Maternal care as a model for experience-dependent chromatin plasticity? Michael J. Meaney 1 and Moshe Szyf 2 1 Douglas Hospital Research Center, 6875 LaSalle Boulevard, Montre ´ al, Que ´ bec H4H 1R3, Canada 2 Department of Pharmacology and Therapeutics, McGill University, 3655 Sir William Oslar Promenade, Montre ´ al, Que ´ bec H3G 1Y6, Canada It is widely acknowledged that the nature of the maternal care a child receives can have long-term reper- cussions, and that children raised in deprived environ- ments can have severe cognitive and behavioural difficulties that last into adulthood. The mechanisms underlying these effects are not understood, but recent data from rodents provide insight into a potential molecular mechanism. Like humans, rodent maternal behaviour towards offspring can effect long-term changes in responses of the offspring to stress through- out the rest of their lives. Remarkably, these changes reflect permanently altered gene expression, so-called ‘environmental programming’, and its downstream effects on the hypothalamic–pituitary–adrenal axis. This review discusses the nature of this environmental programming – the mechanism by which it occurs in rats, its long-term implications, and opportunities for its reversal in rodents and ultimately in humans. Introduction The quality of early family life influences health through- out life [1]. In part, such influences appear to be mediated by effects of parent–offspring interactions on the develop- ment of neural systems, including those that mediate responses to stress [2–6]. There is evidence in humans that parental care can affect endocrine and autonomic responses to stress that endure into adulthood. Dramatic examples derive from studies on the effects of sexual and/or physical abuse on stress responses [7]. These findings represent environmental programming – instances where exposure to an environmental event in develop- ment stably alters phenotype in adulthood. A model for such programming effects lies in older studies on hand- ling of newborn rats. Such handling decreases the mag- nitude of hypothalamic–pituitary–adrenal (HPA; Figure 1) responses to stress in adulthood [8–10]. Interestingly, these effects are mediated by changes in maternal care. Handling increases pup licking and grooming (LG) by the rat mother [11–13]. Predictably, adult offspring of mothers that naturally (i.e. in the absence of any experimental manipulation) show increased levels of pup LG over the first week postpartum (high-LG mothers) show reduced plasma adrenocorticotropin hormone (ACTH) and cortico- sterone responses to acute stress compared with adult offspring of low-LG mothers [12,14]. These effects are, in part, mediated by the influence of maternal care on gene expression. The offspring of high-LG mothers show Hippocampus Hypothalamus CRF ACTH Glucocorticoids Pituitary Adrenal glands TRENDS in Neurosciences Figure 1. In response to stress, CRF, and co-secretagogues such as vasopressin, are released from paraventricular nucleus of the hypothalamus (dark oval) into the portal blood supply of the anterior pituitary, where they stimulate the synthesis and release of ACTH. Pituitary ACTH, in turn, causes release of glucocorticoids from the adrenal gland. CRF synthesis and release is subsequently inhibited through a glucocorticoid negative-feedback system mediated by mineralocorticoid and glucocorticoid receptors in several brain regions, including the hippocampus. Corresponding authors: Meaney, M.J. (michael.meaney@mcgill.ca), Szyf, M. (moshe.szyf@mcgill.ca). Available online 27 July 2005 Opinion TRENDS in Neurosciences Vol.28 No.9 September 2005 www.sciencedirect.com 0166-2236/$ - see front matter Q 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.tins.2005.07.006