Brain Compound's Anti-Aggression Effects Appear To Reverse In Monogamous Male Rodents

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 new results from researchers at The Johns Hopkins University.

Scientists found evidence suggesting that the male vole's brain chemistry more closely resembles nursing mouse females than it does 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 at Hopkins. "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 byproduct 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 related 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," says Gammie. "Also, while voles are relatively non-aggressive, 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 Hopkins professor of psychology and neuroscience, exposed mated and non-mated 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," Gammie says..

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 is being presented at the annual meeting of the Society for Neuroscience in Miami Beach.