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.
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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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http://www.ncbi.nlm.nih.gov/pubmed/25560763