Experiments reveal how genes can change behavior

By William J. Cromie

Gazette Staff

It was a surprising and puzzling result. The mice looked normal enough, but they would not nurse their newborn pups. Most of the offspring died from neglect.

Researchers in the laboratory of Michael Greenberg, professor of neurology at Children's Hospital, had deleted a gene from the negligent moms. Called fosB, the gene is also present in humans, and the scientists were trying to determine its function. Evidence already existed that a close relative, c-fos, played a role in the daily sleep/wake cycle and, possibly, in learning and memory. One good way to find out what a gene does is to breed animals without the gene then compare them to normal animals.

"At first, the mutant mice looked completely normal," notes Jennifer Brown, an M.D.-Ph.D. student who did the experiments. "But when we mated the mutants, we found that both parents neglected their offspring. The mothers left the pups scattered around the cage, and did not nurse them. When we placed some of the pups with normal mothers, they did fine."

The inescapable conclusion: fosB is crucial to nurturing behavior and survival of the young. "It is the first gene found to be involved in nurturing behavior," Greenberg says.

That doesn't mean one gene determines one type of behavior, nature directly driving nurture. Biology is much more complex. Rather, fosB becomes activated by a change in the environment; in this case, the presence of newborn pups. FosB then turns on other genes, and the end result is an adaptive response to a change in an animal's surroundings. Without the gene, there's no response.

Greenberg strives to discover which genes get involved in which behaviors. He wants to know exactly how they work, not in general terms, but on a molecule by molecule level. "The more we understand what goes on within cells, the greater the potential for finding treatments when something goes wrong," he says.

For example, researchers know certain factors can activate genes in brain cells in a way that contributes to the cells' degeneration. Knowing precisely how this happens raises the possibility of finding new ways to treat maladies like Alzheimer's, Parkinson's, Huntington's, and Lou Gehrig's diseases.

"Eventually, it might be possible to develop drugs that slow, even stop, the loss of cells underlying such problems," Greenberg speculates. "Since aging also is associated with degeneration of brain cells, it may even be feasible to selectively enhance the survival of cells involved in learning, memory, and other cognitive functions that deteriorate with age."

How Brains Change

Greenberg focuses his investigations on the fos family of genes, because they are among the first to be switched on in situations ranging from sleep and alertness to brain development and disease.

He is specifically attempting to puzzle out how fosB exerts major effects on nurturing behavior. Control of such behavior seems to involve fosB in the preoptic area of the hypothalamus, a cherry-sized knob of brain cells located directly behind the eyes. This area is known to play a critical role in the nurturing behavior of not only mice but humans and other mammals.

When female or male mice become exposed to pups that are not their own, they do not nurture them at first. But repeated exposure to the pups, particularly to their smell, elicits a change in the working of the brain.

Projections of brain cells extend from the nose to the amygdala, a center of emotion in humans, and from there to the preoptic area. The connections continue to the brain stem above the spinal cord, where signals to muscles prompt the mother to retrieve her pups.

Knocking out fosB in the preoptic area short-circuits this response. Half of the knockout moms did not retrieve pups and actually moved away from them; the other half moved no more than one pup back to the nest. Normal mothers retrieved pups within minutes.

How fosB works in normal moms remains a mystery. Greenberg suspects that it stimulates production of hormones that, by way of nerve cells, control nurturing behavior.

"The same kind of mechanism may underlie a variety of other adaptive behaviors including associative learning, the sleep/wake cycle, and drug addiction," he notes. "A biological regulator, like a fos gene, stimulates responses from other genes in brain cells, strengthening connections between them and making brain circuits sensitive to a memory or learning experience, the pleasures of a drug, or the time of day."

Ties to Learning and Sleep

Greenberg and researchers at other labs have found evidence that c-fos, a genetic sibling of fosB, also turns on during nurturing, as well as during learning, memory, and daily sleep/wake rhythms. In reaction to sights, sounds, emotions, or other inputs from the senses, so-called neurotransmitters are released. Among other things, these chemicals attach to the surface of brain cells, and, by a complicated signaling pathway, turn on genes in the core, or nucleus, of the cell. When that happens, brain cells change in a way that can increase a mouse's or human's behavioral response to its surroundings.

Nurture alters nature which alters nurture.

As an example, mice placed in a box and given a series of electric shocks, soon associate the two. When put in the box, they show fear even when no shocks occur. However, when researchers block a chemical that turns on c-fos, the mice never develop memories, hence a fear of the box.

"Learning and memory are responses to the environment," Greenberg points out. "So is becoming sleepy when it gets dark, and so is nurturing. In fact, we have identified a signaling chemical, a protein called CREB, which turns on both c-fos and fosB."

Besides playing a role in behavior, master-switch genes like those of the fos family are thought to contribute to the survival or death of brain cells in aging or disease. Laboratory discoveries in this area of research have prompted drug and biotechnology companies to test chemicals that show potential as drugs for treating degenerative diseases such as Alzheimer's and Parkinson's diseases."

One approach is to design small molecules capable of mimicking or replacing faulty components of the signaling system that turns genes on and off. Another approach involves injecting the factors directly into the brain or spinal cord. This has been done, unsuccessfully so far, in attempts to curb the muscle wasting of Lou Gehrig's disease.

Brain cell degeneration is also part of normal aging, so it, too, is a plausible target for this kind of treatment.

"People should be aware that genes, in addition to culture and other factors in the environment, play an important role in determining behavior," Greenberg says. "Without any question, detailed knowledge of how this happens offers great promise for understanding the brain and treating diseases that affect it."