A gene engaged in the process of regulating circadian rhythms - daily rhythms, including the wake/sleep cycle - may also play an essential role in the manic phase of bipolar disorder.
Mice having a specific mutation in the CLOCK gene, which is fundamental in regulating circadian rhythms, demonstrated behavior very analogous to manic behavior in humans. Given lithium, a medication that is used for the treatment of bipolar disorder, the mice came back to many of their normal behaviors.
The findings of the research could constitute a launching point for further study into bipolar disorder, whose mechanisms keep on eluding researchers.
"It provides us with a really nice model of mania to be able to learn how mania develops and how the methods of treatment for mania act, due to the fact that a lot of the actions of mood stabilizers have always been a mystery," explained Colleen McClung, research senior author and assistant professor of psychiatry at the University of Texas Southwestern Medical Centre at Dallas. "Bipolar has been complicated to inspect."
David J. Earnest, a professor of neuroscience and experimental therapeutics at Texas A&M Health Science Centre College of Medicine, added: "It really does offer something beyond an associative or correlative observation that circadian rhythms are distressed when patients are developing bipolar disorder. In this animal model, this mutation in the CLOCK gene produces behavioral patterns that are analogous to bipolar disorder."
Researchers have believed for a long time that circadian rhythms might be engaged in psychiatric disorders, especially bipolar disorder.
One thing that is characteristic for bipolar disorder is alternating swings of very high and very low - or depressed - moods, together with alterations in energy and the ability to function.
Nearly all people experiencing this disorder also suffer irregularities in circadian functions such as sleep/wake, hormonal, appetite and body temperature. The main disruptions in the sleep/wake cycle can activate a bipolar episode. And lots of methods of treatment for bipolar disorder, such as lithium, can change circadian rhythms.
There has been some suggestion that the CLOCK gene, one of the most significant genes involved in circadian rhythm, might also be implicated in the disorder. However, the evidence hasn’t been ultimate.
"I am convinced that the correlation has always been there, however the majority of the studies were correlative," Earnest explained. "We really weren’t able to conclude that there was a definitive link between circadian rhythm disturbances. It was just an association."
For the latest research, which emerges in this week’s Proceedings of the National Academy of Sciences, McClung and her team examined mice with a mutation in the CLOCK gene to find out whether there were similarities to humans experiencing bipolar disorder.
Definitely, the mice demonstrated hyperactivity, more risk taking, a preference for "reward" substances including cocaine and sugar, and less depression.
And as the mice received lithium, their behavior became stable.
"When taken at the same time, this whole profile of behaviors is very analogous to bipolar patients when they are in a manic stage," McClung informed. "This is very significant, due to the fact that there hasn’t been a good or full model of human mania. This is the most comprehensive model ever described."
The scientists went one step further in order to try to find out which part of the brain was involved. When they put a functional clock gene back into the dopamine cells of the mice (dopamine is involved in reward and regulation of the mood), they discovered that this also rectified some of the manic behaviors.
"This is thrilling, due to the fact that it identifies the area of the brain where CLOCK is functioning," McClung informed. "We really didn’t know what CLOCK was doing there. It looks like CLOCK is controlling dopamine activities, and that could be what’s producing these sorts of behaviors."
But Earnest also gave out some caveats.
"The general behavior of the mice seems to be very similar to what you see in humans experiencing bipolar disorder," he explained. "However, how do we fully associate what we see in their activity to a clinical situation with regard to bipolar depression? We may argue one way or the other that this is completely indicative of an animal model for bipolar depression."
