Rising Star Awardee Dr. Colleen McClung has identified a molecular mechanism in mice by which disruption in a gene which regulates sleep/wake rhythms results in mania-like behavior.

Someone well-versed in bipolar disorder’s mercurial moods can tell you that disrupting your sleep cycle can result in disruptions to emotional stability-and that the process seems to feed on itself. Clearly, healthy sleep and stable moods are linked-but by what process? Understanding this phenomenon on a molecular level could lead to the development of better treatments for bipolar disorder.

One Mind / Johnson & Johnson Rising Star Award winner Colleen McClung, Ph.D. of University of Pittsburgh has just published a paper in Molecular Psychiatry on her lab’s identification of a molecular mechanism by which the Clock gene, which regulates daily sleep/wake rhythms, also regulates mood. Taking advantage of an original mouse model in which this gene is disrupted in a specific way (ClockÃ_â€ù19), she found that this model simulates human bipolar mood cycling: During the day, mice with this mutation behave analogously to human mania, for example, displaying markedly lower anxiety when exploring open areas or precarious platforms, and partaking of a sweet treat in the form of a sucrose solution much more often than “healthy” wild-type mice did. At night, these mice behave euthymically, i.e. more stably calm. Observing this mouse model’s analogy to bipolar behavior, Dr. McClung and her team set out to figure out the mechanism behind it.

McClung and her team started with a hypothesis. They knew that the mutant mice’s manic-like behavior coincided with acceleration in the firing of dopamine neurons in the brain’s reward center, the ventral tegmental area (VTA). They already knew of evidence implicating boosted dopaminergic activity in human mania, so they hypothesized this mechanism could be a part of their mouse model’s story. They tried directly stimulating wild-type mice’s VTA dopamine neurons optogenetically, with light, and found, indeed, that the mice showed manic-like behaviors.

Next, McClung’s team also knew that an enzyme called tyrosine hydroxylase (TH) accelerates dopamine neuron activity. So, they hypothesized that the disrupted Clock gene in their mutant mouse somehow could not adequately suppress TH during the day, resulting in increased dopamine activity, and thus manic-like behavior. Comparing the neurochemical profiles of the brains of wild-type and mutant mice from varying times of day, they found useful evidence: during the day, the Clock protein suppresses the molecule which promotes TH, but the mutant mouse brain lacked a critical protein that enables this suppression to occur efficiently.

Finally, Dr. McClung and her team hypothesized the mutant mice’s daytime manic-like behavior could be remedied with a drug that suppresses TH. In administering the TH suppressor AMPT to the mutant mice during the day, their prediction was confirmed. “Importantly, all behavioral components of the ClockÃ_â€ù19 mouse manic-like phenotype were reversed to wild-type levels with daytime AMPT treatment,” says McClung’s team.

Putting it all together, McClung’s team has found evidence that a specific mutation (ClockÃ_â€ù19) inhibits the Clock gene’s ability to suppress tyrosine hydroxylase, which in turn dials up dopamine synthesis in the brain’s reward center (the ventral tegmental area) at a time of day when the circuit is not equipped to handle the excess dopamine, and this results in mania-like behaviors.

Can the discovery of this mechanism lead to better, targeted treatments for bipolar disorder and more? McClung and her team hope so: “Given the paucity of effective treatment options for bipolar disorder, the current findings represent a novel therapeutic avenue and extend to a multitude of diseases that involve dysfunction in limbic dopaminergic circuitry.”

We at One Mind are deeply impressed with Dr. McClung’s work, and appreciate the generosity of our donors in enabling us to fund related research in her lab.

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Basic ResearchBipolar DisorderColleen McClungMania