Circadian rhythm abnormalities are strongly associated with bipolar disorder, however the role of circadian genes in mood regulation is unclear. Previously, we reported that mice with a mutation in the Clock gene (ClockΔ19) display a behavioral profile that is strikingly similar to bipolar patients in the manic state.
Here, we utilized RNA interference (RNAi) and viral-mediated gene transfer to knock-down Clock expression specifically in the ventral tegmental area (VTA) of mice. We then performed a variety of behavioral, molecular and physiological measures.
We found that knock-down of Clock specifically in the VTA results in hyperactivity and a reduction in anxiety-related behavior which is similar to the phenotype of the ClockΔ19 mice. However, VTA specific knock-down also results in a substantial increase in depression-like behavior, creating an overall mixed-manic state. Surprisingly, VTA knock-down of Clock also altered circadian period and amplitude, suggesting a role for Clock in the VTA in the regulation of circadian rhythms. Furthermore, VTA dopaminergic neurons expressing the Clock shRNA have increased activity compared to controls, and this knock-down alters the expression of multiple ion channels and dopamine-related genes in the VTA which could be responsible for the physiological and behavioral changes in these mice.
Taken together, these results suggest an important role for CLOCK in the VTA in the regulation of dopaminergic activity, manic and depressive-like behavior, and circadian rhythms.