"Tis education forms the common mind; just as the twig is bent, the
tree's inclined," wrote Alexander Pope in 1734, but he probably wasn't
thinking about DNA methylation and glucocorticoid receptors in rats.
Nevertheless, one of the brightest areas of psychiatric research suggests
that early social experiences give rise to adaptive forms of individual
differences in neural and endocrine responses to stress, and so are relevant
to health risks later in life, Michael Meaney, Ph.D., told listeners at the
fourth annual Conference on the Neurobiology of Amygdala and Stress, held in
April at the Uniformed Services University of the Health Sciences in Bethesda,
Michael Meaney, Ph.D.: Development is a dialogue between genes and the
Credit: Aaron Levin
Meaney is the James McGill Professor in the departments of psychiatry,
neurology, and neurosurgery and director of the Program for the Study of
Behavior, Genes, and Environment at McGill University in
Development is a dialogue between genes and the environment, said Meaney.
Early environmental experiences—like a mother's care or lack of
it—can induce chemical changes on the DNA strand by adding or deleting
methyl groups, altering genetic expression without changing the underlying DNA
These chemical changes are now thought to include gene expression, not just
suppression, as had been previously hypothesized. This interaction can occur
at varying points during development, further increasing the opportunities for
Such epigenetic mechanisms permit a common genotype to produce multiple
Recent research has looked at how early nurturing behavior in rats leads to
such changes in DNA structure and expression and how that later leads to
changes in phenotype.
Mother rats spend some time licking and grooming their infant offspring
during the first week of life. The amount of this activity varies naturally
from one mother rat to another, but remains consistent for each individual
animal throughout her reproductive career. As adults, the offspring of
low-licking mothers show more hypothalamus-pituitary-adrenal (HPA) response to
stress, greater emotionality, and worse performance on some cognitive tests,
compared with the offspring of high-licking mothers. The female offspring of
low-licking mothers also show increased sexual receptivity as adults.
"The adult offspring of mothers that exhibit increased pup licking
and grooming show increased glucocorticoid receptor expression in the
hippocampus, enhanced negative feedback inhibition, and more modest HPA
responses to stress," he said.
Furthermore, cross-fostering experiments show that licking behavior is not
simply determined by heredity, said Meaney.
"Putting pups from low-licking mothers into litters nurtured by
high-licking mothers, or vice-versa, reverses these effects," he
He and other researchers have traced the path that leads from infant care
to adult behavior.
The tactile stimulation of maternal licking activates nerve growth
factor-inducible-A (NGFI-A), which reduces methylation, which in turn
increases the number of glucocorticoid receptors in the hippocampus, said
Meaney. Only unmethylated sites respond to NGFI-A.
Humans, of course, don't exhibit such stereotypic behavior toward their
young, so researchers have looked for analogues. For instance, postmortem
study of hippocampi from the brains of people who committed suicide show fewer
glucocorticoid receptors compared with controls. That association appears even
stronger among suicide victims who had a childhood history of abuse, he
"A social event drives a series of intracellular
modifications," said Meaney. "Variations in parental care may
drive neural structures that regulate stress responses."
One more thing, said Meaney. In rats, at least, pharmacological
manipulations can reverse the phenotype by increasing levels of NGFI-A enough
to drive the overexpression of the glucocorticoid receptors, suggesting that
someday drugs might do something similar for humans. ▪