Meddling with the internal biological clock of mice turns them manic, say U.S. researchers.

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SYDNEY: Defects in the body's circadian rhythms could underlie manic-depressive disorder, according to a new study.

Mice with altered daily rhythms have been found to display some of the hallmarks of the 'manic' component of the condition, also known as bipolar disorder. The mice, which carry a mutated version of the circadian rhythm gene Clock, even respond to the drug lithium - used as a mood stabiliser to treat bipolar disorder in people.

The research, led by Colleen McClung from the University of Texas Southwestern Medical Centre, is published this week in the U.S. journal Proceedings of the National Academy of Sciences.

Circadian rhythms - and the genes that make up our internal biological clock - have long been implicated in bipolar disorder, which involves alternating cycles of mania and depression. Most sufferers have disrupted sleep, appetite, and hormonal cycles, which has led researchers to postulate a link between the disorder and abnormalities in the body's circadian rhythms.

McClung's team investigated this link by creating mice with a non-functional version of Clock, one of the most important genes regulating circadian rhythm.

In a series of behavioural tests, these mice displayed symptoms eerily reminiscent of human mania – such as reduced anxiety, hyperactivity and sleeplessness. Like human manics, they also got an increased kick out of cocaine, sucrose, and stimulation of the medial forebrain bundle, a part of the brain implicated in addiction.

"Once we analysed all of the behavioural data and realised that these mice had this unique behavioural profile, that was so similar to human mania, we became very excited," said McClung.

Aside from suggesting an important link between circadian rhythms and bipolar depression in people, these mice could also help researchers study the disorder. One of the reasons why our understanding of a complex mental illness such as this have been limited, is the lack of similar disorders in laboratory animals.

"Taken together, our results indicate that the Clock mutant mice represent a bona fide model of human mania," the researchers wrote. "These mice will be very useful."

"We can't ask the mouse to tell us if it feels euphoric or has feelings of self-importance," said McClung. "However, there have been several mouse models of depression and these mice have lead to the development of effective antidepressant treatments for human patients."

The fact that the mice respond to lithium - the same treatment as humans, is particularly intriguing, commented Matthew Kempton, who researches bipolar disorder at London's Institute of Psychiatry.

"As well as demonstrating that the Clock mutant mice have behavioural responses which appear similar to patients with mania, the behaviour is reversed with lithium treatment," he said.

Up until now, the reason for the effectiveness of lithium in the treatment of bipolar disorder has been mysterious, said Kempton. The mice could be useful for testing new drugs for preventing mania, he added.

The new mouse model of the disease will help uncover the mechanisms by which mood stabilizers like lithium lead to their therapeutic effects, said McClung. "This should allow us to develop better and more targeted therapies in the future."

One notable difference between the mice and humans with bipolar disorder is that they showed no signs of depression, making them 'unipolar', rather than bipolar - and potentially hinting that bipolar disorder is controlled by several genes.