NEWSFOCUS The Seductive Allure of Behavioral Epigenetics on July 29, 2010 Could chemical changes to DNA underlie some of society’s more vexing problems? Or is this hot new fi eld getting ahead of itself? MICHAEL MEANEY AND MOSHE SZYF WORK messages from their neighbors. And most of the most vexing problems in society. These in the same Canadian city, but it took a chance scientists who studied DNA methylation ills include the long-term health problems of www.sciencemag.org meeting at a Spanish pub more than 15 years thought the process was restricted to embry- people raised in lower socioeconomic envi- ago to jump-start a collaboration that helped onic development or cancer cells. ronments, the vicious cycle in which abused create a new discipline. Meaney, a neuro- Back in Montreal, the pair eventually began children grow up to be abusive parents, and scientist at the Douglas Mental Health Uni- collaborating, and Szyf’s hunch turned out to the struggles of drug addicts trying to kick versity Institute in Montreal, studies how be right. Their research, along with work from a the habit. early life experiences shape behavior later in handful of other labs, has sparked an explosion Tempting as such speculation may SCIENCE life. Across town at McGill University, Szyf of interest in so-called epigenetic mechanisms be, others worry that the young but fast- Downloaded from is a leading expert on chemical alterations to of gene regulation in the brain. Long familiar growing fi eld of behavioral epigenetics is get- DNA that affect gene activity. Sometime in the to developmental and cancer biolo- ting ahead of itself. They point mid-1990s, both men attended the same meet- gists, these molecular mechanisms Online out that so far there’s very little ing in Madrid and ended up at a bar talking alter the activity of genes with- evidence in humans that epige- sciencemag.org and drinking beer. “A lot of it,” Szyf recalls. out changing their DNA sequence netics connects early life expe- Podcast interview ; (COLLAGE) N. KEVITIYAGALA/ Meaney told Szyf about his fi ndings that (Science, 10 August 2001, p. 1064). with author rience to behavioral or health rat pups raised by inattentive mothers tend to And they have recently become a Greg Miller. problems later in life. Moreover, SCIENCE be more anxious as adults than pups raised by white-hot topic in neuroscience. several experimental obstacles more nurturing mothers. He also described Meaney and Szyf’s work suggests that will make fi nding proof exceedingly diffi cult. how the activity of stress-related genes was epigenetics could explain how early life “I think there’s been a lot of putting the cart altered in the undernurtured pups. At some experiences can leave an indelible mark on before the horse,” says Gregory Miller (no point in the conversation, Szyf had a fl ash of the brain and infl uence both behavior and relation), a psychologist at the University of insight: This difference must be due to DNA physical health later in life. These effects British Columbia (UBC), Vancouver. methylation—the chemical alteration he had may even carry over to subsequent genera- been studying in stem cells and tumor cells. tions. Meanwhile, other researchers have The importance of a loving mother The idea cut against the conventional think- implicated epigenetics in drug addiction. In 2004, Szyf and Meaney published a paper ing in both fi elds. In neuroscience, the pre- Still others have described important roles in Nature Neuroscience that helped launch vailing wisdom held that long-term changes in cognition (see sidebar, p. 27). the behavioral epigenetics revolution. It in behavior result from physical changes in Some researchers speculate that if these remains one of the most cited papers that neural circuits—such as when neurons build rodent fi ndings extend to humans, epigenet- journal has ever published. The paper built on new synapses and become more sensitive to ics could turn out to be at the heart of some more than a decade of research in Meaney’s GEENMAN/ Y. CREDITS: (BRAIN) ISTOCKPHOTO; (ILLUSTRATION) 24 2 JULY 2010 VOL 329 SCIENCE www.sciencemag.org Published by AAAS NEWSFOCUS lab on rodent mothering styles. more time fussing over their own offspring. issue of Biological Psychiatry. In addition, Rat moms vary naturally in their nurtur- Fussed-over daughters in turn tend to grow this methylation pattern, which would tend to ing tendencies. Some lick and groom their up to be nurturing mothers. These changes reduce the amount of BDNF produced, was pups extensively and arch their backs to correlate with a higher density of oxytocin passed on to the subsequent generation. make it easier for their young to nurse. Oth- receptors in some brain regions, the research- Exactly what low BDNF levels mean for a ers spend far less time doting on their pups ers reported last September in Frontiers in mouse isn’t entirely known. However, levels in this way. Behavioral Neuroscience. Champagne’s lab of this growth factor are reduced in mouse Meaney had found that the type of moth- is now investigating whether that higher den- models of depression and anxiety, at least ering a rat receives as a pup calibrates how sity could be due to epigenetic modifi cations. in certain brain regions, and restoring it can its brain responds to stress throughout its “What’s exciting to me is that the social world, mimic the effect of antidepressant drugs. In life. Rats raised by less-nurturing mothers which can be perceived as being this ethereal 2006, Eric Nestler, currently at Mount Sinai are more sensitive to stress when they grow thing that may not have a biological basis, can Medical Center in New York City, and col- up. When confi ned to a Plexiglas tube that affect these mechanisms,” she says. leagues reported in Nature Neuroscience restricts their movement, for example, they that the Bdnf gene is down-regulated in the exhibit a greater surge in corticosterone, a Adversity takes its toll hippocampus of adult mice exposed to social hormone pumped out by the adrenal glands Whereas a nurturing environment can pre- stress—in the form of chronic bullying by a in times of stress. The likely cause is reduced dispose a rodent to be calmer in adulthood bigger mouse. In the same paper, Nestler’s numbers of a receptor for steroid hormones and raise a nurturing family of its own, an team linked this reduction in Bdnf activity to in the brain. This so-called glucocorticoid adverse environment can have the oppo- epigenetic modifi cations involving histones, receptor is part of a negative feedback loop site effect. There’s evidence that this effect, tiny protein spools that keep DNA wrapped that dials down the volume on communica- too, may involve epigenetic changes. Last up. Chronic stress triggered an increase in a tion between the brain and adrenal glands, year, researchers led by Tania Roth and type of histone methylation that suppresses thereby reducing reactivity to stress. J. David Sweatt of the University of Alabama, gene activity by keeping the DNA con- The Nature Neuroscience paper linked Birmingham, helped show this by build- taining the Bdnf gene tightly wound. Anti- on July 29, 2010 this reduction in glucocorticoid receptors ing on earlier work showing that rat mothers depressant drugs, on the other hand, boosted to DNA methylation. Rats raised by less- denied access to the materials needed to make histone acetylation, which helps unwind nurturing moms tended to have more methyl a proper nest become anxious and spend DNA from histones and promote Bdnf activ- groups attached to the promoter region, the less time nurturing their young. Pups raised ity. Such fi ndings hint that epigenetic modi- “on” switch, of the glucocorticoid receptor by these stressed-out rat moms exhibited fi cations could be an important link between gene. These methyl groups block access by increased methylation of the gene for BDNF, adverse life experiences and the risk of psy- the transcription factors that turn the gene a neural growth factor, in the brain’s prefron- chiatric disorders such as depression and on. As a result, fewer receptors are pro- tal cortex, they reported in the 1 May 2009 anxiety, Nestler says. duced. Subsequent experiments showed www.sciencemag.org that enzymes that reverse DNA methyla- tion of the glucocorticoid receptor gene also reverse the effects of unenthusiastic mother- ing on the offspring’s hormonal and behav- ioral responses to stress. Several of Meaney’s students have car- ried on with this work and extended it in Downloaded from new directions. Frances Champagne, a co-author of the 2004 paper, went on to show that female rats raised by nurturing mothers are more nurturing mothers them- selves. She also found that pups raised by less-nurturing moms exhibit greater methylation—and reduced expression—of the gene for a particular estrogen receptor in the hypothalamus, a brain region involved with reproductive behavior. This receptor amplifi es signaling by oxytocin, a hormone that promotes mother-infant bonding. Now at Columbia University, Champagne has been investigating the long-term effects of other kinds of social experiences early in life. She has found that mice raised commu- nally by multiple mothers (as rodents raise their young in the wild) are better socially Different upbringings. Being raised by a nurturing (top left) or a lackadaisical (top right) mother can adjusted as adults: They are less likely to pick cause epigenetic differences that affect a rat pup’s behavior later in life. Whether similar differences a fi ght with a stranger put into their cage, for occur in people raised in wealthy (bottom left) or impoverished (bottom right) neighborhoods remains CREDIT (CLOCKWISE FROM LEFT): MICHAEL MEANEY LAB; TIME & LIFE PICTURES/GETTY IMAGES; PHOTOS.COM; ISTOCKPHOTO example.