Jan. 17, 2005 Dec. 28, 2004 — Mice missing a specific protein from their brains react to stress differently. The genetically engineered mice develop an imbalance in a hormone involved in stress responses, and during stressful situations, they behave as if they are depressed. Genetic variations in the same protein may be a significant cause of human depression, according to researchers at Washington University School of Medicine in St. Louis.
Their report will be published in the Proceedings of the National Academy of Sciences, appearing on-line at the journal's website during the week of Dec. 27 to 31, 2004 and in an upcoming print issue.
"A major obstacle to understanding depression has been finding what triggers its onset," says Maureen Boyle, predoctoral fellow and first author of the report. "We felt it was important to look at elements that regulate the body's stress system."
In response to stress, the brain signals the adrenal gland to release hormones, including glucocorticoid, a hormone that preserves physiological equilibrium in many organs. Because proper levels of glucocorticoid are important for normal function, the brain closely monitors and regulates the hormone.
People with major depressive disorder release excessive amounts of adrenal hormones, including glucocorticoid, possibly because their brains sense stress differently, according to the researchers.
"We wanted to find out if depression stems directly from the inability to sense glucocorticoid in the brain," says senior author Louis Muglia, Ph.D., associate professor of pediatrics, of molecular biology and pharmacology and of obstetrics and gynecology. "To test this, we developed an animal model that would tell us if changes in glucocorticoid receptor function could impart the animal equivalent of depression."
The researchers engineered mice that lose glucocorticoid receptors from their forebrains, specifically from the cortex and hippocampus, beginning at about three weeks of age and continuing until they reach a 95 percent loss at six months. The team felt the gradual loss could simulate the time course typical for human development of depression, which commonly begins in late adolescence.
During several stress-related tests, four- and six-month-old engineered mice showed an increase in behaviors suggestive of depression. The receptor-deficient mice also showed less interest in pleasurable stimuli, drinking significantly less of a sugar water solution than normal mice.
The depression-like behaviors closely corresponded to physiological changes. Four- and six-month-old engineered mice had significantly higher blood levels of glucocorticoid than normal mice. While normal mice suppressed their production of glucocorticoid when given a synthetic substitute hormone, the engineered mice showed no change in glucocorticoid levels, demonstrating an impairment in their ability to properly regulate their stress response.
The abnormal regulation of glucocorticoid in the engineered mice indicates that glucocorticoid receptors in the cortex and hippocampus—forebrain regions associated with higher thought, memory and emotion—regulate adrenal hormone levels. This regulatory role for forebrain cells has not been previously proven.
"Our findings in mice lacking glucocorticoid receptors suggest that some people may have a genetic makeup that reacts to stressful experiences by turning down the activity of the glucocorticoid receptor gene," Muglia says. "This may initiate a process leading to depression."
Using the engineered mice, the researchers next will seek genes that interact with glucocorticoid receptors and investigate the mechanism of action of antidepressant drugs. The projects will provide a fuller understanding of the underlying causes of depression and could lead to the development of new, more effective antidepressants, according to Muglia.
Boyle MP, Brewer JA, Funatsu M, Wozniak DF, Tsien JZ, Izumi Y, Muglia LJ. Acquired deficit of forebrain glucocorticoid receptor produces depression-like changes in adrenal axis regulation and behavior. Proceedings of the National Academy of Sciences, January 2005.
Funding from the National Institutes of Health supported this research.
Washington University School of Medicine's full-time and volunteer faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children's hospitals. The School of Medicine is one of the leading medical research, teaching and patient care institutions in the nation, currently ranked second in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children's hospitals, the School of Medicine is linked to BJC HealthCare.
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