattern-related circadian disruption impairs circadian-orexinergic-serotoninergic system and induces depression-like behaviors in mice.

Unfixed light pattern (ULP) occurring in shift work can lead to circadian disruption (CD), which has been linked to the increasing risk of depression. However, whether ULP-related CD is a risk factor for depression has remained elusive and the underlying mechanism is poorly understood. In this study, mice were subjected to ULP-related CD and we found that CD mice showed prolonged immobility time in the tail suspension test and forced swimming test. This affective damage effect was exacerbated with a longer duration of CD and was reversed by recovery of CD. Mechanistically, it was demonstrated that expression of clock genes in the suprachiasmatic nucleus (SCN), lateral hypothalamus area (LHA), and dorsal raphe nucleus (DRN) showed different degrees of phase shift and arrhythmicity in CD mice during desynchronization period. Furthermore, we found phase shift but normal amplitude for the expression of SCN cFOS, and mesor decrease and phase shift for the expression of the downstream of SCN--LHA OX-A, DRN OX-A, and DRN 5-HT in mice during desynchronization period, which worsened with longer CD duration and restored after recovery of CD. Altogether, this study suggests that ULP-related CD may be a risk factor for depression and the circadian-orexinergic-serotoninergic pathway might involve in it, which may provide new insights for the prevention and treatment of depression induced by ULP-related CD occurring in shift work.