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Vol 7 n° 2 - New Psychiatric Classification based on Endophenotypes

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of family function and early life events as predictors of

health in adulthood.¹ As adults, victims of childhood

physical or sexual abuse, emotional neglect, family con-

flict, and conditions of harsh, inconsistent discipline are

at considerably greater risk for mental illness, as well as

for obesity, diabetes, and heart disease.^2-17 These difficult

conditions, in part, define the developmental origin of

Keywords: maternal behavior; glucocorticoid receptor; stress response; DNA

methylation; gene expression; histone acetylation; NGFIA (nerve growth fac-

Author affiliations: McGill Program for the Study of Behavior, Genes and

Environment, Department of Pharmacology, McGill University; Douglas

Address for correspondence: Prof Michael Meaney, Douglas Hospital Research

Centre, 6875 Boulevard LaSalle, Montreal, Quebec, Canada H4H 1R3

Early experience permanently alters behavior and physiology. These effects are, in part, mediated by sustained alter-

ations in gene expression in selected brain regions. The critical question concerns the mechanism of these environ-

mental “programming” effects. We examine this issue with an animal model that studies the consequences of varia-

tions in mother–infant interactions on the development of individual differences in behavioral and endocrine responses

to stress in adulthood. Increased levels of pup licking/grooming by rat mothers in the first week of life alter DNA struc-

ture at a glucocorticoid receptor gene promoter in the hippocampus of the offspring. Differences in the DNA methy-

lation pattern between the offspring of high- and low-licking/grooming mothers emerge over the first week of life;

they are reversed with cross-fostering; they persist into adulthood; and they are associated with altered histone acety-

lation and transcription factor (nerve growth factor–induced clone A [NGFIA]) binding to the glucocorticoid receptor

promoter. DNA methylation alters glucocorticoid receptor expression through modifications of chromatin structure.

Pharmacological reversal of the effects on chromatin structure completely eliminates the effects of maternal care on

glucocorticoid receptor expression and hypothalamic-pituitary-adrenal (HPA) responses to stress, thus suggesting a

causal relation between the maternally induced, epigenetic modification of the glucocorticoid receptor gene and the

effects on stress responses in the offspring. These findings demonstrate that the structural modifications of the DNA

can be established through environmental programming and that, in spite of the inherent stability of this epigenomic