Mice reveal possible source of depression

Mice missing a specific protein from their brains react to stress differently.

Genetically engineered mice developed an imbalance in a hormone involved in stress responses, and during stressful situations, they behaved as if they were depressed.

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

Their report was recently published in the Proceedings of the National Academy of Sciences.

“A major obstacle to understanding depression has been finding what triggers its onset,” said 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, the researchers explained.

“We wanted to find out if depression stems directly from the inability to sense glucocorticoid in the brain,” said 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 3 weeks of age and continuing until they reach a 95 percent loss at 6 months.

The team felt the gradual loss could simulate the time typical for human development of depression, which commonly begins in late adolescence.

During several stress-related tests, 4- and 6-month-old engineered mice showed an increase in behaviors suggestive of depression. The receptor-deficient mice also showed less interest in pleasurable stimuli.

The depression-like behaviors closely corresponded to physiological changes. Four- and 6-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 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 had not been previously proven.

“Our findings in mice lacking glucocorticoid re-ceptors 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 said. “This may initiate a process leading to depression.”