Credit: Image by S. Fenwick.

'Bad mothers' have long been held responsible for behavioural problems in their children; remember, for example, the now disgraced idea that 'refrigerator mothers' bear the blame for children's autism. In rats, we know that the amount of nursing care a dam lavishes on her pups influences their adult response to stress. New work from Michael Meaney's group, published in Nature Neuroscience, indicates a plausible mechanism to explain how early maternal behaviour might wield such long-term influence over the offspring.

Stress activates the hypothalamic–pituitary–adrenal (HPA) axis, which increases plasma glucocorticoid levels. By means of a negative-feedback loop, glucocorticoids dampen the HPA response. In adult rats that enjoyed high levels of maternal care in their first week of life, glucocorticoid receptor (GR) expression in the hippocampus is increased, making the whole HPA axis more sensitive to glucocorticoid feedback. Possible mechanisms have been suggested for how maternal care might acutely increase GR expression, but how this effect is maintained throughout life remains a mystery.

The regulation of gene transcription is highly complex, and one mechanism that is involved is DNA methylation. Weaver et al. compared methylation of the GR promoter in the adult offspring of high-caring and low-caring dams. In the 'high-care' group, methylation of a particular cytosine in the binding site for the transcription factor NGFI-A was 90% less than in the 'low-care' group. This cytosine is highly methylated in newborn pups of either high- or low-caring dams, but in pups that were nursed (not necessarily born) by a high-caring dam, methylation dropped within six days, and remained low thereafter. Reduced methylation correlated with increased NGFI-A binding to the promoter, which is expected to increase GR transcription.

To perturb the system, the authors infused trichostatin A (TSA), an inhibitor that should indirectly reduce DNA methylation, into the brains of adult rats. As hypothesized, TSA treatment of 'low-care' rats decreased methylation of the vital cytosine, increased NGFI-A binding, and increased GR expression in the hippocampus. Finally, TSA treatment of 'low-care' rats reduced their plasma levels of the glucocorticoid corticosterone under both basal and stressed conditions, implying normalized HPA axis function.

DNA methylation patterns tend to be stable over time in postmitotic cells. Indeed, one of the questions arising from the Weaver et al. study is how exactly the de-methylation of the GR promotor cytosine is accomplished in 'high-care' pups. But the very stability of methylation also offers an intriguing explanation for how the effects of maternal care might last throughout a rat's lifespan.