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McClung and Colleagues

Daytime spikes in dopaminergic activity drive rapid mood-cycling in mice
Sidor MM, Spencer SM, Dzirasa K, Parekh PK, Tye KM, Warden MR, Arey RN, Enwright III JF, Jacobsen JPR, Kumar S, Remillard EM, Caron MG, Deisseroth K and McClung CA
Molecular Psychiatry, Published Online

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 the mechanistic understanding of mood switching. In this study, investigators from the Department of Psychiatry found 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. 

Collaborating with her mentor, Dr. Colleen McClung, and other investigators, Dr. Michelle Sidor conducted a study to determine the significance of daytime increases in VTA dopamine activity to manic behaviors.  Dr. Sidor and her colleagues developed a novel optogenetic stimulation paradigm that produces a sustained increase in dopamine neuronal activity and found that this increase induces a manic-like behavioral state. Time-dependent dampening of TH activity during the day reverses manic-related behaviors in ClockΔ19 mice. Additionally, the results of this study showed 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 findings identify a mechanistic connection between circadian gene disruption and the precipitation of manic episodes in bipolar disorder.

Contributors: 
Michelle M. Sidor, PhD, Puja K. Parekh, BS, John F. Enwright III, PhD and Colleen A. McClung, PhD (Department of Psychiatry, University of Pittsburgh)Sade M. Spencer, PhD, Rachel N. Arey, PhD (Department of Psychiatry, University of Texas Southwestern Medical Center)
Kafui Dzirasa, MD, PhD, Sunil Kumar, PhD, Marc G. Caron, PhD (Department of Psychiatry and Behavioral Sciences, Center for Neuroengineering, Duke University Medical Center)

Kay M. Tye, PhD (Department of Brain and Cognitive Sciences, Picower Institute for Learning and Memory, Massachusetts Institute of Technology)

Melissa R. Warden, PhD (Department of Neurobiology and Behavior, Cornell University)

E. Marielle Remillard, BS (Department of Biology, Austin College)

Jacob P.R. Jacobsen, PhD (Department of Cell Biology, Duke University Medical Center)

Karl Deisseroth, MD, PhD (Departments of Bioengineering and Psychiatry and Behavioral Sciences, Stanford University)

This article is published online in the journal Molecular Psychiatry.  Click here to view the abstract.