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 Research & Giving News Article  and 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. These rhythms are controlled by several genes, including one that scientists call Clock. Colleen A. McClung, Ph.D., an assistant professor at the University of Texas Southwestern Medical Center and a 2005 NARSAD Young Investigator, led the research team, whose intriguing results appeared in the April 10 issue of Proceedings of the National Academy of Sciences (PNAS). Eric Nestler, M.D., Ph.D., chairman of UT Southwestern’s Department of Psychiatry and a member of NARSAD’s Scientific Council, also made significant contributions to the study. Disrupt the gene that regulates the biological clock in mice, the team found, and the mice become manic, exhibiting behaviors similar to humans with bipolar disorder. "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," Dr. McClung commented. Bipolar disorder, also known as manic-depressive illness, is characterized by episodes of mania and episodes of depression usually interspersed with periods of relatively normal mood. During the manic phase, affected individuals exhibit elevated mood, irritability, increased activity, reduced sleep, hypersexuality, and increased goal-directed activities. Bipolar disorder in its various forms affects about 2.6 percent of the adult population in the United States and is associated with a high risk for suicide, substance abuse, and vocational disability. Although several animal models for major depressive disorder have been developed, there are no plausible models for bipolar disorder. Considerable evidence accumulated over the last 30 years supports the notion that bipolar disorder involves a fundamental disruption in circadian rhythms, according to Joseph T. Coyle, M.D., of McLean Hospital and Harvard Medical School and a 2004 NARSAD Distinguished Investigator and Scientific Council member, whose commentary on the paper just published by Dr. McClung and colleagues also appears in the April 10 issue of PNAS. Episodes of mania and depression in bipolar disorder generally develop a regular periodicity, Dr. Coyle wrote, often linked to the seasons of the year. Within an episode, disrupted circadian rhythms including the sleep–wake cycle, hormonal secretions, and daily variation in mood are evident. Current treatments to prevent the recurrence of episodes of mania/depression emphasize maintaining a stable daily pattern of activity along with pharmacologic treatment. In the study whose results Dr. McClung and colleagues have just published, lithium was given to the Clock-mutant mice. A mood-stabilizing medication, lithium 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--essentially 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. These injections of protein also resulted in the mice reverting 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. Nestler stressed that the research is important because it establishes the first complete mouse model for studying bipolar disorder. "The lack of an animal model has been a crucial limitation in our efforts to better understand the biological basis of the disorder," he said. "Dr. McClung’s findings are therefore very important for the field and provide fundamentally new directions for one day developing improved treatments." Dr. Coyle, in his commentary, suggested that the mutant Clock model had one important limitation: "it re-creates only the behavioral homologues of mania but not the mood oscillations characteristic of bipolar disorder." This is significant because in the clinic, persistent mania is, in his words, "quite uncommon." While acknowledging this, Dr. McClung emphasized that the new mouse model "is a huge step forward in allowing us to better understand the development of this complex disorder." The study was supported by grants from the National Institute on Drug Abuse and the National Institute of Mental Health. This story has been adapted in part with permission of the University of Texas Southwestern Medical Center. |
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