On Assignment for the Investigations section of Pitt Med Magazine at the University of Pittsburgh School of Medicine. My research article on "explorations and revelations taking place in the medical school" highlighted the work of Colleen McClung, PhD, associate professor of psychiatry. At the time, she had discovered the correlation between the genes that control circadian rhythms and those in the mood-related circuits of the brain. She explains how rodents with a mutation in their Clock gene, a model for mania, behave very similarly to rodents with impaired dopaminergic activity.
Read below or download/view PDF of Investigations section.
Goodnight (Manic) Mouse
Modeling the link between mood disorders and the circadian clock
By Nikolas Charles
Spring 2013
It may sound surprising, but like humans, mice can exhibit both depressive and manic behavior. At times, the behavior seems to be linked to the “Clock gene.” Humans have the same gene, which is inextricably linked to the “24-hour rhythm in each of us,” says Colleen McClung, a PhD associate professor of psychiatry at the University of Pittsburgh School of Medicine.
It’s long been known that disturbances in the circadian clock—the master timekeeper of the body’s physiological processes — go hand in hand with mood disorders. (See our Summer 2012 issue cover story, “Sleeping’s Beauty.”)
“However, it wasn’t really understood why the genes involved in regulating circadian rhythms also affect mood,” says McClung. By using viral gene manipulation and pharmacological approaches, McClung has made a direct correlation between the genes that control circadian rhythms and those in the mood-related circuits in the brain. Her data suggest that new compounds that alter the circadian system might be developed into effective therapies.
Working in the Department of Psychiatry’s Translational Neuroscience Program, McClung studies how genes influence circuits of the brain that control mood. She does this by knocking out genes or by breeding mice with different kinds of transgenes— genes that overexpress functional or mutant proteins.
“We’ve used this method to create mice that demonstrate behavioral responses similar to bipolar mania,” she says. “These particular mice have a mutation in the Clock gene (Clock Delta19) that renders this protein inactive.”
The method for creating this Clock mutant mouse was developed by other scientists in the 1990s; but it was McClung who characterized its mood-, reward-, and anxiety related behaviors. Once she discovered that the mutant mice displayed the hallmarks of mania, such as hyperactivity, risk-taking behaviors, decreased anxiety, and lower levels of despair, she began a series of experiments that led to a Rising Star Translational Research Award from
the International Mental Health Research Organization, bestowed in July 2012.
The method for creating this Clock mutant mouse was developed by other scientists in the 1990s; but it was McClung who characterized its mood-, reward-, and anxiety related behaviors. Once she discovered that the mutant mice displayed the hallmarks of mania, such as hyperactivity, risk-taking behaviors, decreased anxiety, and lower levels of despair, she began a series of experiments that led to a Rising Star Translational Research Award from
the International Mental Health Research Organization, bestowed in July 2012.
“The search for better treatment options for bipolar disease has been difficult due to the lack of suitable animal models,” McClung says. “The models that we’re working with are appropriate for screening new compounds that
might be effective in treating this chronic and debilitating disease.”
might be effective in treating this chronic and debilitating disease.”
McClung’s team studied responses to stimuli in the Clock mutants compared to healthy mice, measuring behaviors consistent with mania. The Clock mutant mice were then viven mood-stabilizing drugs (lithium or valproate) for periods of up to 14 days, and then the tests were performed again. The team found that these medications restore healthy behavior in the mice.
The team also identified a group of enzymes known as histone deacetylases (HDACs) that may present better targets in bipolar disorder treatment. HDACs repress the expression of the dopamine regulator cholecystokinin (CCK), among other genes. McClung found that inhibiting HDACs actually counteracts the effects of Clock mutations.
With her Rising Star grant, she is now searching for the best HDAC to take aim at and the best agent to inhibit it.
“Although [lithium and valproate] have proven effective in treating bipolar disorder, their use has been shown to lead to liver and renal impairment, weight gain, nausea, and tremors,” she says.
“Although [lithium and valproate] have proven effective in treating bipolar disorder, their use has been shown to lead to liver and renal impairment, weight gain, nausea, and tremors,” she says.
Her hope is that, by inhibiting specific HDACs, it might be possible “to have the desired results of the drugs without the toxic effects.”
McClung has had several papers on her work with the Clock mouse published, as early as 2007 in Proceedings of the National Academy of Sciences. The most recent was- October 2012 in the European Journal of Neuroscience. Her lab also has current grants from the National Institute of Mental Health and the National Institute of Drug Abuse.