Behavioral Epigenetics

Agenda

*Presentation times are subject to change.

Day 1: Friday, October 29, 2010

Session I: Background and Perspectives

What is Behavioral Epigenetics?

Barry M. Lester PhD
Warren Alpert Medical School of Brown University, Providence, RI

The emergence of the field of epigenetics has forever changed the way we think about how we are affected by our genetic make-up. Although scientists have known about epigenetic marks since the 1970s there has been a more recent explosion of work on epigenetic mechanisms. There are ongoing discussions about how to define epigenetics including attempts to develop a consensus definition of “epigenetics” for consideration by the broader research community. The application of epigenetics to the study of behavior has ushered in the new fast-growing field of behavioral epigenetics but this field has not been described. In this presentation, we attempt to characterize and describe behavioral epigenetics as a discipline. We will provide an overview of the work that has been done in this field including behavioral processes, epigenetic mechanisms, species, tissues and “stressors” that have been studied. This review will help us understand how far we have come. It will also highlight some of the special issues and problems that are unique to the study of behavioral epigenetics and suggest directions for future work in this relatively new frontier. Some of these issues will be discussed here and will also be discussed throughout this conference.

Epigenetics: Basic Processes and Mechanisms

Eric J. Nestler MD, PhD
Fishberg Department of Neuroscience, Mount Sinai School of Medicine, New York, NY

Epigenetic regulation, also known as chromatin remodeling, in neurons describes a process where the activity of a particular gene is controlled by the structure of chromatin in that gene’s proximity. Chromatin remodeling is complex and involves multiple covalent modifications of histones (e.g., acetylation, phosphorylation, methylation), ATPase-containing protein complexes which move histone oligomers along a strand of DNA, methylation of DNA, and the binding of numerous transcription factors and transcriptional co-activators and co-repressors, all of which act in a concerted fashion to determine the activity of a given gene. Epigenetic regulation is crucial for nervous system development, and several common mental retardation syndromes and related neurodevelopmental disorders are caused by abnormalities in chromatin remodeling mechanisms. Epigenetic regulation also occurs in the mature, fully differentiated brain, and provides unique mechanisms which may underlie stable changes in gene expression in brain both under normal conditions (e.g., learning and memory) and in several pathological states (e.g., depression, drug addiction, and schizophrenia). In some rare cases (e.g., gene imprinting), epigenetic modifications can be transmitted to offspring, which raises the possibility that behavioral experience in adult life might influence gene expression in subsequent generations. However, there has not to date been definitive evidence for epigenetic transmission of behavioral experience. While work on epigenetic mechanisms in brain is still in early stages, it promises to improve our understanding of brain plasticity and the pathophysiology of psychiatric disorders as well as possibly lead to the development of fundamentally new treatments for these conditions.

Epigenetics, Intergenerational Inertia, And Human Adaptation: Hypotheses And Policy Implications

Christopher W. Kuzawa PhD MSPH^1
1Department of Anthropology, Northwestern University, Evanston, IL
²Cells 2 Society: The Center for Social Disparities and Health at the Institute of Policy Research, Northwestern University, Evanston, IL

The rapid pace of human evolutionary expansion has provided minimal opportunities for genetic adaptation to the diverse social and ecological conditions that human populations inhabit. As such, the success of our species has largely relied upon non-genomic adaptive mechanisms that allow more rapid adjustment than that afforded by natural selection. The capacity to modify developmental biology in response to environmental change (developmental plasticity), undergirded by epigenetic and other processes, is one such adaptive mode and an important contributor to modern human biological variation. Although plasticity allows tailoring of behavior and biology to local conditions, many important developmental decisions are made early in development and may not be reversed (e.g. critical periods). Because the human lifespan lasts for multiple decades and ecological change is often stochastic rather than predictable, it follows that the suitability of a behavioral or developmental phenotype established in response to early environments will invariably decline with age. In this talk, I will review evidence that a subset of epigenetic processes work around this problem by integrating information across generations, thereby yielding relatively stable signals of typical social or physical conditions in the recent past. The tendency for parental experiences to leave a lingering imprint on developmental and epigenetic settings in offspring and grandoffspring (phenotypic inertia) could help lineages track more durable, sustained ecological trends, and thereby provide the developing organism with a higher fidelity cue of conditions likely to be experienced across its lifecycle. Predictions of this model and policy implications will be discussed.

Session II: Learning and Memory

Epigenetic Mechanisms In Memory Formation

J. David Sweatt, PhD
UAB School of Medicine, Birmingham, AL

This presentation will address the idea that conservation of epigenetic mechanisms for information storage represents a unifying model in biology, with epigenetic mechanisms being utilized for cellular memory at levels from behavioral memory to development to cellular differentiation.

The area of epigenetics is unfamiliar to many neurobiologists: epigenetic mechanisms typically involve alterations in chromatin structure, which in turn regulate gene expression. “Epigenetics” is functionally equivalent to the mechanisms allowing stable maintenance of gene expression that involve physically “marking” DNA or its associated proteins through post-translational modification. Thus, regulation of chromatin structure and regulation of direct methylation of DNA are the principal mechanisms of epigenetic regulation.

Do epigenetic mechanisms operate in behavioral memory formation? We have generated several lines of evidence that support this idea. 1. Contextual fear conditioning triggers alterations in hippocampal histone acetylation, and contextual latent inhibition training triggers similar but distinct changes in histone acetylation. 2. The methyl-DNA binding protein MeCP2 (the Rett mental retardation syndrome gene product) alters chromatin structure and regulates hippocampal LTP and memory formation. 3. Inhibitors of DNA methylation block both hippocampal LTP and associative learning in vivo.

Conclusions - An emerging idea is that the regulation of chromatin structure, mechanistically via histone modification and DNA methylation, may mediate long-lasting behavioral change and learning and memory. We find this idea fascinating because similar mechanisms are used for triggering and storing long-term "memory" at the cellular level, for example when cells differentiate.

The Role Of Chromatin Modifying Enzymes In Long-Term Memory Processes

Marcelo Wood PhD
University of California-Irvine, Irvine, CA

Chromatin, the complex of DNA and associated proteins, is a physical barrier to transcription mechanisms. The manipulation of chromatin is critically involved in regulating gene expression for a number of processes including the formation of long-term memory. Chromatin modifying complexes, which contain histone-modifying enzymes, regulate access to the underlying genomic DNA by relaxing chromatin structure and providing docking sites for additional regulatory factors. The enzymes that regulate levels of histone acetylation are histone acetyltransferases (HATs) and histone deacetylases (HDACs), and the interplay between HATs and HDACs is pivotal for the regulation of gene expression required for long-term memory processes. The alluring aspect of investigating these enzymes is that chromatin modifications may provide transient, and subsequently, potentially stable epigenetic marks in the service of activating and/or maintaining transcriptional processes. These in turn may ultimately participate in the molecular mechanisms required for neuronal changes subserving long-lasting changes in behavior. As an epigenetic mechanism of transcriptional control, chromatin modification has been shown to participate in maintaining cellular memory (e.g. cell fate) and may underlie the strengthening and maintenance of synaptic connections required for long-term changes in behavior. We use a combined genetic, molecular, pharmacological, and behavioral approach to examine the role of specific HATs and HDACs in learning and memory. Our results demonstrate that the CREB-binding protein (CBP) is a key HAT necessary for long-term memory formation and that histone deacetylase 3 (HDAC3) is a key negative regulator of long-term memory. Further understanding of these mechanisms promise to elucidate basic mechanisms underlying learning and memory and provide novel therapeutic strategies for treatment of cognitive disorders.

Signaling and Epigenetic Mechanisms in Stress-Related Memory Formation

Johannes M. H. M. Reul PhD
Henry Wellcome Laboratories for Integrative Neuroscience and Endocrinology, University of Bristol, United Kingdom

Adaptation to emotionally stressful events is thought to involve changes in gene expression in limbic brain regions such as the amygdala and hippocampus. We identified distinct signaling and epigenetic mechanisms in hippocampal dentate gyrus granule neurons that are critical for appropriate behavioral adaptation including memory formation of stressful events. We found that stressful challenges such as forced swimming (FS), novelty, Morris water maze (MWM) and fear conditioning (FC) training evoke specific post-translational changes (i.e. Serine10 phosphorylation (S10p) and Lysine14 acetylation (K14ac)) in the nucleosomal protein histone H3. These epigenetic changes were only observed in dentate gyrus neurons and resulted in the induction of c-Fos and other gene products. Signaling to the chromatin occurred through glucocorticoids and glutamate acting via glucocorticoid receptors (GRs) and NMDA receptors (NMDA-Rs), respectively. NMDA-R activation led to activation of the ERK MAPK pathway in these dentate neurons resulting in the activation of at least two downstream kinases, i.e. mitogen- and stress-activated kinase1 (pMSK1) and Ets-like protein-1 (pElk-1). Formation of pMSK1 (a H3 kinase) and pElk-1 (through recruitment of p300, a histone acetyl transferase) resulted in the phospho-acetylation of H3 and induction of gene expression (e.g. c-Fos). GRs strongly facilitated pMSK1 and pElk-1 formation in dentate neurons. Furthermore, a series of studies of us and others showed that these dentate epigenetic mechanisms are critical for the formation of memories associated with stressful events such as FS, MWM and FC.
Support: BBSRC and MRC, UK

Conference Location:

UMass Boston Campus Center
100 Morrissey Blvd.
BALLROOM 3550
3rd Floor
Boston, MA 02125

Directions

Public Transportation (Recommended)

Subway:
Take the Red Line to JFK/UMass Station. A free shuttle bus will carry you to the campus.

For more information click here.

Commuter Rail:
Take the commuter rail to the JFK/UMass station from the South Shore on the Middleboro and Plymouth lines.

Bus:
Kenmore Square stop (service all day): Take the Number 8 bus; the last one leaves campus at 1 a.m.
Forest Hills stop (rush hour only):Take the Number 16 bus

Taxi services

Bay State Taxi: 617-566-5000

Metro Cab: 617-782-5500

Independent Cab: 617-426-8700

Checkered Cab: 617-536-7000

Calling from the Campus Center:
Next to the elevator bank located on the UL level of the Campus Center (entry level from the parking lots) there is a phone with 3 pre-programmed phone numbers for taxi services. Those wishing to use a cab service can call any of these numbers indicating both pick-up and drop-off locations, and form of payment.

Driving Directions

From the North:
Take Interstate 93 South through Boston to exit 15 (JFK Library/South Boston/Dorchester) and follow the University of Massachusetts signs along Columbia Road and Morrissey Boulevard to the campus.

From the South:
Take Interstate 93 North to exit 14 (JFK Library/Morrissey Boulevard) and follow Morrissey Boulevard north to the campus.

From the West:
Take the Massachusetts Turnpike (Interstate 90) east to Interstate 93. Take I-93 South one mile to exit 15 (JFK Library/South Boston/Dorchester) and follow the University of Massachusetts signs along Columbia Road and Morrissey Boulevard to the campus.

Parking on Campus

All visitors to the Campus Center are encouraged to park in the North Lot (see Map) $6 per single use Pickup/drop off is allowed at the Main entrance on the circular road in front of the building.

Suggested Hotel Accommodations in Downtown/Financial District and Back Bay
(within walking distance of the T’s Red line or Green line)

Club Quarters in Boston
161 Devonshire Street
Boston, MA 02110
Phone: 617-357-6400
Website: http://www.clubquarters.com/loc_boston.aspx

Boston Marriott Copley Place
110 Huntington Avenue Boston
Boston, MA 02116
Phone: 617-236-5800
Website: http://www.CopleyMarriott.com

The Boston Park Plaza Hotel & Towers
50 Park Plaza at Arlington Street
Boston, MA 02116
Phone: 617-426-2000
Website: http://www.bostonparkplaza.com/

Copley Square Hotel
47 Huntington Avenue
Boston, MA 02116
Phone: 617-536-9000
Website: http://www.copleysquarehotel.com

Courtyard by Marriott, Boston Copley Square
88 Exeter Street
Boston, MA 02116
Phone: 617-437-9300
Website: http://www.courtyardboston.com

The Eliot Hotel
370 Commonwealth Ave
Boston, MA 02215
Phone: 617-267-1607
Website: http://www.eliothotel.com

Fairmont Copley Plaza Hotel
138 Saint James Avenue
Boston, MA 02116
Phone: 617-267-5300
Website: http://www.fairmont.com/copleyplaza

The Lenox Hotel
61 Exeter Street
Boston, MA 02116
Phone: 617-536-5300
Website: http://www.lenoxhotel.com/

For more information about these and other hotels in the Downtown/Financial district or Back Bay area please click here

Suggested Hotel Accommodations around UMass Campus Center

DoubleTree Club Hotel Boston Bayside
240 Mount Vernon Street
Boston, MA 02125
Phone: 617-822-3600
Website: http://doubletree1.hilton.com

Comfort Inn Boston
900 Morrissey Boulevard,
Boston, MA 02122
Phone: 617-287-9200
Website: http://www.choicehotels.com/ires/hotel/ma109

Ramada Boston
800 Morrissey Boulevard
Freeport St
Boston, MA 02122
Phone: 617-287-9100
Website: http://www.ramada.com

General Information about Boston

Please click here

Special Needs and Additional Information

For any additional information and for special needs, including child/family care resources available to conference attendees, please e-mail Deanna Vollmer or call Deanna Vollmer 212.298.8611.