Early Neglect, Social Isolation Linked to Cognitive Dysfunction

Deborah Brauser

September 18, 2012

September 18, 2012 — Severe neglect during childhood may lead to abnormal myelination and subsequent long-term cognitive and social impairment, new research suggests.

Investigators from Boston Children's Hospital note that this is the first study to identify the mechanism by which these impairments arise. They found that early-life social isolation can impede the maturation of oligodendrocytes, which make up white matter, leading to a decrease in the production of brain myelin.

Although this is a preliminary study that assessed mice, the researchers write that in the future, these disruptions could potentially be targeted with medications.

"There were a few surprises with this study, including that isolation had such an impact on myelination in these mice, yet an enriched environment did not," senior investigator Gabriel Corfas, PhD, professor in the Departments of Neurology and Otolaryngology at Harvard Medical School in Boston, Massachusetts, and from the FM Kirby Neurobiology Center at Boston Children's Hospital, told Medscape Medical News.

Dr. Gabriel Corfas

Changes in white matter and myelination have been linked in past research to several psychiatric disorders, including schizophrenia.

"Having both too much and too little myelination is bad. This is a pathway that requires very careful regulation," said Dr. Corfas.

The study is published in the September issue of Science.

Impaired Social Interaction

Myelin is "the fatty insulation on nerve fibers that helps them transmit long-distance messages within the brain," explained Dr. Corfas. It is also produced by oligodendrocytes.

For this study, mice were placed into either a standard 4-mice-per-cage environment; into a cage by themselves; or into an "enriched environment," which included a large cage with a total of 8 mice, as well as toys.

Four weeks later, all mice were given a social interaction test and a working memory/non-matching-to-place test.

Results showed that when isolation began 2 weeks after weaning (called "the critical period"), oligodendrocytes did not reach maturation in the prefrontal cortex, the brain region responsible for both cognitive function and social behavior. These mice had reduced myelin basic protein and myelin-associated glycoprotein, and thinner coatings of myelin on nerve fibers.

The socially isolated mice also had less neuregulin-1, a protein important in the development of the nervous system.

"These findings indicate that social experience regulates prefrontal cortex myelination through neuregulin-1/ErbB3 signaling," write the investigators.

In addition, these mice had impaired social interactions and working memory.

Shaping the Brain

The researchers note that the effects were timing-dependent. The mice that were isolated during the critical period never regained lost functioning — even after being placed back into a social environment. However, those isolated at a later time did not experience any dysfunction.

"Our findings indicate that the effects of childhood isolation and neglect on adult mental health might be caused, at least in part, by alterations in oligodendrocytes and myelin development," write the researchers.

"In general, the thinking has been that experience shapes the brain by influencing neurons," said Dr. Corfas in a release.

"We are showing that glial cells are also influenced by experience, and that this is an essential step in establishing normal, mature neuronal circuits. Our findings provide a cellular and molecular context to understand the consequences of social isolation," he added.

The study was supported in part by a grant from the National Institute of Neurological Disorders and Stroke, by Lori and Joel Freedman and Nara Medical University, and by an Intellectual and Developmental Disabilities Research Center grant from the National Institutes of Health. The study authors have disclosed no relevant financial relationships.

Science. 2012;337:1357-1360. Abstract