Brain’s white matter diminished in isolated mice

Changes in the brains of mice that were isolated as young pups may help explain the profound behavioral problems of severely neglected children. The mouse experiments suggest that neglect during a specific developmental window irreversibly stunts brain development, researchers report in the Sept. 14 Science.

Over the last decade, researchers have catalogued brain deficits and behavioral problems in Romanian orphans who were raised in bare-bones environments with little social stimulation. Many of these children display hyperactivity, impulsivity and compulsive behavior such as arm flapping. Although superficially friendly, these kids have trouble forming meaningful relationships.

By studying mice that had been isolated early in life, researchers led by Gabriel Corfas of Children’s Hospital Boston and Harvard Medical School hoped to uncover how social deprivation can affect the developing brain. After the mice had weaned, the researchers put them into one of three environments: One was a deluxe suite, enriched with fresh toys every other day and populated by friends of similar ages, one was a standard laboratory cage holding four mice, and one was a holding cell for total isolation.

After two weeks, mice in the deluxe suite and the regular cage showed no abnormalities in their behavior or brains. But mice that were isolated showed big changes. These animals were socially stunted, showing less signs of exploratory behavior and a diminished working memory. What’s more, the researchers uncovered stunted development in the brain’s white matter, which helps nerve cells communicate.

In a brain region called the prefrontal cortex, isolated mice had less of a fatty insulating substance called myelin that wraps around nerve cells and helps carry their messages. This part of the brain is thought to be crucial for high-level tasks like social interactions. Myelin-making cells called oligodendrocytes were also stunted. Normally these cells have elaborate, winding tendrils full of complex branches. But isolated mice’s oligodendrocytes were smaller and less elaborate, with fewer branches. The result “shows how sensitive the development of myelin is to experience,” Corfas says.

The two-week period after weaning was critical. If isolation happened three weeks after weaning, the mice didn’t show these deficits. Nor could the isolation effects be reversed later by moving the isolated mice into a better situation.

“What I find fascinating is that this is the neurobiological counterpart of the behavioral changes,” says pediatric neurologist Harry Chugani of Wayne State University in Detroit and Children’s Hospital of Michigan.

This result echoes what Chugani and his colleagues have seen in their studies of neglected Romanian orphans. Children moved from an orphanage to a foster home before age 2 do much better than children removed later. During this window, social interaction has a profound effect on the brain, Chugani says. “The brain demands that you present it with a certain environment.”

Corfas and his team also turned up some clues about how social isolation can lead to these brain changes. When the team reduced production of a molecule called ErbB3 receptor protein, mice raised in an enriched environment acted more like mice raised in isolation. They also found that production of another protein, called neuregulin-1, is muted by isolation.

These molecules have been implicated in schizophrenia and bipolar disorder, Corfas says, as have alterations in white matter in the brain — raising the possibility that the effects of social isolation could be similar to what happens in those disorders.

For now, Corfas says, the team is looking for a way to undo the harm.