Brain chemical may aid mouse mothering.

The maternal instinct is one of the strongest directives animals possess, making scientists all the more puzzled by a strain of mutant mice in which mothers apparently neglect their offspring.

A research team led by Richard D. Palmiter of the Howard Hughes Medical Institute at the University of Washington in Seattle created the mouse strain several years ago by disabling the gene that encodes an enzyme called dopamine beta-hydroxylase.

This enzyme makes norepinephrine, a chemical that nerve cells release in order to communicate with other cells. Yet plans to study how the absence of this neurotransmitter alters rodent behavior were put on hold when the scientists discovered that the mutant mice die in the womb, apparently from heart failure.

The investigators then found that when they added a synthetic precursor of norepinephrine to a pregnant mouse's drinking water, the mutant fetuses would survive to birth. This precursor, known as DOPS, is converted to norepinephrine by a second enzyme. Once born, the mice reach adulthood without further administration of DOPS.

While studying the reproductive behavior of these mutant mice as adults, Palmiter and his colleague Steven A. Thomas recently noticed that the majority of pups born to mothers lacking the norepinephrine-making enzyme die within days of birth. The dead pups had no milk in their stomachs, even though the mothers were lactating, the scientists report in the Nov. 28 Cell.

They also found that the mutant mice, both male and female, do not promptly retrieve newborns placed away from the home nest.

Curiously, mothers lacking dopamine beta-hydroxylase will nurse and care for foster pups that have been briefly nurtured, and perhaps trained to feed, by normal mothers. Moreover, if injected with DOPS just before giving birth, the mutant females often seemed to take appropriate care of their litter.

"Without norepinephrine, maternal behavior is clearly impaired. Under certain conditions, however, it can be restored," concludes Thomas.

In the 1970s and early 1980s, several research groups offered some hints that norepinephrine plays a role in maternal behavior, notes Michael Numan of Boston College in Chestnut Hill, Mass. More recently, however, investigators have focused on other neurotransmitters, such as dopamine.

"This study will bring people back to looking at norepinephrine," predicts Numan.

Additional behavioral tests of the mutant mice are needed to confirm the flawed maternal behavior, be adds. If norepinephrine's absence is indeed responsible for the poor mothering, researchers will try to determine what brain circuits are involved.

Further studies may compare this mouse strain to one lacking a protein called FosB; the latter strain also show impaired maternal behavior.

"It will be interesting to explore the relationship between norepinephrine and FosB," says Thomas.