Johns Hopkins Gazette: November 27, 1995

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

     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

     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

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