Posted March 04, 2011
Epigenetic modulation—which biochemically alters DNA and chromosomes, but unlike mutation does not change the DNA sequence—can occur in response to environmental signals and have enduring effects on gene expression. New research is beginning to show that epigenetic mechanisms are active in the brain throughout a lifetime. They may play a role in everything from learning and memory to drug addiction to neurodevelopmental disorders such as autism—and some studies suggest the epigenetic marks affecting behavior could be transmitted into future generations.
One of the first conferences to explore the interface between epigenetics and behavior was held October 29–30, 2010, at the University of Massachusetts, Boston. Jointly sponsored by the New York Academy of Sciences and Brown Alpert Medical School, it brought together developmental psychologists, molecular psychiatrists, neurobiologists, anthropologists, and others to discuss the promise and the challenges of this emerging interdisciplinary approach.
Use the tab above to find a meeting report and multimedia from this event.
Presentations available from:
Ted Abel (University of Pennsylvania)
Christopher W. Kuzawa (Northwestern University)
Barry M. Lester (Warren Alpert Medical School of Brown University)
Ian Maze (Rockefeller University)
Carmen Marsit (Brown University)
Lisa Monteggia (University of Texas Southwestern Medical Center)
Eric J. Nestler (Mount Sinai School of Medicine)
David H. Skuse (University College London, UK)
J. David Sweatt (University of Alabama at Birmingham)
Marcelo Wood (University of California, Irvine)
- 00:011. Introduction
- 02:442. Classes of epigenetic modifications; Huntingtin Fly study
- 06:423. Valproic acid and autism; HDACs; Cognitive impairments
- 10:504. Transcriptional regulation; CBP; Matthies and Levenson/Sweatt studies
- 14:305. Regulation by HATs and HDACs; Conditional deletion of Sin3a; Memory enhancement
- 18:506. Synaptic plasticity; Enhancement of LTP; CREB and CBP recruitment
- 24:377. Nuclear hormone receptors; Nr4a and memory enhancement; BDNF expression
- 28:478. Epigenetics of memory storage; Summary and acknowledgement
- 00:011. Introduction
- 05:052. Transplacental mechanisms; Behavioral outcomes; MLS study
- 08:523. MR imaging; Prenatal mouse model; Cell migration analysis
- 14:084. Addiction as drug-induced neural plasticity; Persistent molecular maladaptations; Liability for addiction
- 17:025. Epigenetic and molecular analyses
- 24:206. Behavioral analyses
- 26:587. Cue-induced fear condition and extinction training
- 30:188. Summary; Multimodal imaging and molecular endophenotypes
- 32:189. Acknowledgements and conclusion
- 00:011. Introduction; Examples - early environment
- 05:452. Developmental plasticity; Human adaptability
- 11:153. Studies and findings
- 14:374. Species commitment to biological and behavorial strategies; Leptin studies
- 21:425. Fetal gestational environment; Birth weight studies
- 26:406. The Cebu study
- 35:127. Fetal nutrition tracks mother's nutritional history; Speculation
- 39:358. Summary and policy implications
- 43:129. Acknowledgements and conclusio
- 00:011. Introduction; DNA methylation
- 02:372. Placenta as key to development; Environmental influence
- 05:183. Residual tissue study; Findings
- 09:394. Genome-wide study; Findings
- 14:015. Profiles of methylation; Role of placental epigenome; Cohort study
- 20:446. Moving forward; Summary and acknowledgement
- 00:011. Introduction
- 05:142. The 2009 Renthal study; G9a studies
- 19:413. G9a and Delta FosB; Dendritic spines and structural plasticity
- 25:554. Drd1 vs. Drd2 receptor stimulations
- 28:355. Co-morbidity between addiction and depression
- 37:056. Reductions in CREB activity; Conclusion and acknowledgement
- 00:011. Introduction
- 04:072. Regulation reflected at the chromatin level; Nucleosome structure
- 07:013. Histone modifications; DNA methylation
- 14:124. Epigenetic readers; Nucleosome sliding; Histone substitution
- 19:165. Transcription activation and repression
- 22:366. Chromatin immunoprecipitation; Transcriptional mechanisms in vivo
- 30:087. Long-lasting adaptations
- 36:558. New approaches; Epigenetic transmission of behavior
- 44:149. Conclusio
- 00:011. Introduction; Memory at the cellular level
- 05:272. Memory and chemical modification of DNA
- 10:003. Fear conditioning studies
- 16:174. DNMT1 and DNMT3a studies
- 19:525. The molecular basis for DNMT control; Anterior cingulate cortex gene methylation
- 30:426. 30-day remote memory study; Is pesistent methylation necessary?
- 34:257. Conclusions and acknowledgement
- 00:011. Introduction
- 04:242. Regulation via histone modification; HATs, HDACs, and CBP
- 13:123. Novel object recognition study
- 18:494. Inducing a histone hyperacetylated state; HDAC inihibition and memory modulation
- 21:505. HDAC3 disruption and RGFP136 studies
- 30:136. Nr4a1 and Nr4a2 studies; Interplay between HAT and HDAC
- 36:467. Thoughts on HDAC function; Acknowledgement
Epigenetics and Neuropsychiatric Diseases: Mechanisms Mediating Nature and Nurture
This volume of the Annals of the New York Academy of Sciences is an outgrowth of a symposium entitled "Epigenetics and Neuropsychiatric Diseases: Mechanisms Mediating Nature and Nurture" presented at the 88th Annual Conference of the Association for Nervous and Mental Diseases, held on December 5, 2008, at the New York Academy of Medicine.
This is a new blog including relevant coverage of the 2010 Society for Neuroscience meeting. "A neuroscientific exploration of epigenetics, plasticity and gene–environment interactions."
Nature Reviews Genetics Web Focus: Epigenetics
A special issue of Nature Reviews Genetics from 2004.
NIH Roadmap Epigenomics Program
Several large-scale projects are underway to map the human epigenome. The U.S. National Institutes of Health's Roadmap Epigenomics Program began its first comprehensive data release in October 2010.
Science Magazine Special Online Collection: Epigenetics
A special issue of Science magazine published on October 29, 2010, devotes a section to epigenetics.
Jablonka E, Lamb MJ. Evolution in Four Dimensions: Genetic, Epigenetic, Behavioral, and Symbolic Variation in the History of Life. Cambridge, MA: The MIT Press; 2006.
Paul AM. Origins: How the Nine Months Before Birth Shape the Rest of Our Lives. New York: Free Press; 2010.
Abel T, Zukin RS. Epigenetic targets of HDAC inhibition in neurodegenerative and psychiatric disorders. Curr. Opin. Pharmacol. 2008; 8(1):57-64.
Bale TL, Baram TZ, Brown AS, et al. Early life programming and neurodevelopmental disorders. Biol. Psychiatry 2010; 68(4):314-319.
Day JJ, Sweatt JD. DNA methylation and memory formation. Nat. Neurosci. 2010; 13(11):1319-1323.
Day JJ, Sweatt JD. Cognitive neuroepigenetics: A role for epigenetic mechanisms in learning and memory. Neurobiol. Learn Mem. 2010.
Ecker DJ, Stein P, Xu Z, et al. Long-term effects of culture of preimplantation mouse embryos on behavior. Proc. Natl. Acad. Sci. USA 2004; 101(6):1595-1600.
Kuzawa CW, Quinn EA. Developmental Origins of Adult Function and Health: Evolutionary Hypotheses. Annual Review of Anthropology 2009; 38:131-147.
Maze I, Covington HE, Dietz DM, et al. Essential role of the histone methyltransferase G9a in cocaine-induced plasticity. Science 2010; 327(5962):213-216.
McQuown SC, Barrett RM, Matheos DP, et al. HDAC3 is a critical negative regulator of long-term memory formation. J. Neurosci. 2011;31(2):764-774.
Meaney MJ. Epigenetics and the biological definition of gene x environment interactions. Child Dev. 2010; 81(1):41-79.
Monteggia LM, Kavalali ET. Rett syndrome and the impact of MeCP2 associated transcriptional mechanisms on neurotransmission. Biol. Psychiatry 2009; 65(3):204-210.
Reul JMHM, Hesketh SA, Collins A, Mecinas MG. Epigenetic mechanisms in the dentate gyrus act as a molecular switch in hippocampus-associated memory formation. Epigenetics 2009; 4(7):434-439.
Roth TL, David Sweatt J. Annual Research Review: Epigenetic mechanisms and environmental shaping of the brain during sensitive periods of development. J. Child Psychol. Psychiatry 2010.
Skuse DH, James RS, Bishop DV, et al. Evidence from Turner's syndrome of an imprinted X-linked locus affecting cognitive function. Nature 1997; 387(6634):705-708.
Sweatt JD. Experience-dependent epigenetic modifications in the central nervous system. Biol. Psychiatry 2009; 65(3):191-197.
Tsankova N, Renthal W, Kumar A, Nestler EJ. Epigenetic regulation in psychiatric disorders. Nat. Rev. Neurosci. 2007; 8(5):355-367.
van Batenburg-Eddes T, de Groot L, Steegers EAP, et al. Fetal programming of infant neuromotor development: the generation R study. Pediatr. Res. 2010; 67(2):132-137.
Vecsey CG, Hawk JD, Lattal KM, et al. Histone deacetylase inhibitors enhance memory and synaptic plasticity via CREB:CBP-dependent transcriptional activation. J. Neurosci. 2007; 27(23):6128-6140.
Weaver ICG. Epigenetic programming by maternal behavior and pharmacological intervention. Nature versus nurture: let's call the whole thing off. Epigenetics 2007; 2(1):22-28.
Barry M. Lester, PhD
Barry Lester is professor of psychiatry & human behavior and pediatrics and director of the Brown University Center for the Study of Children at Risk at Brown Medical School and Woman and Infants Hospital. The Center provides research and clinical services for infants at risk and their families as well as research and clinical training. Lester received his PhD in developmental psychology from Michigan State University in 1973. He also completed a postdoctoral fellowship in pediatrics at Harvard Medical School. His specialty is developmental processes in infants at risk, including infants with prenatal substance exposure. He is particularly interested in the interplay between the biological, parenting, and social environmental forces that drive development. His research has been supported by NIH grants for over 30 years.
A past member of NIH study sections, Lester is currently a member of the National Advisory Council on Drug Abuse and member of the Expert Panel at the National Institute of Environmental Health Sciences Center for the Evaluation of Risks to Human Reproduction. He is past president of the International Association for Infant Mental Health and the author of more than 200 scientific publications and 17 books.
Edward Tronick, PhD
Ed Tronick is a developmental and clinical psychologist and is recognized internationally as a researcher on infants, children and parenting. He received his PhD from the University of Wisconsin, Madison, and completed post graduate training at Harvard University. Tronick is a University Distinguished Professor of Psychology at the University of Massachusetts, Boston, is Director of the Child Development Unit at Children's Hospital, a Lecturer in Pediatrics, Harvard Medical School and an Associate Professor at both the Graduate School of Education and the School of Public Health at Harvard.
Tronick developed the Still-face paradigm and with Barry Lester the NICU Network Neurobehavioral Assessment Scale. He continues to do research on the effects of maternal depression and other affective disorders on infant and child social emotional development. His current research focuses on infant memory for stress. He has published more than 200 scientific articles and 4 books, several hundred photographs and appeared on national radio and television programs. His research has been funded by NIDA, NICHD, NIMH, NSF and the McArthur Foundation. He has also served as permanent member of an NIMH review panel, and reviews for the National Science Foundations of Canada, the US and Switzerland.
Eric J. Nestler, MD, PhD
Eric Nestler is the Nash Family Professor (chair) of Neuroscience and Director of the Mount Sinai Friedman Brain Institute. His laboratory studies the molecular mechanisms of drug addiction and depression in animal models. He is also a professor of pharmacology and systems therapeutics and a professor of psychiatry at Mount Sinai School of Medicine. Nestler earned his medical degree from Yale University School of Medicine and his PhD from Yale University after which he completed an internship in medicine and psychiatry at Mclean hospital. From there he was awarded and completed two fellowships at Yale University School of Medicine, one in psychiatry and one in pharmacology. Board certified in psychiatry, Nestler uses animal models of drug addiction and depression to identify the ways in which drugs of abuse or stress change the brain to yield addiction- or depression-like syndromes. His work helps guide the development of improved treatments for these disorders.
Ted Abel, PhD
Barry Kosofsky, MD, PhD
Christopher W. Kuzawa, PhD
Ian Maze, PhD
Carmen Marsit, PhD
Michael Meaney, PhD
Lisa Monteggia, PhD
Johannes M. H. M. Reul, PhD
David H. Skuse, MD, PhD
J. David Sweatt, PhD
Marcelo Wood, PhD
Jessica Ruvinsky, PhD, is a field biologist who has rotted leaves in Costa Rica, trapped rats in California, and hunted flowers in the Rockies. This led to a doctorate from Stanford and a deep respect for floral obscenity. In college at Yale she sang with the Slavic Chorus, did ethnobotany in Belize, and backpacked through California. Her writing career started with the AAAS Mass Media Fellowship in 2002. She was on staff at DISCOVER magazine for three years, where she edited the reviews section until September, and is currently freelancing in New York.
This event was funded in part by the Life Technologies™ Foundation.
Funding for this conference was made possible (in part) by 1 R13 DA029985-01 from the National Institute on Drug Abuse, Eunice Kennedy Shriver National Institute of Child Health & Human Development, National Institute on Mental Health and National Institutes of Health Office of the Director. The views expressed in written conference materials or publications and by speakers and moderators do not necessarily reflect the official policies of the Department of Health and Human Services; nor does mention by trade names, commercial practices, or organizations imply endorsement by the U.S. Government.
This activity was funded in part by:
An Independent Medical Education Grant from AstraZeneca.
March of Dimes Foundation Grant No. 4-FY10-458.
A charitable contribution from Bristol-Myers Squibb Research and Development.
An educational grant from Janssen, Division of Ortho-McNeIl-Janssen Pharmaceuticals, Inc., administered by Ortho-McNeIl Janssen Scientific Affairs, LLC.
Early life experience has enduring effects. But exactly how does experience come to program certain behaviors? Epigenetics, a level of control "on top of" genetics, offers a mechanism that sits at the interface between nature and nurture. By physically and chemically altering the chromosomal material in response to the environment, epigenetics provides a possible pathway from an event in the outside world to a persistent change in the organism—a way that such diverse stimuli as a mother's love, a father's diet, or drug abuse could stably alter gene expression. Research into the relationship between behavior and epigenetic changes in the brain is just beginning: What causes them? And can they be undone?
Epigenetics also provides an avenue for investigation into neuropsychiatric diseases, where purely genetic approaches may come up short. Epigenetic processes have been implicated in depression, schizophrenia, and suicide; neurodevelopmental disorders including autism and Rubinstein-Taybi syndrome; and neurodegenerative diseases such as Alzheimer's disease. Epigenetic regulation has also recently been found to play a role in learning and memory, where the mechanisms operate in a surprisingly dynamic and rapid manner. Aberrations of epigenetic processes may underlie the cognitive dysfunction common to many disorders.
The 2-day conference on "Behavioral Epigenetics," one of the first in this pioneering field, brought together molecular biologists and behavioral scientists who don't normally share a stage. The event at the University of Massachusetts, Boston, on October 29–30, 2010, was jointly sponsored by the New York Academy of Sciences and The Warren Alpert Medical School of Brown University, and will be the focus of an upcoming Online Meeting Report to be published in the Annals of the New York Academy of Sciences.
Celia Moore, a psychobiologist, professor, and director of the Developmental Sciences Research Center at the University of Massachusetts, Boston, opened the conference by pointing to the demise of the nature-nurture dichotomy and the emergence of a more integrated model of development in which epigenetic mechanisms likely play a central role. Understanding these mechanisms could also open the door to new treatments for mental illness. "There are many reports of [epigenetic] histone deacetylase (HDAC) inhibitors basically curing every neurologic and psychiatric syndrome in animal models that's been studied to date," says Eric Nestler, molecular psychiatrist at the Mount Sinai School of Medicine and co-organizer of the conference. Turning these enzymes into human pharmaceuticals is harder; the related drugs that are in the pipeline for cancer are broad-acting and very toxic, cautions Nestler. "But maybe there are subtypes of these enzymes that can be targeted." Studies have already shown that the epigenetic effects seen in rat pups that have been neglected by their mothers can be reversed with drugs.
Background and perspectives
The word "epigenetics" was coined by Conrad Waddington in the 1940s to refer to genetic aspects of the unfolding of phenotype during development: Cells with identical DNA differentiate into liver and brain cells, muscles and skin cells, and then they stay that way. A liver cell's daughter cell inherits not just a sequence of genes, but also the epigenetic state of being a liver cell.
Epigenetics has since broadened to encompass a number of (sometimes incompatible) ideas. Some scientists define epigenetics as heritable changes in gene function that cannot be explained by changes in gene sequence. The heritability can be between generations of an organism as well as within cell lineages. Mechanisms of chromatin biology that can account for such stable (and sometimes environmentally sensitive) changes in gene function continue to be elucidated, and a common use of "epigenetics" now refers to those mechanisms, whether they are heritable or not.
At this conference, talks focused on DNA methylation and histone modification, a subset of mechanisms that mediate gene expression by changing the structure of chromatin. Every mammalian cell packs about two meters of DNA, tightly wound around histone proteins, into a single, microscopic nucleus. An inaccessible gene won't be expressed. In DNA methylation, methyl groups covalently bind to DNA and repress transcription. In histone modification, the various molecules that attach to the tails of the histone proteins form a complex regulatory code.
The extent to which behavior affects and is affected by these epigenetic mechanisms was the subject of the present conference. Alongside extraordinary examples in the animal literature, participants discussed the application of behavioral epigenetics to humans, on whom research is still extremely limited by insufficient access to brain tissue. Whether there is transgenerational inheritance of behavioral traits remains controversial in both humans and animals, but there are very well-developed models of how environmental stimuli can create stable, long-term change within an animal's lifetime.
This stability is what makes epigenetics an attractive candidate to explain the developmental origins of health and disease, one of the inspirations for this conference for co-organizer Barry Lester of The Warren Alpert Medical School of Brown University and Women & Infants Hospital of Rhode Island. Whole lifetimes can be marked by experiences in the womb. For example, low birth-weight babies gestated during the Dutch "Hunger Winter" famine of 1944–1945 had a higher incidence of metabolic and cardiovascular disorders when they grew up, possibly because their development was primed for scarcity. "The concept that the fetus is actually making adaptations through programming to 'prepare' for the postnatal environment in response to signals raises a whole host of fascinating questions," Lester said. "In the case of fetal origins we're primarily talking about undernutrition. But can these effects or similar effects be produced by environmental insults or factors other than undernutrition? What might be the underlying mechanisms? Is there applicability of this kind of model, beyond chronic disease, to behavior?" In fact, low birth weight is associated not only with chronic disease, but also with schizophrenia, depression, and psychological distress; and it is a basic tenet of psychology that early experiences can mark us for life.
While thousands of studies of epigenetics have been conducted over the last 40 years, the application of epigenetics to the study of behavior is just beginning. Lester reported on a literature search of citations which found only 96 articles to date on behavioral epigenetics. These articles addressed substance use, psychiatric illness, learning/memory, neurodevelopment, parenting, stress, and neurodegenerative disorders. Most were on mice, rats, and humans (though one used snails). The majority of studies analyzed brain samples (about 15 of them human); some studied blood, and a few collected cheek swabs, semen, or other tissues. Lester also broke the literature down by the epigenetic mechanisms that were studied (DNA methylation, histone modification, genomic imprinting, or noncoding RNA) and by the particular genes investigated.
Christopher Kuzawa, Northwestern University
David Sweatt, University of Alabama, Birmingham
Marcelo Wood, University of California, Irvine
Johannes M.H.M. (Hans) Reul, University of Bristol
Michael Meaney, McGill University
Carmen Marsit, Brown University
Barry Kosofsky, Weill Cornell Medical College
- Epigenetic marks may preserve information about environmental conditions over the long term.
- The behavior of nurturing and attentive rat mothers toward their pups changes the methylation status of the pups' stress receptor gene, which decreases the pups' anxiety level for life.
- In rats, the epigenetic effects of a mother's touch may allow her to shape her offspring's behavior in a way that is appropriate to the current environment.
- The reason one may remember scary events better than benign ones is that stress engages epigenetic mechanisms to enhance memory formation.
- One component of long-term memory may be written directly on the genes in the form of methylation.
Listen to your grandmother
Some aspects of an infant's metabolism may be set for life well before the age of one. So for what kind of world should the developing child prepare: harvest season, or hunger? Extreme drought, or rainfall-as-usual? In an unpredictable environment, indicators of typical nutritional intake—such as the mother's body weight—may serve as more reliable gauges of average food availability than does her diet during nine months of pregnancy, said biological anthropologist Christopher Kuzawa of Northwestern University. One reason that maternal nutritional supplementation programs in the developing world have often failed to increase birth weight by more than an ounce may be that the fetus takes its cues from its mother's nutritional history rather than from its own.
Such an integrative signal of decades of experience is possible: After birth, an indicator of the mother's body weight passes to the infant in the form of the hormone leptin in breast milk, which helps establish the infant's growth rate. It is conceivable that epigenetic states could be established in the womb that similarly draw on the mother's life experience, from as far back as when she was a fetus: According to data from a pilot study in the Philippines, among the best predictors of a baby's birth weight may be how much the baby's grandmother ate when she was pregnant.
Integrating information over lifetimes and generations could serve a useful function, Kuzawa speculated. Humans are extremely adaptable, responding physiologically over seconds, hours, and days, and evolving by natural selection over millennia and millions of years. For dealing with conditions that change in the intervening decades, developmental plasticity is our best option. And the stable, cellular memory of epigenetics may be the key to responding appropriately over that timescale.
Inheritance of acquired characteristics
Was Lamarck right after all? If our experience changes our genes, can our children inherit those changes? The extent to which epigenetic marks are passed down through generations is still subject to controversy. Epigenetic mechanisms do not change the gene sequence, just the molecules attached to it, and these patterns are thought to be wiped clean in the embryo. It is conceivable, but not yet proven, that DNA methylation in egg or sperm could persist through development and differentiation in particular cell types in such a way as to affect the brain and behavior. If true, the social and psychological consequences of this hypothesis are enormous.
Several studies have now reported the inheritance of acquired behavioral characteristics. Male mice separated from their mothers at birth get depressed, and so do the daughters of those male mice, even though they themselves were raised well, Swiss researchers showed in Biological Psychiatry last year. Both generations' depressive-like behavior correlates with specific DNA methylation profiles in the brain.
The experience of having an abusive mother also has epigenetic effects. Mother rats who have been deprived of adequate nesting material get anxious. They drop and step on their pups more, and they lick them less than do better-off mother rats. David Sweatt of the University of Alabama at Birmingham and others reported in Biological Psychiatry in 2009 that the pups of these stressed mothers show increased methylation of the brain-derived neurotrophic factor (BDNF) gene, a locus that has been linked to various psychiatric disorders. The change lasts the pups' entire life. It affects BDNF expression in the adult prefrontal cortex, and the abused rats grow up to mistreat their own offspring—who have the same altered DNA methylation pattern, even when raised by a foster rat.
Until a mechanism is shown by which epigenetic DNA modifications can be passed on to offspring, "reports of transgenerational transmission must be treated with grave skepticism and caution," Nestler said. "It's possible, but we don't understand yet how that can occur." Nestler has preliminary evidence for what he says may prove to be epigenetic transmission of stress vulnerability in his social defeat model of depression. Repeatedly bested mice lose interest in social interaction; the sons of those defeated mice are more anxious, and more vulnerable to social defeat.
Learning and memory
For long-term memories to form, gene expression has to change. "There's a constant dynamic interplay between the environment and the genome in your central nervous system," said Sweatt. "There really is no dichotomy between genes and environment, in the sense that your experiences are constantly impacting the genome."
Methylation, which chemically changes the DNA, was thought to be nearly immutable. Sweatt found that the process of learning can alter DNA methylation in the brain. In rats' hippocampi, these changes are rapid and dynamic during contextual fear conditioning. In the cortex, they're as stable as the memory is: Reducing methylation in the cortex with an enzyme inhibitor attenuated the memory. Sweatt believes that one component of long-term memory may be written directly on the genes, in a kind of epigenetic code.
Histone modification, the other major category of epigenetic mechanisms, can also transform long-term memory. Marcelo Wood of the University of California, Irvine, can make mice remember and forget the locations of blue legos by genetically manipulating the "writers" and "erasers" of histone acetylation. He can specifically delete the genes for these writers or erasers from the hippocampus of an adult mouse's brain, or inject enzyme inhibitors that target a specific deacetylase.
By inhibiting the erasers and thereby over-acetylating the histones, "you can transform a learning event that meant nothing to the animal, as far as we can tell, into a learning event that now is perfectly encoded in long-term memory," said Wood. An amount of training that wouldn't even have created short-term memory suddenly creates memory that nothing can override.
What this means is that not-remembering is an active molecular process. An eraser enzyme called histone deacetylase (HDAC) 3 and its corepressors are constantly reining in long-term memory formation, like "molecular brake pads that are always clamped on," said Wood. "The question we should be asking really is, 'Why don't we encode everything into long-term memory?'"
One of the stimuli that releases those brake pads is stress. That could be good because it gives us selective long-term memory for the important (dangerous or emotionally provocative) things. But it could also be bad if it produces perfect and unchangeable memories of the worst experiences, as in post-traumatic stress disorder. Hans Reul of the University of Bristol is elucidating the signaling pathways through which the glucocorticoid hormones released during stressful events lead to epigenetic changes, gene induction, and memory.
As an understanding of the mechanisms behind long-term memory grows, so does the promise of manipulating it. Epigenetics appears to mediate neurodegenerative diseases, normal cognitive aging, and anxiety disorders such as PTSD. More and more specific tools to investigate and alter epigenetic processes are being developed, and pharmacotherapies may be on the way.
What makes us who we are? It's as if genes were a musical instrument, says co-organizer Ed Tronick of the University of Massachusetts, Boston: "We've always known that experience is playing the harp, but we didn't know what the fingers were." The way epigenetic marks change through development and produce long-term behavioral consequences offers a new way to look at the question of human (and rodent) nature.
The pups of attentive mother rats are calm and curious, and handle stress better than neglected rat pups, who tend to cower in the corner of the cage. The 2004 study by Michael Meaney of McGill University and colleagues that catapulted the field of behavioral epigenetics into prominence showed that the difference in behaviors of the two rat groups correlates with a difference in the methylation status of a particular gene. Meaney found that the newborn rat's experience of being licked and groomed by an attentive mother translates at the molecular level into the removal of methyl groups from the pup's glucocorticoid receptor gene. The gene becomes more active and the rat becomes less anxious, for the rest of its life.
To try to translate these findings to humans, Meaney used tissue available from the Quebec Suicide Brain Bank. He found a decrease in hippocampal glucocorticoid receptor expression among suicide victims with a history of child abuse—similar to the pattern in neglected rats—compared to people without a history of child abuse, whether they had died of suicide or other causes.
Carmen Marsit of Brown University is looking at DNA methylation in humans from the very beginning, inside the womb. An embryo starts out with DNA that is largely unmethylated, and different tissues acquire different methylation patterns throughout development. Marsit is relating DNA methylation in the placenta to infant development. "Some people call [the placenta] a third brain because it produces a lot of the same chemicals," he said. He has found that intrauterine growth, a marker for the environment in the womb, correlates with methylation profiles: Bigger babies have different patterns than smaller ones, including a slight increase in methylation on the glucocorticoid receptor gene. The placental epigenome in turn correlates with neurobehavioral development: The more methylated the glucocorticoid receptor in the placenta, the lower the infant's attention score. Epigenetic patterns set in the womb can affect human behavior.
Crack cocaine-using mice
One thing that is known to affect the intrauterine environment is chronic drug use during pregnancy. Cocaine use increases release of norepinephrine, serotonin, and dopamine. Since these amines cross the placenta, "the fetal brain is bathed in monoamines every time [the mother] does a hit of crack cocaine," said Barry Kosofsky of Weill Cornell Medical College. In mice, this seems to result in epigenetic changes in the medial prefrontal cortex that don't affect specific molecular targets and associated behaviors until that brain structure matures during adolescence. As compared with controls, juvenile mice that have been exposed to cocaine during gestation demonstrate increased social interaction, wanting to socialize even more than their brothers do; as adults these mice demonstrate less social interaction.
The social deficit isn't their only problem. As adults, prenatally cocaine-exposed mice can't get over fear. After being trained to associate a tone with shock, they learn that, in a different setting, the tone does not mean a shock is coming. But they can't consolidate that memory—it's gone the next day. "They learn that it's a safe place, but they don't remember it's a safe place," said Kosofsky.
Ted Abel, University of Pennsylvania
Lisa Monteggia, University of Texas Southwestern Medical Center
Ian Maze, The Rockefeller University
David H. Skuse University College London, UK
- The attention span of a newborn human is correlated with DNA methylation patterns in the placenta.
- Drugs that affect epigenetic states have affected memory, cognition, anxiety, depression, and addiction in animal models.
- Chronic cocaine use makes mice more vulnerable to stress from social defeat through epigenetic mechanisms.
- The parental origin of the X chromosome may affect expression of some X-linked genes in the brain.
Histone deacetylase inhibitors
Drugs that target epigenetic processes have been effective in treating a remarkable number of animal diseases and are in clinical trials for use against human cancers. A few have already been FDA-approved. The problem with them is their lack of specificity: If you're going to use a drug that changes your genome, it's best to know which genes it's affecting.
Histone deacetylase (HDAC) inhibitors are currently very promising targets for behavioral and psychiatric drug development, said Ted Abel of the University of Pennsylvania. HDACs are diverse—valproic acid, long prescribed for epilepsy and bipolar disorder, turns out to be one of them—and many new inhibitors specific to particular HDACs have been developed just in the last few years.
HDAC inhibitors have prevented neuronal death in flies with the fly version of Huntington disease (Stephan et al., 2001) and have restored learning and memory in a mouse model of neurodegeneration (Guan et al., 2009). They have ameliorated cognitive deficits in mice with the neurodevelopmental disorder Rubinstein-Taybi syndrome (Alarcón et al., 2004). They have reversed aspects of Parkinson's disease in the fly (Kontopoulos et al., 2006) and improved memory in aging mice (Peleg et al., 2010). And in a pilot study on the use of HDAC inhibitors to treat symptoms of autism, valproic acid reduced symptoms of irritability in children (Hollander et al., 2010).
It's hard to know exactly how they're working. Histone deacetylases remove acetyl groups from any protein, not just histones. They affect thousands of proteins and hundreds of genes. So which of them are the ones that are changing behavior? Several of the speakers at this conference are trying to find out.
In Ted Abel's lab, research on how histone acetylation modulates memory (some of which was conducted by speaker Marcelo Wood) is leading to potential targets for memory enhancement—the specific genes and gene products that the histone modifications regulate. His goal is to treat the cognitive impairments common to many neurodegenerative and psychiatric disorders, from aging to schizophrenia, that existing therapies do not address.
Lisa Monteggia of University of Texas Southwestern Medical Center is studying a mouse model of Rett syndrome, a syndrome that is one of the leading causes of mental retardation and autistic behavior in girls. Rett syndrome is the result of loss of function mutations in the gene for methyl-CpG-binding-protein-2 (MeCP2), an intimate part of the epigenetic machinery that binds to methylated DNA. Although Rett syndrome is a neurodevelopmental disorder, loss of MeCP2 function in the adult brain leads to functional deficits recapitulating aspects of the Rett syndrome phenotype. Symptoms appear to be triggered by functional deficits at the synaptic level. Monteggia is tracking synaptic function back to DNA methylation by deleting the MeCP2 gene from adult mouse brains. She is studying regulation of synaptic function by MeCP2-linked gene regulatory processes such as DNA methylation and histone deacetylases.
Ian Maze, now at the Rockefeller University, has identified a critical role for epigenetic mechanisms in addiction. Cocaine is thought to hijack the brain's reward system; Maze found that it does so in part by downregulating G9a, an enzyme that methylates histones. Histone methylation is thought to be particularly long-lasting, as is a vulnerability to relapse. But "If I overexpress G9a, which blocks transcriptional induction, I can actually decrease an animal's preference for cocaine," Maze said.
Drug addiction makes both people and mice more vulnerable to depression. For a mouse chronically exposed to cocaine, it takes only eight (instead of ten) episodes of being bullied by a bigger mouse to send it into a funk. In work he did in Eric Nestler's lab at the Mount Sinai School of Medicine, Maze showed that cocaine and social stress lead to depression through the same pathway. He was able to restore mouse resilience, creating anti-depressant-like effects, by intervening downstream of G9a.
Parental contributions to X-linked gene expression
David Skuse of University College London is examining sexually dimorphic risk factors in social communication disorders that lie along a continuum running from autism to much less severe behavioral traits in the general population. People with these disorders have trouble recognizing and responding to the feelings of others, they tend to be inflexible in their behaviors, and they have verbal communication difficulties, among other traits. Across this span, males are more likely to be vulnerable to social communication disorders than females, particularly at the higher end of the verbal IQ range.
One possible source of this behavioral difference is the expression of X-linked genes. Males receive their X chromosome from their mothers; hence all their X-linked traits are derived from maternal genes. Females receive one X chromosome from each parent. X-inactivation silences expression of one X chromosome in each cell, resulting in mosaic expression of the paternal and maternal X-linked genes across tissues. Another layer of regulation is genomic imprinting, a phenomenon in which a particular paternal or maternal allele is silenced by methylation of DNA near the gene.
To examine the role of paternal or maternal X-linked gene expression on social communication disorders, Skuse and his colleagues assessed females with a single X chromosome, a condition known as Turner syndrome. Females who inherited the paternal chromosome were found to be similar to XX females in their score on a social and communication disorder (SCDC) test, as well as on tests that assessed empathy and behavioral inhibition. In contrast, females with a maternal X chromosome had scores more similar to males for all these factors.
Skuse’s team created the mouse equivalent of Turner syndrome—animals with only a single paternally-derived or maternally-derived X chromosome. In a test of perseverative and association responses, indicative of the autism spectrum disorder traits of rigidity and failure to learn rapidly, mice with the maternally-derived X chromosome made more perseverative errors and learned new associations less quickly than those with paternally-derived X chromosomes. At the molecular level, the group found an imprinted gene XLr3b that was associated with increased perseverative behavior in males. The gene is preferentially expressed in males (from the maternally-derived X chromosome). Interestingly, deletions of the region containing the gene’s human homolog, FAM9B, were associated with autism in three females, though expression of the gene has thus far only been found in the testes.
Recently, a study by Catherine Dulac’s group at Harvard University found that there is widespread preferential transcription of genes of maternal or paternal origin in mouse brain tissue, including preferential expression of maternally-derived Xlr3b in the pre-optic area of the brain, which associated with behavior. Taken together, these results suggest that epigenetic mechanisms may result in differences in gene expression in daughters versus sons. Some of the affected genes may play a role in brain development, behavior, and disease.
Think tank: Should epigenetics be its own discipline?
Research in epigenetics has exploded over the last decade, but some of the speakers were questioning whether it should be considered a field unto itself. Hans Reul suggested that each research question—cancer, development, memory—can benefit from incorporating epigenetic approaches independently: It's just another mechanism. Michael Meaney would just as soon subsume epigenetics under a wider umbrella. Genomics is already such a moving target, he said, that "trying to subdivide a field that studies its regulation doesn't make a whole lot of sense." So why not just join the club? Barry Lester observed that applying epigenetics to the field of behavior brings up issues that wouldn't otherwise surface. "That's a good point," Meaney acknowledged. Ed Tronick pointed out that given what is now known about environmental effects, "joining the club" may not be sufficient because there needs to be as much effort put into characterizing the environment as has gone into characterizing molecular mechanisms. At the moment environmental "phenotyping" is crude even in experimental studies, and what may seem like stable epigenetic changes may actually be the result of stable environments renewing the epigenetic change.
Can human behaviors be traced back to epigenetic causes without access to living brain tissue?
How much do epigenetic factors, on top of genetic and environmental ones, contribute to individual differences?
How do epigenetic processes function in normal development?
Are behavioral epigenetic changes adaptive?
How stable are they, and what determines that stability?
Can they be inherited between generations, and how?
Do other epigenetic mechanisms, such as RNA silencing and nucleosome remodeling complexes, contribute to behavioral outcomes?
In what ways do epigenetic mechanisms function differently in neurons than in dividing cells?
Why does an intervention as extremely broad as increasing global histone acetylation or DNA methylation have very specific, targeted effects?
How can we translate knowledge of chromatin modification mechanisms into therapeutic approaches?
Can those approaches be behavioral and preventative as well as pharmacological?