Mice study may offer insight into depression

ST. LOUIS -- Mice whose brains lack a specific protein react differently to stress than other mice, possibly offering a clue into the source of human depression, researchers at Washington University said in a study released Monday. The St. Louis researchers, using genetically engineered mice, found they developed an imbalance in a hormone involved in stress response. During stressful situations, those mice behave as if they are depressed. The study will be published in an upcoming issue of Proceedings of the National Academy of Sciences and appears on the journal's Web site this week. Depression affects more than 23 million adult Americans each year, according to the Chicago-based Depression and Bipolar Support Alliance.

The organization called it the most common serious brain disease in the United States.

The research was welcome news to Sue Bergeson, vice president of the organization.

"The treatments we have now are effective for some people, but others don't receive benefits," Bergeson said. "The possibility down the line for treatments based on this missing protein could mean better treatment, fewer side effects and even the possibility of a cure."

Genetic variations in the same protein may be a significant cause of human depression, the researchers said.

"A major obstacle in understanding depression has been finding what triggers its onset," said Maureen Boyle, predoctoral fellow and first author of the study. "We felt it was important to look at elements that regulate the body's stress system."

The brain responds to stress by signaling the adrenal gland to release hormones, including glucocorticoid, which preserves physiological equilibrium in many organs, researchers said.

People with serious depression release excessive amounts of adrenal hormones, including glucocorticoid, and that could cause their brains to sense stress differently, the researchers said.

"We wanted to find out if depression stems directly from the inability to sense glucocorticoid in the brain," said Dr. Louis Muglia, senior author of the study.

Researchers engineered mice that gradually lose glucocorticoid from about three weeks of age until they reach 95-percent loss at six months. The gradual loss was aimed at replicating a course typical for development of depression in humans, which commonly begins in late adolescence.

During stress-related tests, the engineered mice showed an increase in behaviors suggesting depression as well as less interest in pleasurable activities. For example, they drank less of a sugar water solution than normal mice.

The depression-like behaviors corresponded to physiological changes, according to the study. The engineered mice had significantly higher blood levels of glucocorticoid than normal mice.

Normal mice suppressed production of glucocorticoid when given a synthetic substitute, but the engineered mice showed no change in glucocorticoid levels. Researchers said that demonstrated an impairment in their ability to properly regulate stress response.

Researchers said they will next seek genes that interact with glucocorticoid receptors in hopes of determining the causes of depression. They hope the work can lead to the development of more effective antidepressants, Muglia said.

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On the Net:

Washington University: http://www.wustl.edu

Proceedings of the National Academy of Sciences: http://www.pnas.org/

Depression and Bipolar Support Alliance: http://www.dbsalliance.org/