Scientists link missing gene in mice to violent behavior Only males affected by induced defect


New research suggests that males may be like autos with their accelerators welded to the floor, their aggressive and sexual urges held in check by constant application of the brakes.

Scientists at the Johns Hopkins University reported today in the British journal Nature that male mice with a single gene switched off -- so their brains can't produce nitric oxide -- exhibit a startling pattern of behavior.

They appear fearless when hanging upside down from miniature tightropes, lingering while normal mice scramble to right themselves. They chase squealing female mice around their cages for hours, even when the females are not in heat. Male mice typically quickly stop trying to mate with females that are not in estrus.

Most strikingly, genetically altered males fight other males to the death, continuing their assaults even when their victims adopt a submissive posture.

"We've never seen it before," said Dr. Randy J. Nelson, professor psychology at Hopkins. "Mice are very docile creatures." The animals fight only to establish dominance, he said, and rarely kill each other.

Critics of efforts to find biological causes for violence say the Hopkins scientists have been too quick to interpret the actions of the altered mice as aggression, and to suggest that the work may apply to humans.

The Hopkins scientists say their study is the best demonstration so far of the link between brain chemistry and apparently hostile or impulsive behavior.

"These animals were very, very aggressive -- dramatically so," said Dr. Nelson. "They don't seem to recognize social cues which would normally turn off" reckless, impulsive or violent behavior.

Female mice with the inactivated gene did not display any

increase in aggression.

In other respects, the genetically altered mice -- called "knockouts" because they have had a gene "knocked out" -- seem to see, smell and behave normally, Dr. Nelson said. That suggests the loss of the gene doesn't cause brain damage or other neurological problems that might explain their behavior.

The research does not establish a link between an absence of nitric oxide in the human brain and vicious behavior. But the study's authors said their work hints that such a link might exist, at least in some cases.

The brains of rodents and people are very similar, said Dr. Solomon H. Snyder, a Hopkins neurobiologist and a co-investigator in the study.

An examination of the DNA in families with a history of aggression might, he said, turn up a defect in the gene that enables the brain to produce the chemical.

And the research, he said, could lead to new drugs that deliver nitric oxide to the brain, for the treatment of people who have difficulty controlling their anger.

Investigators added, though, that they have not found a gene for crime -- which might be defined as a mythical genetic defect shared by all criminals but absent in the law-abiding population. Other studies, they said, suggest that violence is triggered by a complex web of factors -- social, political and economic.

"When you find a genetic basis for a behavior, that doesn't mean people with the gene are destined to exhibit that behavior," Dr. Nelson said.

"There's all sorts of other environmental influences that have to come into play."

Nitric oxide is a gas that is produced by a relatively small group of brain cells, or neurons, for use as a neurotransmitter. Neurotransmitters are chemicals that neurons use to communicate with each other.

There is evidence that other neurotransmitters play a role in controlling aggressive behavior. Many researchers think there is a link, for example, between low levels of serotonin in the synapses, or gaps between neurons, and violence.

The Hopkins scientists did not set out to study aggression, or any other type of behavior. Instead, they acquired the altered mice from researchers at Harvard to study the effects of stroke on the brain. During a stroke, up to 70 percent of the brain damage is caused by the excess production of nitric oxide.

Dr. Ted M. Dawson, a professor of neurology at Hopkins, said that, soon after establishing a breeding colony of the animals, researchers began finding dead male mice in cages. Typically, four or five males are housed together.

At first, they thought the males were dying because of some physiological problem caused by deleting the gene. Soon, though, they realized they had cages full of killer mice.

Some other researchers were intrigued by the discovery.

"It might be one of the neurotransmitters that puts a brake on our social behavior," said Margaret M. McCarthy of the University of Maryland's School of Medicine.

But she also pointed out that the research only deals with the complete absence of nitric oxide, a situation that may be extremely rare or nonexistent in nature.

Also, she said, it does not demonstrate that lowered levels of nitric oxide produce somewhat violent behavior and elevated levels produce nonviolent behavior. The presence or absence of the chemical may simply act as an on-off switch.

That could reduce its significance in understanding the chemistry of aggression. Serotonin levels, by contrast, are thought to help fine-tune the brain's response to various stressors.

Critics of efforts to link genes and violence attacked the Hopkins study.

"The search for the source of violence in the genetics of individuals is a social cop-out," said Dorothy Nelkin of New York University, author of "The DNA Mystique." "I think it fits with the whole thrust of politics these days to avoid putting responsibility for social problems on society and to place them on individuals."

Dr. Nelkin said the researchers' interpretation of their findings was influenced by the nation's conservative political climate.

"Is it entirely coincidental," she asked, "that they should be observing this effect at the time when the genetics of crime is such a fad? Right now scientists are very alert to, quote, criminal genes."

Evan S. Balaban, a scientist with the Neuroscience Institute in San Diego, said the authors' claims that nitric oxide brakes aggressive behavior is "a gross over-interpretation" of the data.

The paper, he said, presents "a very outdated view of the nervous system. Neurotransmitters are found throughout the brain. They don't do just one thing, like inhibit certain behaviors." They perform several tasks in concert with other neurotransmitters, he said.

"There's a subtext in this article, and that is rape," he said. "I really worry about that. I think that's rather inflammatory."

Dr. Nelson said it might not be accurate to say that the male knockout mice were trying to "rape" females, since they were only persistent, not violent. Male knockouts only bit and scratched other males, not females.

Not only were the altered mice more aggressive, researchers said, they seemed stronger and -- if human emotions can be ascribed to mice -- more determined.

The knockout animals completed tasks more quickly and efficiently, and appeared stronger than their unaltered cousins.

"We have not found anything they're bad at," Dr. Nelson said. "One simplistic view is that they're more motivated -- to find the cookie and eat, to fight, to copulate. That's the simplistic view, but that fits the data."

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