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'Mad mice' provide unique model to study anxiety, hyper-aggression
By Anissa Anderson Orr

David Sweatt, PhD

Even mild-mannered Mickey Mouse would need anger management therapy if he were born without the Pet-1 gene.

Researchers at Baylor College of Medicine and Case Western Reserve University found that knocking out the Pet-1 gene in mice creates an anxious, “super-aggressive” version of the lab animal.

“In one test, we put a mouse in a cage and then introduced a new mouse to environment,” said David Sweatt, PhD, a professor of neuroscience at Baylor. “These mice would immediately attack each other. They were really mean.”

Besides being scary, the mice have another purpose. They are unique study models for psychiatric problems such as anxiety and hyper-aggression.

“It is very difficult to model these types of human behaviors, such as anxiety, fear and aggression in a mouse,” Sweatt said. “This particular mouse line is a new tool, a new way to approach screening for compounds that might affect this behavior.”

One mean gene

The Pet-1 gene, which the super-aggressive mice lack, controls the serotonin system in the brain. Serotonin is a chemical that allows neurons to communicate with one another in the brain and the spinal cord. Scientists don’t know exactly how the serotonin system works, but they think it controls subtle and complex types of behavior, like emotions or social interactions. Antidepressant drugs such as Prozac and Zoloft work by increasing serotonin activity.

Edwin Weeber, PhD

Sweatt and his colleague Edwin Weeber, PhD, an instructor in the division of neuroscience, were studying how serotonin modulates the strength of the connections between the neurons and the hippocampus area of the brain when they learned of the Pet-1 knockout mice developed by Dr. Evan Deneris, an associate professor in the department of neurosciences at Case Western Reserve University School of Medicine.

“What got us interested in studying the knockout mice to begin with was the idea that serotonin might play a role in modulating memory formation,” Sweatt said. “The idea was that your mood might have some influence on your memory capacity. We were interested in categorizing these mice that were missing their serotonin system to see if they had any learning or memory deficits.”

Their focus quickly shifted after putting the mice through the first series of tests. The results were published in the Jan. 23 issue of the science journal Neuron.

“It was shocking how aggressive they were,” Sweat said. “None of us has ever seen anything like it before.”

Be aggressive

Normally, Sweatt’s laboratory puts mice through a series of baseline measurements to see if they have any abnormalities. The researchers only got halfway through their battery of tests when the mice started showing extremely aggressive behavior.

When an intruder was dropped in the cage of a knockout mouse, the mouse frequently attacked it within 10 seconds. Normal mice rarely attacked at all. In another experiment, knockout mice spent less time than normal mice in the center of a test chamber. Mice have a natural tendency to avoid open, unprotected areas, but eventually wander out when they become more comfortable. The knockout mice rarely ventured from the side of the chamber. To test this finding further, researchers put the mice in an elevated maze. The knockout mice spent less time in the center of the maze and none of them moved into the open arms of the maze for the entire five-minute test period.

“They showed clear signs of anxiety,” Sweatt said.

Of mice and men

What can a biting lab animal tell us about the road-raging guy in the SUV? A lot, said Sweatt, since the serotonin system is similar in humans and mice. The Pet-1 gene is also contained in the human genome.

“Less serotonin in some people might lead to the propensity for aggressive behavior, or an anxious state,” Sweat said. “Alternatively, there is the possibility that if you could somehow increase serotonin, you might be able to diminish anxiety, or fear or decrease depressive types of behavior.”

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