Circadian genes may be involved in bipolar disorder

Disrupt the gene that regulates the biological clocks in mice and they become manic, exhibiting behaviors similar to humans with bipolar disorder, UT Southwestern Medical Center researchers have found.

In a study available online in the Proceedings of the National Academy of Sciences, scientists from UT Southwestern show that the Clock gene, which controls the body's circadian rhythms, may be integrally involved in the development of bipolar disorder. Circadian rhythms include the daily ups-and-downs of waking, eating and other processes such as body temperature, hormone levels, blood pressure and heart activity.

 "There's evidence suggesting that circadian genes may be involved in bipolar disorder," said Dr. Colleen McClung, assistant professor of psychiatry and the study's senior author. "What we've done is taken earlier findings a step further by engineering a mutant mouse model displaying an overall profile that is strikingly similar to human mania, which will give us the opportunity to study why people develop mania or bipolar disorder and how they can be treated."

Bipolar disorder, also known as manic-depressive illness, is a brain disorder that causes dramatic shifts in a person's mood, energy and ability to function - much more severe than the normal ups and downs that most people experience. About 5.7 million American adults, or about 2.6 percent of the adult population, suffer from the psychiatric disorder.

The study included putting the mutant mice through a series of tests, during which they displayed hyperactivity, decreased sleep, decreased anxiety levels, a greater willingness to engage in "risky" activities, lower levels of depression-like behavior and increased sensitivity to the rewarding effects of substances such as cocaine and sugar.

"These behaviors correlate with the sense of euphoria and mania that bipolar patients experience," said Dr. McClung. "In addition, there is a very high co-morbidity between drug usage and bipolar disorder, especially when patients are in the manic state."

During the study, lithium was given to the mutant mice. Lithium, a mood-stabilizing medication, is most commonly used in humans to treat bipolar patients. Once treated with the drug on a regular basis, the majority of the study's mice reverted back to normal behavioral patterns, as do humans.

The researchers also injected a functional Clock gene protein - basically giving the mice their Clock gene back – into a specific region of the brain that controls reward functions and where dopamine cells are located. Dopamine is a neurotransmitter associated with the "pleasure system" of the brain and is released by naturally rewarding experiences such as food, sex and the use of certain drugs. This also resulted in the mice going back to normal behaviors.

"While the Clock gene is expressed throughout the brain, it's really only been studied in one particular brain region, which is the one that's involved in circadian rhythms," said Dr. McClung. "This is one of the first studies to show that Clock has a major effect on behavior in a different brain region - specifically the one that controls reward responses and mood."

Dr. Eric Nestler, chairman of UT Southwestern's psychiatry department and also a study author, said the research is important because it establishes the first complete mouse model for studying bipolar disorder.

"The lack of an animal model for bipolar disorder has been a crucial limitation in our efforts to better understand the biological basis of the disorder," said Dr. Nestler, who holds the Lou and Ellen McGinley Distinguished Chair in Psychiatric Research. "Dr. McClung's findings are therefore very important for the field and provide fundamentally new directions for one day developing improved treatments."

Other researchers from UT Southwestern's psychiatry department contributing to the study were: Dr. Shari Birnbaum, assistant professor; Dr. Sumana Chakravarty, assistant instructor; Dr. Scott Russo, postdoctoral research fellow; research technicians Ami Graham, Joseph Peevey and Kole Roybal; and Vaishnav Krishnan, MSTP student. Researchers from Harvard University, the Veterans Affairs North Texas Health Care System, Northwestern University and Howard Hughes Medical Institute also contributed.

The study was supported by grants from the National Institute on Drug Abuse and the National Institute of Mental Health.