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CONTRIBUTORS
SchahramAkbarian
DepartmentofPsychiatry,andDepartmentofNeuroscience,IcahnSchoolofMedicine
atMountSinai,NewYork,USA
AngelBarco
InstitutodeNeurociencias,UniversidadMiguelHerna´ndez-ConsejoSuperiorde
InvestigacionesCient´ıficas,Alicante,Spain
ElisabethB.Binder
DepartmentofTranslationalResearchinPsychiatry,MaxPlanckInstituteofPsychiatry,
Munich,Germany,andDepartmentofPsychiatryandBehavioralSciences,Emory
UniversitySchoolofMedicine,Atlanta,Georgia,USA
ErboDong
ThePsychiatricInstitute,DepartmentofPsychiatry,CollegeofMedicine,Universityof
IllinoisatChicago,Chicago,Illinois,USA
JaninaGaller
JudgeBakerChildren’sCenter,HarvardMedicalSchool,Boston,Massachusetts,USA
DennisR.Grayson
ThePsychiatricInstitute,DepartmentofPsychiatry,CollegeofMedicine,Universityof
IllinoisatChicago,Chicago,Illinois,USA
AlessandroGuidotti
ThePsychiatricInstitute,DepartmentofPsychiatry,CollegeofMedicine,Universityof
IllinoisatChicago,Chicago,Illinois,USA
LeahN.Hitchcock
DepartmentofBehavioralNeuroscience,OregonHealth&ScienceUniversity,Portland,
Oregon,USA
TimothyJ.Jarome
DepartmentofNeurobiology,UniversityofAlabamaatBirmingham,Birmingham,
AL,USA
K.MatthewLattal
DepartmentofBehavioralNeuroscience,OregonHealth&ScienceUniversity,Portland,
Oregon,USA
RobertH.Lipsky
InovaNeurosciencesInstitute,InovaHealthSystem,FallsChurch,andDepartmentof
MolecularNeuroscience,TheKrasnowInstituteforAdvancedStudy,GeorgeMason
University,Fairfax,Virginia,USA
SermsakLolak
DepartmentofPsychiatry,TheGeorgeWashingtonUniversitySchoolofMedicineand
HealthSciences,Washington,DistrictofColumbia,USA
ix
x Contributors
JoseP.Lopez-Atalaya
InstitutodeNeurociencias,UniversidadMiguelHerna´ndez-ConsejoSuperiorde
InvestigacionesCient´ıficas,Alicante,Spain
FarahD.Lubin
DepartmentofNeurobiology,UniversityofAlabamaatBirmingham,Birmingham,
AL,USA
AmandaMitchell
DepartmentofPsychiatry,andDepartmentofNeuroscience,IcahnSchoolofMedicineat
MountSinai,NewYork,USA
CyrilPeter
DepartmentofPsychiatry,andDepartmentofNeuroscience,IcahnSchoolofMedicineat
MountSinai,NewYork,USA
NadineProvenc¸al
DepartmentofTranslationalResearchinPsychiatry,MaxPlanckInstituteofPsychiatry,
Munich,Germany
DanielleGallerRabinowitz
JudgeBakerChildren’sCenter,HarvardMedicalSchool,Boston,Massachusetts,USA
CarinaRampp
DepartmentofTranslationalResearchinPsychiatry,MaxPlanckInstituteofPsychiatry,
Munich,Germany
PanosRoussos
DepartmentofPsychiatry;DepartmentofNeuroscience,andDepartmentofGeneticsand
GenomicSciences,IcahnSchoolofMedicineatMountSinai,NewYork,USA
PimSuwannarat
DepartmentofGenetics,Mid-AtlanticPermanenteMedicalGroup,Rockville,Maryland,
USA
JasmyneS.Thomas
DepartmentofNeurobiology,UniversityofAlabamaatBirmingham,Birmingham,
AL,USA
NadejdaTsankova
DepartmentofNeuroscience,andDepartmentofPathology,IcahnSchoolofMedicineat
MountSinai,NewYork,USA
PatriciaTueting
ThePsychiatricInstitute,DepartmentofPsychiatry,CollegeofMedicine,Universityof
IllinoisatChicago,Chicago,Illinois,USA
LuisM.Valor
InstitutodeNeurociencias,UniversidadMiguelHerna´ndez-ConsejoSuperiorde
InvestigacionesCient´ıficas,Alicante,Spain
PREFACE
ThisissueofProgressinMolecularBiologyandTranslationalScienceisfocusedon
neuroepigenetics, a still relatively “young” area of research exploring the
roles of chromatin structure and function in the context of development,
adulthood, and disease. In the broadest sense, epigenetics could be viewed
as the mechanisms and molecular bridges by which countless internal and
external factors (re)organize the genomic material that is packaged inside
the nuclei of brain cells, thereby potentially affecting synaptic plasticity
and behavior. Epigenetic mechanisms, which among many others include
proper regulation of DNA cytosine methylation, histone modifications,
andnucleosomalorganization(anucleosomeistheelementaryunitofchro-
matin, with 147bp of genomic DNA wrapped around a core of eight his-
tone proteins), are thought to play an important role in various
neurodevelopmental and neurological disorders.
Someofthesekeyconceptslinkingepigeneticmechanismstoneuronal
plasticityand(mal)adaptivemechanismsintheimmatureandalsoadultbrain
arehighlightedintheeightchapterspublishedinthisissue.Thefirstchapter,
written by Jarome, Thomas, and Lubin, provides a general overview and
detailed discussion on regulatory mechanisms governing covalent DNA
andnucleosomalhistonemodificationsduringmemoryformationandstor-
age in the mammalian brain. Next in Chapter 2, Rampp, Binder, and
Provenc¸al discuss gene(cid:1)environment interactions in the context of
traumatic memory and posttraumatic stress disorder, with particular focus
on steroid hormone and other stress-responsive pathways. In Chapter 3,
Hitchcock and Lattal describe the increasingly recognized importance of
histone methylation and acetylation and other modifications for plasticity-
dependentphenomenainthebrain’srewardcircuit,andthepotentialimpli-
cationsforthetreatmentofaddictionandsubstanceabuseanddependence.
Chapters 4, written by Guidotti, Dong, Tueting, and Grayson, and 5,
written by Lolak, Suwannarat, and Lipsky, discuss epigenetic risk factors
in the context of mood and psychosis spectrum disorders, including
schizophrenia and depression. Next, Lopez-Atalaya, Valor, and Barco in
Chapter 6 provide a highly informative discussion of Rubinstein–Taybi
syndrome (RSTS), a neurodevelopmental syndrome caused by mutations
in the genes encoding the lysine acetyltransferases CBP and p300. RSTS
servesasaprototypeexampleofmonogenicneurologicaldiseaseassociated
xi
xii Preface
with epigenetic dysregulation (histone acetylation in this case), affecting
both the developing brain and mature circuitry via multiple mechanisms.
While aforementioned reviews focus on environmental or genetic mecha-
nisms directly impacting theepigenome of brain cells, Chapter 7 by Galler
and Galler Rabinowitz explores intergenerational effects of early adversity,
includingthepotentialroleofepigeneticsinintergenerationaltransmission.
The final chapter of this issue, written by Mitchell, Roussos, Peter,
Tsankova, and Akbarian, embarks on future developments in the field of
neuroepigenetics(whichwillincludetheexplorationofthenonrandomness
in three-dimensional chromosomal organization and other principles often
referred to as “higher order chromatin”) and how such type of molecular
approaches could provide further insights into genetic and epigenetic risk
architecture of cognitive disorders unique to the human brain.
We,asvolumeeditors,haveaskedtheauthorsofthesevariouschapters
notonlytosummarizetheevidencecollectedsofarintheirfieldbutalsoto
highlightsomeoftheimportanttopicsthataresubjecttoongoingdebateor
hithertounderexplored.Itisourhopeandexpectationthatsuchtypeofdis-
cussionwillfurtherstimulateinterestinepigeneticapproachesandexcitethe
younger generation of neuroscientists about these lines of research. Just to
mentionafewexamplesofdebatementionedinthisissue:Chapter1high-
lights the bulk of the epigenetics literature pertaining to the learning and
memory field and is preoccupied with mechanisms that are primarily rele-
vant for initial acquisition of memory, while much less attention has been
giventotheequallyimportantstagesofconsolidation,retrieval,andextinc-
tion. This chapter also highlights the potential epigenetic targets that may
serve to improve or enhance memory function, while Chapter 5 cautions
on the effects of neurological therapies on these epigenetic mechanisms.
Severalchaptersincludesomeremarksontissuespecificityofepigeneticsig-
nals, which is particularly relevant in the context of approaches aimed at
exploring epigenetic signals in blood and the periphery as biomarkers for
brain-relateddisease(Chapter2)orchromatinstatemappingsinbraintissue
with its extremely complex and highly heterogenous mixture of neuronal
and glial subpopulations (Chapter 8). Furthermore, Chapter 3 points to
twootherimportantproblemsinneuroepigeneticsincludingtheoftenunre-
solvedquestionofcorrelationalassociationversuscausalmechanism,andthe
difficulties and challenges in linking the molecular and behavioral pheno-
typestotheprevailingtheoriesonrewardandmemory.Chapter7touches
upon the still very novel and provocative concept of transgenerational
inheritance.
Preface xiii
We, as volume editors, are extremely grateful for the privilege to have
worked with an outstanding group of colleagues. We would like to thank
Ms. Helene Kabes for outstanding editorial assistance and the editors of
the PMBTS series, Dr. Michael Conn and Ms. Mary Ann Zimmermann,
for their support.
SCHAHRAM AKBARIAN
FARAH LUBIN
CHAPTER ONE
The Epigenetic Basis of Memory
Formation and Storage
Timothy J. Jarome, Jasmyne S. Thomas, Farah D. Lubin
DepartmentofNeurobiology,UniversityofAlabamaatBirmingham,Birmingham,AL,USA
Contents
1. IntroductiontotheNeurobiologyofLearningandMemory 2
2. EpigeneticMechanismsofMemoryConsolidation 5
2.1 Histoneacetylation 5
2.2 Histonemethylation 6
2.3 Histonephosphorylation 8
2.4 Histoneubiquitinationandsumoylation 9
2.5 DNAmethylation 10
2.6 Summaryofepigeneticregulationofmemoryconsolidation 12
3. EpigeneticMechanismsofMemoryReconsolidation 14
3.1 Histonemodificationsduringmemoryreconsolidation 14
3.2 DNAmethylationduringmemoryreconsolidation 16
3.3 Epigeneticregulationofreconsolidation-dependentmemoryupdating 16
3.4 Summaryofepigeneticregulationofmemoryreconsolidation 17
4. EpigeneticMechanismsofMemoryExtinction 19
5. FutureDirectionsandConclusions 20
Acknowledgments 24
References 24
Abstract
Theformationoflong-termmemoryrequiresaseriesofcellularandmolecularchanges
thatinvolvetranscriptionalregulationofgeneexpression.Whilethesechangesingene
transcriptionwereinitiallythoughttobelargelyregulatedbytheactivationoftranscrip-
tionfactorsbyintracellularsignalingmolecules,epigeneticmechanismshaveemerged
asanimportantregulatoroftranscriptionalprocessesacrossmultiplebrainregionsto
formamemorycircuitforalearnedeventorexperience.Duetotheirself-perpetuating
natureandabilitytobidirectionallycontrolgeneexpression,theseepigeneticmecha-
nismshavethepotentialtonotonlyregulateinitialmemoryformationbutalsomodify
and update memory over time. This chapter focuses on the established, but poorly
understood, role for epigenetic mechanisms such as posttranslational modifications
ofhistone proteinsandDNAmethylationatthedifferent stagesofmemorystorage.
Additionally, this chapter emphasizes how these mechanisms interact to control the
ProgressinMolecularBiologyandTranslationalScience,Volume128 #2014ElsevierInc. 1
ISSN1877-1173 Allrightsreserved.
http://dx.doi.org/10.1016/B978-0-12-800977-2.00001-2
2 TimothyJ.Jaromeetal.
idealepigeneticenvironmentformemoryformationandmodificationinneurons.The
readerwillgaininsightsintothelimitationsinourcurrentunderstandingofepigenetic
regulationofmemorystorage,especiallyintermsoftheircell-typespecificityandthe
lackofunderstandingintheinteractionsofvariousepigeneticmodifierstooneanother
toimpactgeneexpressionchangesduringmemoryformation.
1. INTRODUCTION TO THE NEUROBIOLOGY OF
LEARNING AND MEMORY
The process of encoding long-term memories in the brain for later
recall is complex, requiring simultaneous engagement of neurons across
multiple brain regions. The neuronal circuits recruited for this process
canvarybasedonthetypeofbehavioraltaskbutincludeneuronsinthehip-
pocampus for processing of contextual and spatial information,1 the amyg-
dala for processing of emotional content,2 and the insular cortex for
processingofgustatoryinformation.3Forexample,oneofthemostutilized
behavioralparadigmsforelucidatingthemolecularandcellularmechanisms
of memory formation and storage is Pavlovian fear conditioning.4 In this
paradigm, a neutral conditioned stimulus (CS) is paired with a noxious
unconditionedstimulus(UCS).Oncepaired,presentationoftheCSbyitself
canelicitemotionalandphysiologicalresponsessimilartothoseproducedby
theaversiveUCS.Duetotheemotionalcomponentofthetask,associations
acquiredusingPavlovianfearconditioningrequirestheamygdalaforlong-
termmemoryformationandstorage.However,somefearmemories,suchas
those that are contextually based, also require the hippocampus, anterior
cingulatecortex(ACC),andretrosplenialcortex,whereasotherfearmem-
ories, such as those that are auditory-based, do not rely on these regions
(reviewed in Ref. 5). Thus, memory storage is a dynamic process that
requires synaptic plasticity in many different brain regions, though the
memory-related brain regions required can vary greatly depending on the
behavioral paradigm used.
Once acquired, memories can go through several different stages of
modificationandstorage (Fig.1.1). Forexample,followingtheacquisition
of a fear conditioning task, there is a time-dependent process (<6h) that
occurs at the molecular level within the hippocampus and other brain
regions, which is necessary to transfer labile short-term memories to stable
long-termmemories,aprocessreferredtoasmemoryconsolidation.6Once
TheEpigeneticBasisofMemoryFormationandStorage 3
Figure 1.1 Memories go through several distinct phases of storage at the molecular
level. In this example, a rat is trained to a contextual fear conditioning paradigm in
whichanovelcontextispairedwithamildaversivefootshock.Followingthetraining
experience,thelearnedassociation(contextplusfootshock)willconsolidateaprocess
wheregenetranscriptionandproteinsynthesisoccur.Whentheanimalisreexposedto
the training context in the absence of the footshock, it displays increased freezing
behaviorasanindicationofmemoryretention.Additionally,uponretrieval(reexposure
tothetrainingcontext),theconsolidatedmemoryentersanewstateoflabilityneces-
sary for memory updating and modification, known as reconsolidation. This process
maintainsorincreasesfearonlatertests.However,iftheanimalisexposedtothetrain-
ingcontextmanytimesoverwithoutreceivingtheshock,thememorywillextinguish,
which results in a reduction in fear on later tests. Red lines denote theoretical time
courseoftheconsolidationandreconsolidationprocesses.
amemoryisconsolidated,itwasgenerallybelievedtobenolongersuscep-
tible to disruption. However, upon retrieval, a once consolidated memory
“destabilizes” and undergoes a new time-dependent molecular process
(2–6h) termed reconsolidation, which is necessary to return the memory
tolong-termstorage.7Thisreconsolidationprocessisthoughttobeaunique
phase in which memories for previously acquired associations or learned
4 TimothyJ.Jaromeetal.
taskscanbemodified.8Consistentwiththis,reconsolidationonlyoccursin
the presence of new information and can be used to persistently attenuate
memoriesfor traumaticevents,9,10suggestingthatthereconsolidationpro-
cess may have important clinical implications. Additionally, upon repeated
exposuretotheCSassociatedwiththeoriginallearningexperiencewithout
the presentation of the UCS, some memories can undergo extinction
wherebytheCSnolongerelicitstheemotionalandphysiologicalresponses
it acquired during the initial learning event. This “extinction” process is a
form of new inhibitory learning that depends largely on the amygdala and
infralimbicregionofthemedialprefrontalcortexandisoftenusedinther-
apeutic settings to help reduce fear and emotional distress associated with
memories for traumatic events.11,12 Thus, memories for learned tasks and
associationscangothroughseveraldifferentstagesofmodificationandstor-
age that allow for it to be altered and persist over time.
For decades, the leading theory supporting the process of long-term
memoryformationandstorageisthatdynamicchangesingenetranscription
and protein synthesis in neurons are required.13 Consistent with this,
numerousstudieshaveshownimpairmentsinlong-termmemoryforavari-
ety of different behavioral tasks following transcriptional or translational
blockade in neurons (reviewed in Ref. 5). Additionally, memory impair-
ments are observed following pharmacological and genetic manipulations
of signaling molecules thought to be upstream of transcription and transla-
tion, including NMDA receptor, protein kinase A, and calcium/
calmodulin-dependent protein kinase II-dependent signaling (for review,
see Johansen et al.14). Furthermore, behavioral training results in bidirec-
tional changes in gene expression, suggesting that memory formation
requires both increased and decreased gene transcriptions in neurons
(e.g., Refs. 15,16). Collectively, these results support the theory that
dynamicregulationofmRNAtranscriptionisacriticalstepinmemoryfor-
mation and storage in neurons. However, while some transcription factors
havebeenimplicatedinmemoryconsolidation(reviewedinRef.17),very
little is known about how up- or downregulation of gene transcription is
altered inmemory-related brainregions during long-term memoryforma-
tionandstorage.Recently,thefieldof“neuroepigenetics”hasemergedasa
viable mechanism to help further define how dynamic gene transcription
changes are modified during the memory storage process. In this chapter,
the reader willgain an understanding of therole of epigenetic mechanisms
intranscriptionalregulationofgenesinneuronsthatarenecessaryforlong-
termmemoryformationandstorage.Further,assumingthattheseepigenetic
