What does a laboratory mouse have in common with Napoleon? Not much, if the mouse's internal clock is ticking normally. But mutate an essential timekeeper gene, and the rodent develops something akin to bipolar disorder, the mental illness that afflicted the famous French general. The new finding provides the strongest link yet between mood disorders and a disruption of the body's natural rhythms.
Each human body literally marches to the beat of its own drum. Our hypothalamus coordinates more than 100 internal clocks--or circadian rhythms--that orchestrate the timely release of chemicals essential for sleep, appetite, and energy. It's perhaps no surprise then that even minor disruptions of these intricate timepieces can have dramatic effects. Indeed, over the past 50 years, researchers have implicated disrupted circadian rhythms in mood disorders, such as bipolar disorder, where irregular sleeping and eating patterns go hand-in-hand with alternating manic and depressive states.
Now the link has been strengthened by a group of researchers led by psychiatrist Colleen McClung at the University of Texas Southwestern Medical Center in Dallas. The team focused on the Clock gene--a critical player in circadian rhythms (ScienceNOW, 21 April 2005). Under a variety of experimental conditions, mice engineered to have a mutated Clock gene behaved similarly to patients with bipolar disorder. Mutant mice took greater risks, hanging out in an open enclosure 13 times longer than normal mice, for example. (Mice associate such open environments with predators.) In addition, Clock mutant mice ate more cocaine and sucrose, mimicking the addictive behavior of bipolar patients. And like people with the mood disorder, the mutant mice were "cured" with lithium, a medication used for decades to treat the manic-depressive illness. "It's an indication that Clock seems to be very involved in bipolar," says McClung, whose team reports its findings online this week in the Proceedings of the National Academy of Sciences.
"It's an excellent study because it shows for the first time a direct relationship between the Clock gene and manic behavior," says psychiatrist Alessandro Serretti of University of Bologna in Italy. Still, he cautions that scientists shouldn't draw too many parallels between the mouse mutant and humans with bipolar disorder. "Mania can't be due to only Clock genes in humans," he says. "It's much too complex." McClung agrees that the Clock mutants don't completely fit the bipolar bill. So far, she says, the mutant mice have displayed only the manic side of the disorder. Further testing will be needed to see if they get depressed as well.
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