Gene Controls Aggression, Anxiety in Mice

Altered animals attacked, hid in corners

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HealthDay Reporter

THURSDAY, Jan. 23, 2003 (HealthDayNews) -- In the ongoing crusade to decode the brain chemistry underlying our behaviors, scientists have discovered a gene that appears to control aggression and anxiety.

Researchers at Case Western Reserve University in Cleveland bred genetically altered mice, and then watched as they hid in corners and automatically attacked other approaching mice. They report their findings in the Jan. 23 issue of Neuron.

The only difference between normal mice and the mean-spirited mutants is a single gene: Pet-1. That gene works in the brain by regulating the production of serotonin, an essential neuron that controls communication between brain cells. Serotonin levels are thought to influence emotion, learning memory, and pain detection.

"These small number of neurons have the ability to sprinkle serotonin all over the brain. That's why they have been implicated in so many brain processes and psychiatric disorders. But we know extremely little about them. This is the first gene we've found to control this," says study author Evan Deneris, an associate professor of neuroscience at Case Western.

Such research illustrates a shifting tide in brain science. In the past, researchers focused most of their attention on the later stages of the chemical processes that determine thoughts and behavior. Now they can manipulate the earliest steps in the cycle. For example, instead of targeting the receptors that use serotonin, scientists can now change DNA to remove it completely from the brain.

"We're in the age where we can identify the control points in a cell that allow the cell to function. Once we understand that, we may be better able to treat disorders," Deneris says.

The "knockout mice" in these experiments grew up without serotonin. Although many of their behaviors, such as eating and moving, remained unaffected, the mice acted much more impulsively since the lack of serotonin clouded their judgment, Deneris says.

"These mice have never seen a normal level of serotonin, and that's why we think they suffer from heightened anxiety and aggression," he says. In a future experiment, he plans to add more Pet-1 genes to mice brains, to see if it creates "mellow" mice by boosting their serotonin.

Such testing is instructive but not reflective of normal human brain function, says Dr. Dan Rujescu, head of molecular neurobiology at Ludwig-Maximilians University in Munich, Germany. These mice have no serotonin, but even the most abnormal human brain has at least some amount of it, he says. Moreover, there are other chemicals that also control emotion.

"It's not just one gene, it's a combination of genes," Rujescu says. "In a knockout mouse you can remove a gene and see a large effect. But in humans, or normal mice, you wouldn't see such an effect. The genetic variations that make normal people different from each other are much smaller."

Rujescu studied serotonin levels in 86 people who had shown suicidal tendencies. Although their levels were off slightly, he concluded in a study last year that it wasn't possible to predict a person's risk of suicide by examining their genes.

Still, understanding how genetics influences behavior has become "a major effort by the National Institute of Mental Health," Deneris says.

"We need to identify the genes that are needed for proper neuronal function," he says. "We haven't identified a cure for psychiatric disorders. But with our understanding of this process, we may be able to diagnose people at risk."

More information

To see movies of the altered mice in action, visit Case Western Reserve University. Or to learn more about the genetics of mental disorders, go to the National Institute of Mental Health.

SOURCES: Evan Deneris, Ph.D., associate professor, neuroscience, Case Western Reserve University, Cleveland; Dan Rujescu, M.D., head, molecular neurobiology, Ludwig-Maximilians University, Munich, Germany; Jan. 23, 2003, Neuron

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