Disruptions in circadian rhythms and dopaminergic activity are involved in the pathophysiology of bipolar disorder, though their interaction remains unclear. In this report, Sidor and colleagues studied a mouse model that displays spontaneous cycling between mood states. Mice with a mutation in the circadian CLOCK gene (ClockΔ19) exhibited rapid mood-cycling, with a manic-like phenotype emerging during the day following a period of euthymia at night. Mood-cycling coincided with abnormal daytime spikes in ventral tegmental area dopaminergic activity, tyrosine hydroxylase levels and dopamine synthesis. The authors developed an optogenetic stimulation paradigm that produces a sustained increase in dopamine neuronal activity as well as a manic-like behavioral state. Dampening of tyrosine hydroxylase activity during the day reversed manic-related behaviors in these mice. CLOCK was found to be a negative regulator of tyrosine hydroxylase transcription, which they associated with the cyclic changes in mood-related behavior. Taken together, these studies suggest a mechanistic connection between circadian gene disruption and the precipitation of manic episodes in bipolar disorder.
Sidor MM, Spencer SM, Dzirasa K, Parekh PK, Tye KM, Warden MR, Arey RN, Enwright JF 3rd, Jacobsen JP, Kumar S, Remillard EM, Caron MG, Deisseroth K, McClung CA: Daytime spikes in dopaminergic activity drive rapid mood-cycling in mice. Molecular Psychiatry [Epub ahead of print, Jan. 6, 2015; doi: 10.1038/mp.2014.167.]

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