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Body Clock Disruption Brings on Manic Behavior

New mouse model could help researchers better understand bipolar disorder
wild woman



© ISTOCKPHOTO/SATU KNAPE
In the past, when researchers sought clues in mouse models for insomnia, hyperactivity, irresponsible risk-taking, drug abuse and other behavior associated with mania, they shot up the animals with amphetamines and monitored their actions. But those experiments yielded only limited information.

"Obviously, that's not a great model because you are giving an animal amphetamines; it's not a genetic condition," says Colleen McClung, a psychiatrist at the University of Texas Southwestern Medical Center at Dallas.

So instead of injecting speed into the mice, McClung and several colleagues tested mutant mice, with a single-point mutation in the so-called Clock gene, which helps control the body's circadian rhythms: waking, sleeping and eating times as well as the maintenance of proper body temperature, heart and blood functions, and hormone levels. The researchers studied the mutant mice in several different situations to determine the behavioral impact of the missing genetic component. Their goal was to try to understand what happens during mania in the hope of coming up with successful new treatments.

Their findings, published in the Proceedings of the National Academy of Sciences: the flawed Clock gene induced a manic state in mice that had a profile similar to that of humans suffering from bipolar disorder or manic depression, a condition during which a person cycles from deep depression to manic behavior.

The mutant mice showed increased response to reward stimuli in several hedonic scenarios. When trained that depressing a pedal would trigger an enjoyable electrical stimulation to the forebrain, the mice pressed it more frequently than their wild (unaltered) counterparts. They acted the same way when the reward was a sugar solution. In the presence of cocaine the mutant mice needed smaller doses than the normal mice to activate their reward circuits, indicating that they were hyperactive. McClung notes that manic people, who are prone to drug abuse, shopping sprees, compulsive gambling and other high-impulse behaviors, "tend to find rewarding things more rewarding" than others do.

When the mice were put in high-stress situations, like in wide-open spaces (ostensibly vulnerable to predators, such as hawks), the wild mice appeared more anxious than their mutant brethren. When they were forced to swim, after being dropped in a bucket filled with seven inches of water, the normal mice did not give up as easily as their mutant peers, proving they are less inclined to be depressed. "In every way that we can think to test them, [the mice with the damaged Clock gene] look like bipolar patients in the manic state," McClung says.

After determining that the mutant mice were indeed manic, the researchers treated them with lithium—a mood-stabilizer known to counteract mania in humans by regulating the circadian clock. Mutant mice, after receiving the drug for 10 days, exhibited behaviors more like that of their normal peers. "By looking at what lithium is doing specifically in these mice," McClung says, "we may be able to find out more about the mechanism of action in [mood stabilizers] and find more targeted drugs in the future."

One method that may be used in the future could be rescuing the function of the Clock gene in certain brain regions. Here, the scientists used a targeted virus to return a proper copy of Clock to cells in the ventral tegmental area, a midbrain region critical in the reward pathway involved in production of the pleasure system neurotransmitter dopamine. After the virus was introduced, the mutant mice began to act more like the control animals but were still a bit more hyper, McClung notes.

The researchers believe their findings could help scientists begin to understand at least the mania component of bipolar disorder, which often onsets in early adulthood and affects 5.7 million adults in the U.S. McClung admits that thus far her team has only succeeded in causing the mania associated with the disease. Moving forward, she and her team are studying other genes implicated in circadian-clock function to see if they can get the mice to take on a depressive state.

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