The male prairie vole's interest in defending his pups, an oddity in male rodents, may come in part from his brain's production of a compound linked to aggressive behavior in mice, according to recent results from researchers at Johns Hopkins.

Scientists found evidence suggesting that the male vole's brain chemistry more closely resembles that of nursing mouse females than that of his feckless male mouse counterparts, an intriguing possibility that could help researchers begin to tease apart some of the complex biochemical roots of mating-related behaviors.

"By focusing on these specialized behaviors, we're starting to pick up on some important similarities in the ways they may be triggered," says Stephen Gammie, a postdoctoral fellow in the Psychology Department in the Krieger School of Arts and Sciences. "When they and their pups are approached by a stranger, both the male vole and the female mouse with pups experience increased production of a compound called citrulline in the brain."

Citrulline is a by-product of the reaction brain cells use to produce the messenger compound nitric oxide, which suggests that nitric oxide plays a role in turning on these forms of aggression.

Hopkins scientists began to investigate nitric oxide's relationship to aggressive behavior four years ago, when they found that a line of genetically engineered mice produced to study brain damage from stroke had suffered an unexpected side effect. The males among the mice were unusually aggressive, relentlessly attacking other males and ignoring female rejection of attempts to mate.

Researchers had given the mice a damaged form of the gene for a protein known as nitric oxide synthase, theoretically leaving the mice with little or no nitric oxide in their brains.

Earlier this year, researchers studied the effects of the modification on female mice. Instead of gaining increased aggressiveness like the males, the females lost their aggressive behavior in the one context where it normally showed up, when they were nursing pups and a strange male mouse came around, putting the pups in danger of an attack.

For the new study, scientists switched over to voles, which are also rodents and look like a stout mouse or rat, but are more closely re-lated to lemmings and muskrats than to mice.

"Voles were interesting to us because, as in humans, the males are monogamous and help take care of the pups they produce," Gammie says. "Also, while voles are relatively nonaggressive, previous research had shown that males experience a dramatic increase in aggression toward intruders after mating."

For the new study, Gammie and co-author Randy Nelson, a professor of psychology and neuroscience in the Krieger School, exposed mated and nonmated male voles and female voles with pups to intruders, and then examined the levels of citrulline in their brains.

They found consistently higher levels of citrulline in the mated males and females with pups--the animals that would aggressively confront a stranger. The increase was focused on an area of the brain known as the paraventricular nucleus.

"That area is located in the hypothalamus, a part of the brain where environmental stimuli are integrated with internal signals from the brain, and a response begins to be produced," says Gammie.

Researchers plan to see if they can suppress nitric oxide production in the voles with a drug. If so, they'll test to see if using this drug in mated male voles reduces their aggression levels. Scientists may also test the possibility of links between nitric oxide and the monogamous behavior of the voles.

Gammie and Nelson's research was funded by grants from the National Institutes of Health and the National Institute of Mental Health. It was presented at the recent annual meeting of the Society for Neuroscience in Miami Beach.