Missing Gene in Mice Linked to Aggression Emil Venere ----------------------------------- Homewood News and Information Serendipity has played a major role in a discovery linking genetics to violent behavior in male mice; what began as research into a specific gene's role in brain damage caused by stroke yielded surprising results. Male mice lacking the gene were unusually aggressive, attacking each other relentlessly and sometimes fatally. Also surprising, the mice without that gene display a dramatic sexual persistence toward females, refusing to back down even when rejected by females not receptive to mating. The research findings could have implications for human behavior, as well. The gene that is missing in the specially bred mouse enables the brain to make the neurotransmitter nitric oxide, a substance that transmits impulses between cells in the brain and nervous system. Nitric oxide is the neurotransmitter found in a number of nerve pathways, or circuits, within brain regions that regulate emotional behavior. The highly aggressive behavior in mice whose brains cannot make nitric oxide appears to be the most pronounced change in aggression ever associated with a neurotransmitter, said Solomon Snyder, director of the Department of Neuroscience at the School of Medicine and a co-investigator in the research. Because the mice's sexual and aggressive behavior are heightened, it appears that removing the gene results in a loss of social inhibition. "Accordingly, nitric oxide may be the neurotransmitter that puts a brake on our social behavior," Snyder said. The research, funded by the National Institutes of Health, was led by Randy Nelson, a behavioral neuroendocrinologist in the Psychology Department of the Krieger School of Arts and Sciences. It was reported in the Nov. 23 issue of the British journal Nature. Previous studies have identified increased aggression in mice after a particular gene has been inactivated. Those mice, however, exhibited other severe physiological and behavioral abnormalities, making it impossible to determine whether the knocked-out gene or the secondary abnormalities were responsible for the aggressive behavior. The mice in the Hopkins study appear normal, and, in fact, they seem to be better than unaltered mice at several tasks that test physical skills and coordination. They also seem to react fearlessly to conditions that unaltered mice would find daunting or disorienting. Nelson, Snyder and their research team plan to conduct studies to find drugs that might reduce the aggressive behavior in the males. The findings could have significant implications for studying the behavior of humans, who are genetically similar to mice, the Hopkins researchers said. They stressed, however, that human behavior is far too complex for one gene to fully explain all violent behavior and issues of sexuality. Considerable work by scientists specializing in the relationships between genetics and human behavior will be necessary to determine the applicability of their findings, they said. "There are so many different physiological pathways involved in aggression and copulation that it's likely that many, many genes contribute to any given behavior," Nelson said. It is possible, however, that some humans who may inherit a defect in the gene could be more likely to experience episodes of uncontrollable or impulsive rage. This behavior often cannot be treated effectively through counseling therapy, the researchers said. It would be relatively straightforward to devise a blood test that would identify defects in the gene, and drugs might one day be developed to counteract the potential effects of the defective gene. The animals used in the research are of a genetically engineered type called "knockouts," products of a process that removes one particular gene so that its role can be evaluated. In this case, scientists at Massachusetts General Hospital in Boston removed--at the embryonic stage--a gene that enables neurons, or brain cells, to make an enzyme needed to produce nitric oxide. The mice produced offspring also lacking the gene, providing a population of animals for scientific study of the gene's effects. Nitric oxide has been the focus of recent research, since its overproduction is implicated in brain damage from vascular strokes. Originally, the researchers intended to use this particular knockout strain to study the neurotransmitter's role in brain damage caused by stroke. But they were puzzled when, in the mornings, they began finding one or two dead animals among each group of five male mice caged together overnight. Soon, they noticed how aggressive the animals were. "We're not used to seeing prolonged fighting in mice," Nelson said. Ted and Valina Dawson, a husband-wife team of Hopkins neuroscientists who were breeding the mice for the stroke research at the School of Medicine, first noticed the behavior. "When we started putting male mice together, we noted that they were fighting a lot, and when you put the male mice in for breeding, the females were screaming a lot," Ted Dawson said. In general, unfamiliar male mice placed in the same cage begin to fight. But the fighting lasts only long enough for one of the males to establish dominance. The other mice then assume submissive roles and the fighting ends. The knockout mice, however, begin fighting almost immediately after being introduced into the same environment, and they keep fighting longer. Also, a female mouse normally is receptive to the male's mating overtures only if she is in estrus. Otherwise, she will not allow the male to mount her. After a short time, the normal male will give up; the knockout males do not. "The male would begin mounting the female and would continue to attempt copulation for hours despite her vocal protests and obvious signs of rejection," Nelson said. The aggressiveness observed by the Hopkins team occurred only in male mice lacking the gene. When researchers introduced an "intruder" female into a cage housing several knockout females, they did not display any aggressive behaviors. That may be, Nelson said, because female mice only fight to protect their young, shortly after giving birth. Otherwise, they do not normally fight each other, so there is no inherently aggressive behavior for nitric oxide to inhibit in the first place. The males are more inclined to display an aggression response, which is inhibited by the gene. Removing the gene, and preventing manufacture of nitric oxide, may remove the inhibition. The researchers also monitored testosterone levels in the mice, since it is an important hormone in male mating behavior and aggression. They found no difference in testosterone levels, however, between normal males and knockout males. Snyder, whose lab has pioneered research into the pivotal role played by nitric oxide as a neurotransmitter, said research with monkeys has demonstrated that "everything about the behavior of nitric oxide [in the brain] and the locations of the nitric oxide neurons is the same in the primates as in mice," he said. "Nitric oxide may perhaps be uniquely important in regulating these types of social behaviors" in people, he said. The human gene that enables brain cells to produce the crucial enzyme, nitric oxide synthase, has been pinpointed on the 12th chromosome.
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