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Brain stimulation alters depressive symptoms in mice

Findings may point the way toward treatment in people

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Signs of depression can be turned on and off in mice with the flip of a switch. Activating or silencing the behavior of certain brain cells with laser light causes the animals to change their depressive behavior, two new studies find.

Although the experiments were done in rodents, the results have direct relevance to human depression, says neurologist Helen Mayberg of the Emory University School of Medicine in Atlanta. The new work may point out places in the human brain that doctors can similarly stimulate to treat depression.

The results, published online December 12 in Nature, took advantage of a technique called optogenetics, which allows scientists to control nerve cell behavior with a tiny fiber-optic light. In the studies, mice were genetically engineered to harbor nerve cell proteins that respond to light. The researchers could make certain nerve cells fire off messages by shining blue light, and quiet them by shining yellow light.

These cells, which produce the chemical messenger dopamine, nestle in a brain region called the ventral tegmental area, a spot known for handling rewards. This system may be skewed in people with depression, since the disorder often keeps people from responding normally to things that used to be enjoyable.

One tiny fiber-optic flash had an instant and profound effect on the mice’s behavior, says psychiatrist and neuroscientist Karl Deisseroth of Stanford University, who coauthored both papers. “That was pretty amazing for us.”

Surprisingly, the effects depend on what kind of stress the animal experiences. When mice experience low-grade chronic stress for days, these dopamine neurons have a straightforward role in depressionlike behaviors: Crank up the cells’ activity, and signs of depression go away within seconds. Hamstring the cells, though, and signs of depression, such as despair and disinterest in formerly pleasurable things (like sugar water), appear.

The second study, led by Ming-Hu Han of Mount Sinai School of Medicine in New York City, tested the same cells’ role in handling more severe stress. After mice had been subjected to an intense bout of stress brought about by exposure to another dominant mouse, more light-driven activity of these dopamine neurons made mice shrink away from another mouse a day later. These mice also didn’t care for tasty sugar water as they normally would. Han and his team found that only a particular kind of nerve cell activity — a machine gun–burst of rapid firing — caused this change. A slower, steadier pattern didn’t trigger the same shift.

“Both studies are consistent in implicating dopamine in depression, and highlight the need for further research in this area,” says neuroscientist Paul Kenny of the Scripps Research Institute in Jupiter, Fla. Especially puzzling, he adds, is the fact that dopamine’s role seems to change depending on the type of stress.

In addition to studying the nerve cells in their home base in the ventral tegmental area, the researchers also explored the cells’ external connections.  Only the cells that send messages to a brain region called the nucleus accumbens could change depressionlike symptoms, researchers found.

With more detailed studies of these cells and this pathway, scientists may eventually gain a deeper understanding of how the human brain creates and alleviates depression. “In this way, bit by bit, we can piece together the circuitry,” Deisseroth says. “It’s a long process that’s just starting, but we have a foothold now.”

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