When we first heard about the NYAS Behavioral Epigenetics conference, we were pretty psyched. We hoped to find some evidence that would blame our bad behavior on a faulty epigenetic makeup instead of just an overall lack of good judgment. No such luck. We were lucky enough, though, to have an expert in both behavior and epigenetics, Dr. Richard Brown, on the scene to help us cover the whole event. Read on to see his conference report.
The Behavioral Epigenetics conference was held in the Campus Centre of UMASS Boston, which sits on a grassy point, overlooking Boston Harbor. The event attracted over 280 people from the U.S. and 19 other countries, consisting of faculty, PDFs, graduate and undergrad students, and even two high school students that were learning about epigenetics in their biology class.
Most people arrived early so that they would be present for the whole meeting. As my flight from Halifax to Boston was only 55 minutes, I had time on the day before the meeting to visit friends and colleagues and spend a sunny afternoon strolling around Harvard Square. Unfortunately, the days of the meeting were much cooler and cloudy.
The meeting opened with a welcome from Marta Murcia, the Senior Program manager at the New York Academy of Sciences and Celia Moore, the director of the Developmental Sciences Research Centre at UMASS Boston, and then moved into the program which began with introductory talks on epigenetics and behavior.
What is Behavioral Epigenetics?
Barry Lester, Brown University
Because the meeting was oriented to psychologists, psychiatrists, and behavioral neuroscientists, who may be unfamiliar with recent advances in epigenetics, the meeting began by addressing the question “What is behavioral epigenetics?” Noting that there is much disagreement about the definition of the term “epigenetic,” he ventured a definition of “behavioral epigenetics” as “the application of the principles of epigenetics to the study of the genetic, physiological and environmental mechanisms underlying the development of behavior in human and non-human animals.” The talk finished with a note on epigenetics in the news, which was particularly appropriate as two recent journals have had special features on epigenetics in the last month: Science (24 October, 2010) and Nature Neuroscience (November, 2010), and concluded that behavioral epigenetics was the application of epigenetic principles to psychological processes, leaving the big question, “Can epigenetics underlie the enduring effects of a mother’s love?”
Epigenetics: Basic Processes and Mechanisms
Eric Nestler, Mt. Sinai School of Medicine
Nestler gave a broad overview of basic epigenetic principles and the methods for the study of gene-chromatin interactions. He focused on some of the issues in studying the effects of drugs such as cocaine on histone acetylation and DNA methylation, and the problems in getting reliable and valid data, the need for informatics methods to deal with the volume of data produced and the need to discover the signal transduction mechanisms underlying drug effects on the epigenome.
Epigenetics, Intergenerational Intertia, and Human Adaptation
Christopher Kuzawa, Northwestern University
In the third introductory talk, Kuzawa examined the relationship between epigenetics and human adaptation from the viewpoint of an anthropologist. How, for example, might patterns of gene expression and gene silencing during development lead to long term epigenetic changes and how does the early environment influence such changes? Two areas of research discussed were the effects of maternal separation on DNA methylation patterns and the role of epigenetic mechanisms underlying developmental plasticity in shaping growth rates and behavioral development. Some examples presented were the physiological adaptations to high altitude living in mountain people, and the effects of prenatal under-nutrition on adult cardiovascular health. In the last part of his presentation, he examined the value of breast milk as an epigenetic regulator of infant development and as a source of information about the external environment for the infant. He showed how the level of leptin in breast milk reflected maternal fat stores and influenced infant appetite, body weight and metabolism. Finally, he discussed the effects of diarrhea in infancy as an epigenetic predictor of child development, cardiovascular health and reproductive future. Data were presented from the Cebu City study which covers 3 generations of people in the Philippines.
Epigenetic Mechanisms in Memory Formation.
J. David Sweatt, University of Alabama, Birmingham
Sweatt focused on the role of DNA methylation in learning and memory. He showed that zebularine, a DNMT inhibitor, when infused into the hippocampus, alters BDNF synthesis and reduces freezing, a measure of memory in the contextual fear conditioning task, indicating that DNA methylation is one of the epigenetic mechanisms necessary for consolidation of fear memories. Likewise, the DNMT inhibitor RG108 also blocked consolidation of contextual fear memory. In addition, he showed how HDAC inhibitors such as valproic acid were able to recover memory loss in Alzheimer model mice. He noted that one important question is to identify the gene targets of epigenetic mechanisms. One target of DNA methylation is calcineurin. Sweatt showed how DNA methylation of the calcineurin gene in the anterior cingulate cortex could provide a mechanism for long term memory.
Chromatin-modifying Enzymes in Long-term Memory
Marcelo Wood, UC Irvine
Wood examined the reciprocal actions of histone acetyltransferase (HAT) and histone deacetyltransferase (HDAC) in long term memory. He focused on the actions of CREB binding protein, a HAT involved in long-term memory for novel object recognition. He showed that HDAC inhibitors such as sodium butyrate can facilitate long term memory. The future is to determine how HDAC inhibitors facilitate memory and whether modulation of HAT and HDAC mechanisms can facilitate the extinction of drug-induced memories. In C57BL/6 mice, for example, the HDAC inhibitor sodium butyrate given during extinction trials facilitated extinction and prevented reinstatement of drug-induced behavioral changes. These results pave the way for the use of histone acetylation modifying drugs to treat a number of memory-related disorders.
Epigenetic Mechanisms in Stress-related Memory Formation
Johannes Reul, University of Bristol, UK
Memories associated with traumatic stress may lead to post-traumatic stress disorders. Most of the focus on stress-related memory formation is on the role of glucocorticoids and the H-P-A neuroendocrine pathway. How, for example, does corticosterone act in the brain to facilitate stress-related memories? Johannes Reul examined the interaction between glucocorticoid receptors (GR) and NMDA receptors and the activation of the ERK-MAPK pathway in the dentate gyrus in fear learning. The dual GR-NMDA-MAPK/ERK mediated signaling cascade leads to the acetylation of H3 in the dentate gyrus which facilitates fear memory formation. In this way, the elevation of glucocorticoids during fear conditioning can facilitate histone H3 5-10 phosphorylation, K19 acetylation and H4 hyper acetylation, leading to the formation of fear memories.
DNA Methylation Alterations in Growth Restriction and Infant Neurobehavior
Carmen Marsit, Brown University
Marsit, a former cancer researcher, focused on the role of DNA methylation in infant growth. In particular, he focused on the placenta as the key to infant development as it provides nutrient transport, immuno-endocrine information and regulates the intra-uterine environment during development. Marsit sees infant growth as a measure of the environment and suggested that the measure of intra-uterine growth predicts future infant health and development. Because toxins ingested by the mother pass through the placenta to the fetus, Marsit examined methylation sites in the placenta and found that an increase in methylation sites was associated with larger babies.
Epigenetic Effects of Mice Exposed to Cocaine in utero
Barry Kosofsky, Weill Medical College of Cornell University
How does prenatal cocaine exposure affect the neuro-behavioral development of babies? Maternal cocaine affects the placenta and fetus, and may alter the expression of a number of genes, including egr1 and bdnf. Mice exposed to cocaine from E8-E17 showed disorganizaton of cortical development, with abnormal GABA interneuron migration patterns. In addition, CREB levels in the striatum are increased so that the adult brain may be more responsive to cocaine. The epigenetic processes that mediate the developmental effects of cocaine include methylation and acetylation of the bdnf gene. In infancy, cocaine exposed mice have higher bdnf and egr-1 gene expression in the prefrontal cortex, and in adulthood, they have decreased expression. Increased acetylation of H3 and decreased mecp2 binding to the BDNF promoters after cocaine exposure may be responsible for these prenatal effects. In adulthood, prenatally cocaine-exposed mice have a deficit in the extinction of fear learning, suggesting that prenatal cocaine acts via epigenetic processes in the PFC to alter fear memory and also social behavior. The result is that prenatal cocaine exposure alters neural development via epigenetic mechanisms in a gene-specific way.
Epigenetic Programming By Maternal Care
Michael Meaney, McGill University, Canada
Meaney was tied with Ian Maze for talking the fastest during their presentations. His research focuses on how maternal behavior acts as an environmental signal for epigenetic changes in developing infants. Meaney examined the effects of variation in maternal licking and grooming (LG) of pups (low versus high LG mothers) on hippocampal GR expression in the developing infants. His presentation showed the neuroendocrine responses of the pups to maternal licking. These involve changes in the H-P-A response to stress and in the number of hippocampal GR. This is mediated via changes in serotonin levels and nerve growth factor-inducible factor A (NGFI-A) gene expression. Methylation of the 5’ NGFI-A site is modulated by maternal LG, with high LG resulting in hypomethylation and low LG in hypermethylation. Maternal LG from postnatal days 1-6 appears to be the critical period for altering methylation. Maternal LG also mediates glutamic acid decarboxylase 1 (GAD1) promoter methylation in the hippocampus of developing rat pups. The offspring of high LG mothers show enhanced hippocampal GAD1 mRNA expression as well as decreased cytosine methylation and increased histone 3-lysine 9 acetylation (H3K9ac) of the GAD1 promoter. Thus maternal care seems to be able to modulate neurodevelopmental parameters in pups through epigenetic effects on the NGF, GABA and 5-HT pathways.
Transcriptional Regulation of Cocaine-induced Behavioral and Structural Plasticity
Ian S. Maze, Rockefeller University
Another rapid-fire speaker, Maze examined epigenetic mechanisms of cocaine addiction, focusing on the dopamine receptors and their signaling cascades. He identified a role for histone 3 lysine 9 demethylation (H3 k9me2) and lysine demethyltransferase G9a in cocaine-induced changes in the nucleus accumbens. Cocaine induced repression of the G9a expression in the nucleus accumbens is regulated by delta FosB. G9a down-regulation increases dendritic spine plasticity of nucleus accumbens neurons, leading to an enhanced preference for cocaine. Cocaine modulation of histone methylation in the nucleus accumbens may be responsible for increased vulnerability to social stress in cocaine users.
Epigenetic Targets In Neurodegenerative and Psychiatric Disorders.
Ted Abel, University of Pennsylvania
Abel is primarily concerned with HAT and HDACs in learning and memory. His research examined the influence of histone acetylation on memory through sin3a, a transcriptional co-represser. HDAC inhibitors such as trictostatin A may alter the expression of specific genes during memory consolidation. Some of these genes may be nr4a1 and nr4a2, members of the nuclear hormone receptor family. Since BDNF is a target of nr4a1 regulation, the epigenetic regulation of memory consolidation may act through the nr4a1 – BDNF pathway. Since nr4a1 proteins are induced by CREB binding protein, they may be important for the ability of HDAC inhibitors to enhance memory.
Epigenetic Mechanisms Regulating Synapse Function and Behavior
Lisa Monteggia, Southwestern Medical Center, Dallas TX
Monteggia’s research examined the role of DNA methylation in the altered synaptic functions which occur in autism spectrum disorders such as Rett Syndrome. Rett Syndrome is the result of mutations in the methyl-CpG-binding protein 2 (MeCP2) gene, resulting in altered synaptic plasticity. Both DNA methylation and histone deacetylation alter synaptic function and she is using a Rett Syndrome mouse model to examine these.
Loss of MeCP2 in the hippocampus and amygdala increases anxiety, social defeat, motor coordination and learning and memory in these mice. These effects appear to be due to an imbalance between excitatory and inhibitory transmission at synapses. Since the HDAC inhibitor Suberoylanilide hydroxamic acid (SAHA) infused into the amygdala increases anxiety, it appears that MeCP2 is a transcriptional repressor in the basolateral amygdala.
Epigenetic Risk Factors In Social Communication Disorders.
David Skuse, University College London, UK
David Skuse is a child psychiatrist at the Institute of Child Health in London, England. His research is on children with social communication disorders in the natural population. The first thing he noted was that social communication disorders are more common in boys than girls, and the prevalence in boys increases with IQ. One hypothesis for the high number of males with these disorders is that they are due to X-chromosome linked factors and the question is how epigenetic factors are involved. In order to examine the effects of X-chromosome genomic imprinting or neural development, they examined girls with Turner Syndrome (45XO) and developed a mouse model of Turner Syndrome. They found an increase in social communication disorders in girls with Turner Syndrome and that girls with maternal X chromosomes had more social communication disorders than girls with paternal X chromosomes. The Turner Syndrome (39XO) mouse is now being used to examine theories of parental origin of the X chromosome and gene imprinting on the development of the brain and behavior.
**EpiGenie would like to thank Dr. Richard Brown, at Dalhousie University’s Dept. of Psychology in Halifax, Nova Scotia, Canada for providing this conference coverage.