Early Experiences Change DNA and Thus Gene Expression

“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, Md.

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 Montreal.

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 sequence.

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 variation.

Such epigenetic mechanisms permit a common genotype to produce multiple possible phenotypes.

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 said.

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 said.

“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. ▪