A study published in tomorrow's issue of the journal Science shows that social interaction during a critical period of early life has irreversible effects on maturation of connections to the frontal lobes of the brain, disrupting social interactions and cognitive ability into adulthood. Children suffering severe neglect are known to have cognitive dysfunctions and impairments in social interaction as adults, but the mechanisms were not understood.
Situated behind the forehead, the prefrontal cortex is responsible for complex analysis, abstract thought, motivation, and controlling socially correct behaviors. Interestingly, connections from other brain regions to the prefrontal cortex are not fully developed until the early 20s. A team led by neurobiologist Gabriel Corfas at the Children's Hospital in Boston reared mice in isolated cages for two weeks after they were weaned from their mothers. When these animals reached adulthood, the nerve fibers (axons) connecting to the prefrontal cortex had a thinner coating of electrical insulation (myelin) than in mice reared in standard cages. Myelin insulation, wrapped around axons like electrical tape, greatly increases the transmission speed of nerve impulses. Slower transmission of information to the frontal cortex could degrade performance of this critical brain region. Indeed, behavioral experiments showed that these animals had poor working memory and impaired social interaction as adults.
"Mice are normally interactive socially and tend to be gregarious and investigative, and in some cases also aggressive among themselves, but these mice [reared in isolation] tend to avoid interacting with animals that are placed into their same cage," Corfas says. He notes that disruptions in social interactions in humans are associated with many psychiatric disorders. Prefrontal lobotomy, the infamous surgical procedure that severed connections to the prefrontal cortex, was used to treat schizophrenia, manic depression, panic disorder, and other psychiatric conditions, but the procedure left patients socially detached, unable to focus, and lacking motivation. Postdoctoral fellow and first author of the study, Manabu Makinodan, is also a psychiatrist.
The researchers found that reintroducing mice into a normal social environment after the two-week period of isolation did not restore normal myelination or improve performance on tests of memory and social behavior as adults. Moreover, social isolation later in life did not have the same effects as social isolation immediately after weaning. This shows that there is a sensitive period in early life when social interactions are necessary for normal myelination of axons to the prefrontal cortex.
"The findings make sense and are consistent with what we've observed in clinical studies on effects of early stress on the brain," says Martin Teicher, a neuroscientist in the Department of Psychiatry at Harvard University. Using MRI brain imaging, Teicher and his colleagues have found that early life stresses, including childhood sexual abuse, witnessing domestic violence, and experiencing verbal abuse from parents or peers, affect the structure of the prefrontal cortex and disrupt fiber connections (called white matter) to this and other brain regions. This new study is a major advance, Teicher says, because human brain imaging can only provide correlations, but animal experiments can demonstrate causation and help identify the underlying mechanisms.
Many alterations in brain tissue could produce the differences seen by MRI in children suffering neglect, but by removing the tissue and examining it under an electron microscope, Corfas and colleagues were able to prove that indeed myelin was thinner on these axons in socially isolated mice. What's more, they were able to identify the cellular and molecular mechanism responsible for the thinner myelin and then manipulate them to test whether thinner myelin was sufficient to cause the behavioral effects seen after isolation.
"This is the first study to show that it is enough to change myelin to produce the behavioral effects that you would expect to be caused by isolation," Corfas says. Their experiments showed that a growth factor in the brain, neuregulin-1, was affected by social isolation. By examining a mouse with the membrane receptor for neuregulin-1 impaired in brain cells that make myelin (oligodendrocytes), the researchers found that myelin insulation on theses fibers was thinner than normal. These animals also exhibited the same reduction in working memory and impaired social behavior produced by social isolation.
Research on this brain region by Jay Giedd, Chief of the Brain Imaging Section and Child Psychiatry Branch at the NIMH, has been cited as an explanation for why adolescents lack adult judgment and impulse control. His MRI research showing that connections from other brain regions to the prefrontal cortex are not fully developed until the early 20s was cited in a recent Supreme Court argument as neurobiological basis for ruling out the death penalty and life sentences for young people committing murder. "The regional specificity of the myelin change is intriguing," says Giedd. "One could argue that social cognition/competence is one of the primary tasks of the adolescent brain and that lack of exposure to social stimuli would therefore have a substantial impact." Geidd wonders what it is about social isolation during this critical period of early life that is responsible for these effects.
"We don't know what in isolation is the signal that is responsible," says Corfas. "Our first hypothesis was that the enriched environment was going to change the myelin." Corfas reared some mice in enriched environments that provided increased social interaction, colorful toys, and other objects to stimulate intellectual development of the young animals. "We were surprised to find that the prefrontal cortex was sensitive to the isolation and not the lack of toys in the enriched environment. It could be that isolation for mice is a kind of stress."
Heidi Johansen-Berg, Professor of Cognitive Neuroscience at John Radcliffe Hospital in Oxford, England, who uses human brain imaging to study how environmental experience changes the structure of the brain, says, "This research adds to a growing body of evidence showing that experience can alter brain wiring. The link between social experience and brain wiring is important... [It] raises hope for potential drug interventions to help to reverse effects of adverse social experiences."
Corfas is hopeful that pinpointing neuregulin-1 as a key molecule controlling myelination will help identify new drug targets for treating such psychiatric conditions and also for treating other disorders of myelin, such as multiple sclerosis.
Corfas notes that white matter disruptions in this brain region have been related to schizophrenia, and variations in the gene for the neuregulin-1 receptor are also associated with the disorder. Mutation in this gene is not enough to cause disease, but Corfas speculates that an interaction between variants of this gene and environmental stresses could contribute to schizophrenia and to other neuropsychiatric disorders such as PTSD, depression, or anxiety disorders. "We are not saying that isolation is producing schizophrenia," he says. "Rather that people with alterations in the neuregulin genes could be more sensitive to environmental stresses that could cause defects in myelination and contribute to neuropsychiatric disorders." Regardless, even in individuals with no genetic problems, connections to the frontal lobes will not develop normally without social interaction in early life.
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