Disruptions in circadian rhythms and dopaminergic activity are involved in the pathophysiology of bipolar disorder, though their interaction remains unclear. Moreover, a lack of animal models that display spontaneous cycling between mood states has hindered our mechanistic understanding of mood switching. Here, we find that mice with a mutation in the circadian Clock gene (ClockΔ19) exhibit rapid mood-cycling, with a profound manic-like phenotype emerging during the day following a period of euthymia at night. Mood-cycling coincides with abnormal daytime spikes in ventral tegmental area (VTA) dopaminergic activity, tyrosine hydroxylase (TH) levels and dopamine synthesis. To determine the significance of daytime increases in VTA dopamine activity to manic behaviors, we developed a novel optogenetic stimulation paradigm that produces a sustained increase in dopamine neuronal activity and find that this induces a manic-like behavioral state. Time-dependent dampening of TH activity during the day reverses manic-related behaviors in ClockΔ19 mice. Finally, we show that CLOCK acts as a negative regulator of TH transcription, revealing a novel molecular mechanism underlying cyclic changes in mood-related behavior. Taken together, these studies have identified a mechanistic connection between circadian gene disruption and the precipitation of manic episodes in bipolar disorder.
Bibliographical noteFunding Information:
This work was supported by funding from the McKnight Foundation, the National Alliance for Research on Schizophrenia and Depression, the National Institute of Mental Health (MH082876), the National Institute on Drug Abuse (DA023988) and the National Institute of Neurological Disorders and Stroke (NS058339). We would like to thank Dr Maisie Lo and members of the Deisseroth Lab for their generosity and assistance in performing the optogenetic experiments. We thank Joe Takahashi for the ClockΔ19 mice. The excellent technical assistance of Heather Buresch, Emily Webster, Edgardo Falcon, Elizabeth Gordon and Ariel Ketcherside is greatly appreciated.