be simpler. As research progresses, the concepts of genetic and physiological pleitropy, context dependence, and taking a life-span perspective on costs and benefits will be essential.

IDENTIFYING GENE-SOCIAL ENVIRONMENT INTERACTIONS AFFECTING HEALTH AND DISEASE

Early Life Experience

Meaney et al. have conducted a comprehensive series of studies showing that early life events, such as maternal separation, handling, or natural variations in maternal care, induce long-term changes in endocrine and behavioral responses to stress that are observed well into adulthood (Meaney, 2001). Using cross-fostering studies, these authors showed that changes in both maternal behavior and stress reactivity can be transmitted through nongenomic mechanisms across generations (Francis et al., 1999). Moreover, these authors also showed that the changes resulting from differences in maternal care are due to “environmental programming” that permanently alters gene expression and has downstream effects on stress-axis responsivity (Meaney and Szyf, 2005). Such epigenetic programming of stress reactivity is mediated by changes in hippocampal glucocorticoid receptor gene expression that are regulated by differences in maternal care and mediated by methylation of the consensus sequence for the transcription factor NGFI-A, which activates glucocorticoid receptor gene expression in the hippocampus (Fish et al., 2004). Increased DNA methylation prevents NGFI-A binding to the promoter for the glucocorticoid receptor gene and hence inhibits transcription, ultimately reducing expression of hippocampal glucocorticoid receptors (Fish et al., 2004). Reduced receptor levels result in reduced sensitivity to corticosterone-mediated negative feedback, which may result in increased and prolonged reactivity of the HPA axis.

These studies illustrate that socially relevant environmental and behavioral factors can induce epigenetic changes in specific brain regions that translate into long-lasting differences in stress reactivity. These experiments provide an excellent example of the advantages that are found in the use of animal models. Aspects of these findings are now being translated to human subjects (Pruessner et al., 2004). In addition, pre- and postnatal exposure to social stressors has been shown to induce significant effects on social and sexual behavior, endocrine responses, and brain sex steroid receptor distribution in adulthood in guinea pigs (Kaiser et al., 2003; Kaiser and Sachser, 2005), and prenatal social stress also has been shown to masculinize female behavior in adulthood (Sachser and Kaiser, 1996).

It may be assumed from these studies that higher stress reactivity may transfer into greater chronic stress burden, which is known to adversely



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