pdf, 2 MiB

Review ArticleStructural Synaptic and Epigenetic Dynamics ofEnduring Memories

Ossama Khalaf and Johannes Graumlff

Laboratory of Neuroepigenetics Brain Mind Institute Faculty of Life Sciences Ecole Polytechnique Federale de Lausanne (EPFL)1015 Lausanne Switzerland

Correspondence should be addressed to Johannes Graff johannesgraeffepflch

Received 18 September 2015 Revised 23 November 2015 Accepted 24 November 2015

Academic Editor Pablo Munoz

Copyright copy 2016 O Khalaf and J Graff This is an open access article distributed under the Creative Commons AttributionLicense which permits unrestricted use distribution and reproduction in any medium provided the original work is properlycited

Our memories are the records of the experiences we gain in our everyday life Over time they slowly transform from an initiallyunstable state into a long-lasting formMany studies have been investigating from different aspects how amemory could persist forsometimes up to decades In this review we highlight three of the greatly addressed mechanisms that play a central role for a givenmemory to endure the allocation of the memory to a given neuronal population and what brain areas are recruited for its storagethe structural changes that underlie memory persistence and finally the epigenetic control of gene expression that might regulateand support memory perseverance Examining such key properties of a memory is essential towards a finer understanding of itscapacity to last

1 Introduction

Based on experience memory is the capacity of an individualto acquire store and retrieve information The physicalsubstrate of suchmemories in our brains is known asmemorytrace or as first coined by the German biologist Semon (1859ndash1918) as ldquoengramrdquo [1ndash3] One of the fundamental questionsin memory research is how the experiences that we acquiretransform into engrams that persist over time It is generallyacknowledged that the records we form from our dailyexperiences are not stored instantaneously but rather retainedin an initially labile state that gradually transforms into amore stable trace or engram that is characterized by resistanceto disruption [4ndash6] Although this view has been challengedby the reconsolidation hypothesis stipulating that even astably stored memory could become transiently sensitive todisruption upon recall [6 7] it is evident that not all forms ofmemories are amenable to disruption [8] This is particularlyrelevant for strong memories induced by an intensive train-ing protocol and long-lasting forms of memories rangingfrom several weeks to months [9 10] in age Based on thesegrounds but notwithstanding several studies testifying tothe amenability of even long-term memories to disruption

[11 12] in this review we focus on 7-day-oldmdashand oldermdashmemories as being remote and with the potential to endureand we outline three mechanisms that might contribute tosuch endurance firstmemory allocation and storage secondstructural neuronal changes and third nuclear epigeneticdynamics (Figure 1)

Memory allocation refers to an early process by whichcertain neural circuits are assigned to stow a specific memoryand what might favor the allocation of a memory into aspecific population of neurons over others In this reviewwe focus on some of the well-described elements that governsuch allocation still it is clear thatwe are only at the beginningof understanding the entire process of memory allocationand manymore aspects thereof remain to be identified Onceallocated the question of where the memory is stored andwhat brain regions upkeep the memory is another one ofutmost importance The whereabouts of a specific memoryis thought to be dependent on how old this memory isThe more nascent it is the more it will be hippocampal-dependent but as it matures it will change such dependenceto higher cortical regions [13 14] Here we describe brainareas that have been defined to be essential for the supportof a long-lasting memory

Hindawi Publishing CorporationNeural PlasticityVolume 2016 Article ID 3425908 11 pageshttpdxdoiorg10115520163425908

2 Neural Plasticity

MeMeDNA methylation

Histone PTMsEpigenetic regulation

Me

Structural plasticity

AcetylationPhosphorylation

Memory allocation HPC

AMY

PFC

PFC prefrontal cortexHPC hippocampusAMY amygdala

Figure 1 Schematic illustrating three essential mechanisms that might contribute to remote memory storage and thus memory endurancein the (rodent) brain which are discussed in this review First during memory allocation learning induces the activity of a specificsubpopulation of cellsmdashlikely spread across different brain areasmdashwhich will become recruited into thememory traceThe amygdala (AMY)the hippocampus (HPC) and the prefrontal cortex (PFC) are known to be activated during memory allocation (for details see text) Secondin cells allocated to a specific memorymdashalso known as the memory engram [1ndash3]mdashstructural changes at the level of dendritic spines havebeen demonstrated by several studies These changes are exclusive to the cells of the memory trace or engram (red) but not observedin other cells (grey) [53] Third memory engram cells are also likely to be characterized by epigenetic changes such as posttranslationalmodifications (PTMs) on histone proteins and methylation of the DNA the core chromatin constituents Note however that such engram-specific engagement of epigenetic mechanisms remains to be experimentally demonstrated

Neural Plasticity 3

Furthermore many neuroscientists believe that mem-ories are encoded into neurons as structural changes insynaptic connections Indeed such structural plasticity isunder comprehensive study in order to understand howbrain circuits are modifying themselves in terms of numberand strength of synaptic connections that correlate with thepersistence of a memory [15ndash17] We discuss these physicalchanges in synapses and their potential to support enduringmemories

Lastly we also discuss the epigenetic modifications thatare associated with long-lasting memories We shed light onsuch modifications to the DNA or the histone tails that couldlead to a cascade of changes in gene expression a key featureof long-term memories [18] and which might thereby beable to assist memories to persist throughout the life of anindividual

2 Memory Allocation and Storage

Once formedmemories gradually transform froman initiallyvulnerable state to amore permanent state that is increasinglypersistent to disruption Such process of postexperiencememory stabilization was first described by Muller andPilzecker referring to it as ldquomemory consolidationrdquo [4 5]Later two different types of memory consolidation have beendistinguished cellularsynaptic and systems consolidationsCellular consolidation is a rather fast process taking placewithin the first fewhours following learning andnecessary forthe initial stabilization of memories in hippocampal circuits[13] In contrast the systems consolidation process is slowerand involves a time-dependent gradual reorganization ofthe brain regions that support the memory with the mem-ory dependence shifting from the hippocampus to corticalregions [14] This led to the contemporary view of systemsconsolidation which states that the hippocampus (HPC) ismerely a temporary store for new information while itspermanent storage depends on largely distributed corticalnetworks [14]

In this section we review what molecular and cellularevents govern memory allocation in or to a certain neuronalpopulation and then what brain regions support long-lastingmemory storage

21 Memory Allocation By definition memory allocationis the set of processes that determine where informationis stored in a particular neural circuit [19] Several studiesshowed that such allocation is not random but rather depen-dent on specific molecular mechanisms [20ndash22] In one ofthese studies [20] using a viral vector Han et al artificiallyincreased the levels of CREB (cAMP responsive element-binding protein) a transcription factor important for thestability of synaptic potentiation andmemory [23] in neuronsof the lateral amygdala (LA) a subcortical brain structureimplicated in emotional memories [24 25] in mice Twenty-four hours after a tone fear conditioning training the micewere tested for the tone and sacrificed 5min later Usingcellular compartment analysis of temporal activity by fluores-cence in situ hybridization (catFISH) LA neurons transfectedwith CREBmdashidentified by its GFP fluorescent tagmdashwere

found to be three times more likely than their neighboringnontransfected cells to express activity-regulated cytoskeletal(Arc) a gene required for synaptic function and memory[26 27] This suggests that CREB levels bias neurons tobecome part of the engram and to be encoded by the toneconditioning in the amygdala

In a subsequent loss-of-function study cells that werevirally transfected with CREB in the same behavioralparadigm were ablated using diphtheria toxin receptor(DTR) In this system the expression of the DTR is inducibleby the Cre-recombinase which is also found in the sameviral construct making all the cells that receive the constructeventually express the DTR Following the tone test (24 hafter training) the mice were injected with the diphtheriatoxin (DT) that will only interact with the cells expressingthe DTR and kill them The experimental group (CREB viralvector transfected and DT injected) showed a significantimpairment in tone conditioning when tested 2 days afterthe DT injection [21] Similar results were obtained usinga different approach that allows for reversible neuronalactivation instead of permanently killing the cells [22]Therethe Drosophila allostatin inhibitory receptor was delivered tothe LA through the same viral construct providing CREBand pronounced amnesia for tone conditioning was obtainedas a result of inactivating these cells by allostatin peptidetreatmentThis amnesia was reversed upon retesting themiceone day later without the allostatin peptides demonstratingthe reversibility of the allostatin effects and the link betweenactivity in theCREB cells and recall [22]Despite the exclusivefocus on CREB in the previous studies the convergentfindings using three different strategies strongly support itsimportant role in memory allocation in the amygdala

Another influential factor that determines the allocationprocess appears to be neurogenesis in the dentate gyrus (DG)Using 5-bromo-21015840-deoxyuridine (BrdU) a permanent stainthat intercalates with dividing DNA allowing the tracing ofnewly born neurons a recent study showed that 4- to 8-week-oldDGneurons are preferentially recruited after spatiallearning [28] In contrast 2-week-old neurons integratedwith lower efficiency and 1-week-old neurons did not inte-grate at all [28] In line with a recent study showing that4-week-old (but not 1-week-old) neurons have the essentialsynaptic structure and physiology to support the appropriateconnectionswith hippocampal circuits [29] this suggests thatthe timing of neuronal development relative to training isindeed vital in the memory allocation process Neverthelessthe nature of memory allocation processes that take place inbrain areas devoid of neurogenesis and outside the amygdalaremains to be determined

22 Memory Storage After the initial allocation of a memoryto a specific neural circuit begins the more prolonged processof systems consolidation that involves gradual reorganizationof the brain regions that support memory formation andstorage [13 14] Classical studies characterizing memoryloss in patients with lesions of the medial temporal lobe(MTL) [30 31] revealed that the hippocampus serves as atemporary store for new information but that permanentinformation storage depends on a broadly distributed cortical

4 Neural Plasticity

network [14] These human data are indeed consistent withobservations that hippocampal lesions in the first week aftertraining but not thereafter disrupt contextual fear memoriesin rats and thus maintaining a proper hippocampal trace iscrucial to establish remote memories in the cortex [32] Frommore refined studies several molecules have in themeantimebeen identified that maintain the hippocampal trace of amemory in the days following training for the persistenceinto a remote memory [33 34] (for a more detailed overviewof other molecules that are involved in memory storagebut that have not been specifically assessed for remotememory storage the reader is referred to [19]) For instancewhen NMDA (N-methyl-D-aspartate) receptor (NMDAR)function was inducibly suppressed in the CA1 region in theweek following the training of two hippocampal-dependenttasks (Morris Water Maze and contextual fear conditioning)remote memory formation for these tasks was blockedHowever when done at later time points the suppressionof the NMDAR function did not affect the remote memoryformation [33] Similar results were obtained when levelsof 120572-calciumcalmodulin kinase II (120572-CaMKII) a signalingenzyme mainly expressed in the excitatory neurons of theforebrain and essential for neuronal plasticity [35] werealtered [34] overexpressing a dominant-negative form of120572-CaMKII in the week after training but not afterwardsblocked the formation of remote contextual fear memories[34] Together these results support the importance of theHPC especially during the first week following encoding formemory consolidation in cortical networks and furthermoresuggest that there is a crucial week-long window duringwhich normal hippocampal activity is needed for the mem-ory to be consolidated

However several studies found that cortical regions arealso implicated in the initial phase ofmemory formation [36ndash39] thus challenging the idea that the HPC is solely involvedin this process In one of the recent studies in this regard[38] real-time optogenetic inhibition of excitatory medialprefrontal cortex (mPFC) neurons during contextual fearconditioning showed that such temporally precise inhibitionimpaired the formation of long-term associative memorytested 30 d after of acquisition [38] In another recent study[39] using a doxycycline-inducible mouse line (TetTag) totag the activated neurons [40] optogenetic stimulation of theactivated neural population during contextual fear memorytraining in the retrosplenial cortex (RSC) a cortical regionimplicated in episodic memories and emotional associations[41ndash44] was sufficient to produce fear memory retrieval evenwhen tested until 2 d after acquisition [39] These resultsare in line with previous studies [36 37] showing that thePFC is critically involved in memory encoding and thatits inactivation by local infusion of NMDAR antagonistcould block contextual memory acquisition in mice [36] andlearning of new paired-associates in rats [37]

In another intriguing study Lesburgueres et al used asocial transmission of food preference (STFP) test where anassociative olfactory memory develops after a study animal(observer) learns about the safety of a certain food (novelodor for the observer) from an interaction session with

another animal that has already tasted the food (demonstra-tor)Then the observer shows reduced fear towards this novelfood upon the first encounter and significant consumptionthereof The authors first showed that the acquisition of suchfood preference memory is dependent on the orbitofrontalcortex (OFC) only for 30-day-old remote memory but notfor recent memory (24 h after training) and that for the firstperiod after training (7 d) it is mainly HPC-dependent [45]Nevertheless the authors then went on to show that there isan intricate interplay between the HPC and the OFC for suchmemory to endure Using the excitatory glutamate receptorantagonist 6-cyano-7-nitroquinoxaline-23-dione (CNQX) toblock the activity of the OFC during the 2-week periodfollowing training an unexpected memory loss to a novelodor test was observed 30 d later Likewise inactivating theOFC immediately before training blocked the memory after30 d and not after 7 d indicating that early cortical activity isrequired for subsequent stabilization of such memory [45]

Beyond memory formation several studies investigatedthe role of extrahippocampal structures in remote memorystorage from which the anterior cingulate cortex (ACC)emerges to play a key role at least in remote contextual fearmemory storage [46ndash49] Thus lidocaine-mediated phar-macological inactivation of the ACC disrupts the retrievalof remote contextual fear memory in mice 18 d and 36 dafter training while inactivating the prelimbic cortex (PL)mdasharegion located near the ACC in the mPFCmdashat the same timepoints did not disrupt the very same memory [46] Similarlythe lidocaine-mediated inactivation of the PFC and the ACCwas shown to impair remote spatial memory retrieval whentested 30 d after acquisition [47] These results are in linewith previously reported data from a study using noninvasivefunctional brain imaging to examine the metabolic activityof different brain regions underlying spatial discriminationmemory storage in mice [48] In this study increasedmetabolic activation in the frontal cortex together with therecruitment of the ACC and temporal cortices was observed25 dmdashbut not 5 dmdashafter acquisition [48] Together thesefindings indicate a high level of involvement of cortical areasduring the retrieval of remote memories postulating theseareas to be vital structures for remote memory storage

Finally from a reconsolidation point of view and howmemory storage could affect such process it has beenpreviously demonstrated that infusing anisomycin (ANI) aprotein synthesis inhibitor to the dorsal HPC (dHPC) orthe ACC after contextual fear memory recall (45 d or 30 dafter acquisition resp) disrupts the memory when tested 1 dafter anisomycin treatment [11 49] Collectively these resultshighlight an equal importance of hippocampal and corticalregions in remote memory reconsolidation which suggestthat probably the process of memory formation and storagedoes not depend solely on a single brain area but is moredistributed among different structures that share the upkeepof the trace

3 Structural Changes

Amongst many aspects that categorize a memory to beremote is persistence yet how this property is achieved

Neural Plasticity 5

is still enigmatic The strength and number of synapticconnections that are formed after an experience offer onepossible explanation as to how remote memories couldendure and last throughout life [18]mdashsincewe know that suchprocessesmdashsuch as increased dendritic spine densitymdashareindeed implicated in 1-day-old memories [15 50 51] In thissection we shed light on the structural changes that modifythe connectivity of brain networks and that might underlieremote memory perseverance

A few years ago Restivo and colleagues used contextualfear conditioning as a behavioral paradigm to show thatrecent and remote memory formation trigger region-specificand time-dependent morphological changes in hippocampaland cortical networks of mice [16] Right after fear condition-ing there was a significant increase in spine density in theCA1 field of the hippocampus compared to the naıve or evenpseudoconditioned groups 36 days later in contrast thisincrease in spine density had developed sequentially whenit reached the cortical regions specifically the ACC Thushippocampal plasticity per se is seemingly crucial in drivingthe structural changes that were observed at a remote timepoint yet its role was merely time limited an observationthat was recently confirmed using time-lapse two-photonmicroendoscopy [52] To further prove this assumptiona hippocampal lesion was generated early at the day ofconditioning where it abolished the growth of significantspine density in theACC (36 d after training) compared to thesham group [16] In contrast when this lesion was introducedat a later time point (24 days after conditioning) it did notprevent the spine density changes in the ACC neurons Thedetected structural changes in either region were directlycorrelated to the strength of the conditioned memory anabsence of these structural changes in the hippocampal or thecortical regions was accompanied by memory impairmentsfor recent and remote memories respectively This is in linewith a recent demonstration that such increase in synapticdensity and plasticity occurs exclusively in engram cells butnot in nonengram cells in the DG 24 h after encoding [53]

Importantly such structural remodeling in hippocampaland cortical regions is essential for memory stabilizationand afterwards for remote memory expression The spinegrowth at the hippocampal neurons is important at an earlytime point after conditioning yet this importance starts tofade with time when a more permanent trace is formedin the cortex [17] as illustrated by the following study Toinhibit the structural changes that occur in the cortex atranscription factor that is known to negatively regulatespine growth myocyte enhancer factor 2 (MEF2) wasoverexpressed through a viral vector to increase the MEF2-dependent transcription in ACC neurons at 2 different timepoints either 1 day or 42 days after conditioning At the earliertime point the stabilization of the conditioned memoryand the associated increase in spine growth was blockedwhereas no effect was observed at the later time point [17]This suggests that the increase in spine growth at the ACCfollowing conditioning happens in a time-dependentmannerand that it is central for the stabilization and persistence ofsuch memory

In contrast to the abovementioned studies another studyshowed a rapid formation of new spines in the motor cortexofmice following a novelmotor skill learning task [54] Usingin vivo superficial dendrites imaging they demonstrated thatthere is an immediate formation of spines in the motorcortex following a novel motor learning task (within 1 h afterlearning initiation) and that these spines are preferentiallystabilized upon subsequent training and endure long aftertraining stops (up to 120 d) [54] This suggests that the earlycortical structural changes during motor learning and thesubsequent stabilization overmonths subserve as long-lastingstructural basis for memory maintenance and persistenceof a motor skill Similarly a more recent study reportedthat the encoding of a long-term episodic memory itselfelicits early structural changes in neocortical regions In thisstudy structural plasticity in the mPFC was significantlyincreased 1 h following contextual fear conditioning [38]investigating the morphology of individual dendritic spineson mPFC pyramidal neurons revealed that the ratio of thethin spines to mushroom spines was significantly increasedfollowing conditioning This suggests that dendritic spineplasticity in the mPFC circuit also contributes to memoryencoding which is surprising as the remodeling of the cortexwas traditionally thought to be limited to the later stages ofmemory processing that promote remote memory storage[55] Further investigations are now needed to have a betterunderstanding of these structural changes and how they areemployed to serve memory lasting or extinction (Box 1)

4 Epigenetic Regulation

Remote memories persist throughout the life of individualswhereas the protein molecules that may subserve thesememory traces are thought to turn over on the order ofdays [56] To address such unanswered questions dealingwith the molecular basis for a lifelong memory it has beenproposed by Crick (1916ndash2004) in 1984 and later on bythe molecular biologist Holliday (1932ndash2014) in 1999 thatepigenetic mechanismsmdashparticularly DNA methylationmdashcould partly explain the persistence of memories over alifetime [57 58] Epigenetics has long been heralded as astable and self-perpetuating regulator of cellular identitythrough establishing persistent and heritable changes in geneexpression across cell divisions [20] Although the nervoussystem is essentially composed of nondividing cells therecent decade has shown that epigenetic mechanisms couldnevertheless play a fundamental role in forming lastingmemories

Commonly DNA is packaged into chromatin through itswrapping around octamers of histone proteins Chromatincan exist either as heterochromatin or as euchromatin het-erochromatin is characterized by condensed chromatin andsubsequent transcriptional repression whereas euchromatinis characterized by a relaxed chromatin state that allows thetranscriptionalmachinery to access theDNA for gene expres-sion [59] Apart from short interfering RNA molecules thatmediate posttranscriptional gene silencing [60] and induceepigenetic changes in gene expression via modifications ofchromatin [61] the switch between both states of chromatin

6 Neural Plasticity

In addition to remote memory storage memory extinctionmdashin the case of remote fearful memoriesmdashalso alters structural spineplasticity For instance remote memory extinction was found to diversely alter the spine density and spine size in the ACC andinfralimbic cortex (ILC) in mice [78] extinction of a 31-day-old contextual fear memory decreased the density of dendritic spinesin the ACC significantly but not the size In contrast the spine density remained elevated in the ILC but the size of spines decreaseddramatically The persistence of spine enlargement in the ACC upon extinction could be essential to warrant that the consolidatedfear and the extinction memory traces are kept in a dormant state to allow their reactivation long after training This may indicatethat the extinction per se partially remodels the neuronal network supporting the original memory representation Intriguinglyanother study described the opposite effects of fear conditioning and extinction on dendritic spine remodeling in the frontalassociation cortex (FrA) of rats [79] Using two-photon microscopy to examine the formation and elimination of postsynapticdendritic spines of the FrA the cued fear conditioning caused rapid and long-lasting spine elimination that was significant over 2and 9 days After 2 days of extinction training the spine formation was significantly increased and its degree predicted theeffectiveness of the extinction to reduce the conditioned freezing response These results paradoxically conclude that fearconditioning mainly promotes spine elimination whereas extinction essentially induces spine formation More studies in differentbrain areas will be of high interest to corroborate these findings

Box 1 Recent insights into structural plasticity and remote fear memory extinction

is governed by two major epigenetic modifications DNAmethylation and posttranslational modifications (PTMs)on histone tails DNA methylation refers to the covalentaddition of a methyl group to the cytosine base by DNAmethyltransferases (DNMTs) while PTMs are the additionand removal of chemical moieties to histone tails whichare dynamically regulated by chromatin-modifying enzymes[22] These modifications includemdashbut are not limited tomdashhistone acetylation phosphorylation and methylation [62](see Tweedie-Cullen et al for a complete overview of recentlyidentified PTMs in the brain [63]) Both types of epigeneticmodifications are associated with learning and memory andmany recent studies have shown that these epigenetic changescould support memory formation and maintenance througha cascade of specific changes to gene expression includingenduring memories

41 DNA Methylation The first study to investigate thepotential role of DNA methylation in regulating memoryformation by Sweatt and colleagues showed that Dnmt geneexpression is upregulated in the adult rat hippocampusfollowing contextual fear conditioning and that its inhibitionblocks memory formation [64] Accordingly fear condition-ing was associated with an upregulation of mRNA levelsof the DNMT subtypes that are responsible for de novomethylation DNMT3A and DNMT3B in the CA1 region30min after training Then to show that the hippocampalDNMT activity is necessary for memory consolidationDNMT inhibitorsmdash5-azadeoxycytidine (5-AZA) or zebu-larine (zeb)mdashwere locally infused right after the trainingwhere they abolished the freezing response of the injectedgroup 24 h after (test day 1) Interestingly when retrainedimmediately after test day 1 and retested 24 h later (test day2) the DNMT inhibitor-treated group showed significantlyhigher freezing than on test day 1 and when retrainedand retested 24 h later (test day 3) they showed equivalentfreezing to the vehicle-treated group But when 5-AZA wasinfused 6 h after training and animals were tested 18 h later(24 h after training) the inhibitor-injected group displayednormal fear memory indicating that the effect of DNMT

inhibition is merely due to blocking consolidation and notdue to any other effects on the retrieval or the performance ofthe animals [64]These experiments suggest that the transientinhibition of DNMT in the hippocampus following trainingblocksmemory consolidation in a resilientmanner that couldbe reverted as soon as the inhibitor clears off and that thenecessary DNAmethylation states for consolidation could bereestablished

In a follow-up study Miller et al found a rapid increasein methylation of a memory-suppressor gene in the hip-pocampal CA1 region 1 h after contextual fear conditioningUsing quantitative real-time PCR the methylation levelsof protein phosphatase 1 (PP1) a memory-suppressor genethat is suggested to promote memory decline [65] weredramatically higher in the fear-conditioned group comparedto the control group This increase in methylation wasassociated with lower levels of PP1 mRNA yet the increasein methylation was attenuated and associated with a twofoldincrease in the mRNA levels when 5-AZAwas infused locally1 h after training Conversely a demethylation of a memory-promoting gene was found in the CA1 region 1 h after con-textual fear conditioning The demethylation of reelin a genethat enhances long-term potentiation and the loss of functionof which results in memory formation deficits [66 67] waspronounced in the trained group with its mRNA levels beingsignificantly higher than the control groupDNMT inhibitionusing 5-AZA led to further demethylation of reelin and evenhigher levels of its mRNA These data suggest that the DNAmethylation is dynamically regulated and that it is a crucialstep in memory formation

Importantly cortical DNA methylation also seems tosupport remote forms of memories [68] The cortical DNAmethylation of the memory-suppressor calcineurin (CaNalso known as Ppp3ca) a gene that downregulates pathwayssupporting synaptic plasticity and memory storage wasinvestigated using methylated DNA immunoprecipitation(MeDIP) in rats CaNrsquos cortical DNA methylation persistedfor at least 30 d after contextual fear conditioning and itsmRNA levels were significantly reduced in the trained group2 h after retrieval 30 d after training Importantly when

Neural Plasticity 7

the NMDA receptor antagonist (AP5) was infused intothe dorsal hippocampus (CA1) just before training CaNmethylation in the dorsal medial prefrontal cortex (dmPFC)7 d after training was blocked indicating that a singlehippocampus-dependent learning experience is sufficient todrive lasting gene-specificmethylation changes in the cortexMoreover intra-ACC infusions of DNMT inhibitors (5-AZAor zeb or RG108) 30 d after training disrupted fear memoryand were associated by a significant reduction in the CaNmethylation levels However the infusion of these inhibitors1 d after training had no effect on fear memory 30 d later[68] These results indicate that cortical DNA methylationis indeed triggered by a learning experience and mostimportantly its perpetuation supports long-lasting persis-tent memories More detailed studies including investigatingDNAmethylation changes on a genome-wide scale or withinengram-bearing cells are clearly warranted to deepen ourknowledge of the implication of these changes in remotememory storage

42 Histone PTMs Newly formed hippocampus-dependentmemories need to be stabilized into a long-lasting ACC-dependentmemory trace [46 69 70] Several studies demon-strated that changes in gene expression in both brain regionsaccompany such stabilization [46 47] This differential geneexpression has recently been associated with epigenetic mod-ifications in terms of histone PTMs [71] Using a novel objectrecognition task on mice serine (S) 10 phosphorylation onhistone (H) 3 lysine (K) 14 acetylation onH3 as well as H4K5acetylation and H3K36 trimethylation in the PFC associ-ated with remote (7 d after training) memory consolidationImportantly the doxycycline-inducible selective inhibition ofthe memory-suppressor gene PP1 in a transgenic mouse lineshowed improved remote memory performance accompa-nied by increased histone PTMs In contrast blocking theoccurrence of these PTMs using a cocktail of inhibitors tar-geting the epigenetic enzymes responsible thereof impairedremote object memory suggesting that these histone PTMsare essential formemory consolidation and retention Finallythese histone PTMs were increased in the promoter regionof Zif268mdashan immediate early gene important for memoryformation and storage [72]mdashand its expression levels shiftfrom the hippocampus to the PFC as the memory matures[71] This study shed light on the spatiotemporal dynamicsof these histone PTMs in the hippocampus and cortexand demonstrated that they could act as molecular markssubserving memory consolidationmdashat least up to 7 d aftertraining

Similar results were obtained for memory consolidationof social transmission of food preferences [45] There asso-ciative olfactory memory was linked to a marked increase inH3 acetylation in theOFC 1 h after training but such increasedisappeared upon inactivating the OFC using tetrodotoxinor CNQX Additionally increasing the OFC histone acety-lation by infusing HDAC inhibitors (sodium butyrate ortrichostatin A) was associated by an increase in memoryrobustness at the remote time point (30 d) [45] Togetherthese results stipulate that this cortical epigenetic markobserved very early during training might be essential for

tagging these neurons to allocating them to the long-termolfactory memory and that thereafter these neurons willparticipate in the system consolidation process driven by theHPC-OFC circuitry in order to help this memory to endureIt would be highly interesting to repeat this study with CREB-transfected OFC neurons in order to test this hypothesis

In addition to histone PTMs a recent study by Zovkic etal has shown that a variant of histoneH2A (H2AZ) is activelyexchanged in the hippocampus and cortex in response to fearconditioning in mice [73] H2AZ is known to be associatedwith nucleosomes adjacent to the transcription start site(TSS) of a gene and its presence has been strongly linkedto dynamic changes in gene expression [74] To investigateits effect on transcriptional changes associated with learningchromatin immunoprecipitation (ChIP) was used Binding ofH2AZ was reduced at the +1 nucleosome (first nucleosomedownstreamof theTSS) ofmemory-promoting genes (Npas4Arc Egr1 Egr2 and Fos) and there was an increase in theexpression of those genes 30min after the contextual feartraining In contrast H2AZ binding was increased for thememory-suppressor gene CaN and associated with reducedexpression of this gene This suggests that H2AZ at the+1 nucleosome restricts memory-related gene transcription[73] Furthermore the methylation of the promoter region ofthe gene encoding H2AZ (H2afz) was shown by MeDIP tobe increased 30min after contextual fear conditioning whenit was accompanied by reduced H2AZ protein expressionthroughout the hippocampus whereas the expression levelsof H2AZ returned to baseline after 2 h [73]

To assess a causal involvement of H2AZ in memoryconsolidation an adenoassociated virus (AAV) depletingH2AZ in the dorsal CA1 region of the hippocampus wasused This approach improved fear memory 24 h and 30 dafter training compared to a scramble-injected control groupIn contrast when H2AZ was depleted from the mPFCthere was no effect on fear memory at the hippocampus-dependent 24 h time point yet the freezing was significantlyhigher at remote time points 7 and 30 days after training[73] Moreover a genome-wide transcriptional analysis wascarried out to evaluate the impact of H2AZ depletion ontraining-induced gene expression in CA1 and mPFC 30minafter trainingThe analysis showed a differential expressionmdashbetween the trained and untrained groupsmdashin many genesincluding a number of the early learning-related genesArc Fos Egr1 and Egr2 [73] Although the study did notascertain the specific target genes through which H2AZregulates memory it clearly demonstrated that H2AZ isdynamically regulated during learning and memory andthat it could be an important epigenetic contributor to thecomplex coordination of gene expression in memory Futuremore refined studies will certainly help to elucidate the role ofhistone exchange and histone PTM processes associated withremote memory storage or extinction (Box 2)

5 Summary

The allocation of a memory to a particular neural circuitis a critical step in memory formation We reviewed howCREB is involved in such process highlighting its important

8 Neural Plasticity

In addition to memory formation and storage a recent study also showed an epigenetic involvement into remote fear memoryattenuation [80] In this study permanent attenuation of remote fear memories was achieved by using a histone deacetylase-2inhibitor (HDAC2i) in combination with reconsolidation-updating paradigms which increased the acetylation levels of histoneH3K914 (AcH3) In contrast to a vehicle-treated control group that was resistant to remote memory attenuation a significantincrease in AcH3 was noticed 1 h after remote fear memory recall in the ACC which stayed elevated even after the extinctiontraining In the HPC no change was observed in the acetylation levels of AcH3 1 h after recall yet a significant increase was seen inthe HDAC2i-treated group after extinction training More specifically this observed increase in acetylation in the HDAC2i-treatedgroup was detected in the promoter region of neuroplasticity-related genes such as cFos Arc and Igf2 which showed a concomitantincrease in expression [81] This clearly displays that attenuating remote fear memories using an HDAC2i promotes increasedhistone acetylation-mediated neuroplasticity and in turn demonstrates an epigenetic contribution to this process

Box 2 Recent insights into epigenetic dynamics of remote memory attenuation

role Additionally electrophysiological studies showed thatcells transfected with CREB viral vectors are more excitablecompared to the neighboring cells or even those transfectedwith the control vector [22] This could partially addressthe preference of allocating the memory to CREB cellssince their increased excitability might render them moreresponsive to sensory inputs and therefore more likely toget activated during conditioning training However it couldstill be possible that there are other molecular determinantsand processes that are important for memory allocationIndeed although CREB is ubiquitously expressed it seemsunlikely that memory allocation depends solely on thistranscription factor Likewise adult neurogenesis is restrictedto only certain brain regions and the data showing thatnew granule cells when mature are increasingly likely to beincorporated into circuits supporting spatialmemory [28 29]is not necessarily the sole determinant of allocating amemoryto a specific neural population

Another important aspect of memory persistence iswhich brain regions maintain its storage and what supportssuch perseverance We highlighted the importance of theACC in the upkeeping of remote memories since its inactiva-tion prevents the recall of remote contextual fear memory aswell as the reconsolidation of such remote memory 24 h afterits retrieval [46 49] Intriguingly a recent study identifiedfor the first time monosynaptic projections from the ACCto the hippocampal CA fields that controls memory retrievalin mice [75] Using retrograde tracers this study character-ized novel connections between ACC and CA fields (AC-CA) that subserve a potential bidirectional communicationbetween the ACC and the hippocampus Manipulating theseprojections optogenetically demonstrated a causal top-downcontrol on memory retrieval where the cells contributing tothe AC-CA projection can activate contextually conditionedfear behavior (3-day-old memory) whereas their inhibitionimpaired the retrieval of such memory [75] Neverthelessfurther investigations are still needed to elucidate the roleof these projections on the regulation of different memoryprocesses

In fact the cellular reconsolidation of a remote memorymight not solely depend on the ACC since it has been shownpreviously that infusing anisomycin in the dHPC blocksthe reconsolidation of remote contextual fear memory andthat optogenetically inactivating the CA1 region would even

impair recalling it [12] Contradictorily another study didnot find any evidence that neither the ACC nor the dHPC isinvolved in the cellular reconsolidation of remote contextualfear memory following retrieval [76] More studies are highlyanticipated to resolve these divergent findings although suchdiscrepancy could be partly attributed to the difference inthe strength and length of the training and retrieval sessionsused or in the inactivation method and its efficiency sinceit has been demonstrated that these experimental conditionssignificantly affect the behavioral outcome [10 77]

Structural plasticity is another key point towards under-standing the endurance of somememories It provides a phys-ical substrate for the storage of memories We highlightedthe synaptic plasticity that follows memory formation at hip-pocampal dendrites and that such plasticity reaches corticalareas in a time-dependent manner [16 17] Nonetheless wealso shed light on two interesting studies supporting the viewof an early cortical reorganization duringmotor skill learning[54] as well as episodic memory acquisition [38] whichdemonstrated the importance of such structural changes forlasting memories The reduced density of spines in corticalareas upon remote fear extinction is in linewith these findingsand suggests remodeling in the cortical circuit of the originalmemory [78] However a contradicting study showed that itis rather fearmemory formation that is accompanied by spineelimination and that extinction involves spine formation[79] These results are quite confusing and although theycould also be reflecting that opposite processes are at play indifferent cortical areas they need to be addressed properlysoon

The epigenetic regulation was the final point we high-lighted in this review and the data we reviewedmdashcollec-tivelymdashsupport a dynamic pattern of epigenetic modifica-tions including both DNA methylation [68] and histonePTMs [71] that subserve a spatiotemporal shift of thememorytrace from the HPC to higher cortical regions during theprocess of memory consolidation Also the early tagging ofcertain neurons with epigenetic marks during encoding iscentral for the memory to be allocated to the tagged neuronsand for the subsequent participation of these neurons inthe circuit supporting such memory [45] Furthermorethe extinction of remote fear memories with an HDAC2iincreased histone acetylation-mediated neuroplasticity [80]and the lack of such plasticity from the hippocampus upon

Neural Plasticity 9

remote memory recall supports the idea of hippocampal dis-engagement for remote memories [46 48 55] Neverthelesswhether memories might indeed be ldquocoded in particularstretches of chromosomal DNArdquo as originally proposed byCrick [57] and if so what the enzymatic machinery behindsuch changes might be remain unclear In this regard cellpopulation-specific studies are highly warranted

Taken together we find ourselves in an exciting periodwitnessing an increasing number of studies which dare toinvestigate remote memory formation storage and persis-tence Yet it is clear that we are still in need of furtherinvestigations to unveil the dynamics of neuronal circuitsand molecular mechanisms mediating such persistenceUltimately deciphering these processes would definitelycontribute to the understanding and possibly dulling ofabnormally long-lasting fear memories like those underlyinganxiety disorders or posttraumatic stress disorder

Conflict of Interests

The authors declare that there is no conflict of interestsregarding the publication of this paper

Acknowledgments

Thiswork is funded by the SwissNational Science Foundation(Project Grant 31003A 155898) by the National Center forCompetence in Research (NCCR) SYNAPSY by the SynapsisFoundation for Alzheimer Research by the Beatrice Ederer-Weber Stiftung and by an Alzheimerrsquos Association NewInvestigator Research Grant to Johannes Graff JohannesGraff is an MQ fellow

References

[1] R Semon Die Mneme als erhaltendes Prinzip im Wechsel desorganischen Geschehens Engelmann Leipzig Germany 1904

[2] Y Dudai ldquoThe restless engram consolidations never endrdquoAnnual Review of Neuroscience vol 35 pp 227ndash247 2012

[3] S A Josselyn S Kohler and P W Frankland ldquoFinding theengramrdquo Nature Reviews Neuroscience vol 16 no 9 pp 521ndash534 2015

[4] G E Muller and A Pilzecker Experimentelle Beitrage zur Lehrevom Gedachtniss vol 1 J A Barth 1900

[5] H A Lechner L R Squire and J H Byrne ldquo100 years ofconsolidationmdashremembering Muller and Pilzeckerrdquo Learningand Memory vol 6 no 2 pp 77ndash87 1999

[6] J R Misanin R R Miller and D J Lewis ldquoRetrograde amnesiaproduced by electroconvulsive shock after reactivation of aconsolidatedmemory tracerdquo Science vol 160 no 3827 pp 554ndash555 1968

[7] K Hader G E Schafe and J E Le Doux ldquoFear memoriesrequire protein synthesis in the amygdala for reconsolidationafter retrievalrdquo Nature vol 406 no 6797 pp 722ndash726 2000

[8] C M Alberini M H Milekic and S Tronel ldquoMechanismsof memory stabilization and de-stabilizationrdquo Cellular andMolecular Life Sciences vol 63 no 9 pp 999ndash1008 2006

[9] M H Milekic and C M Alberini ldquoTemporally graded require-ment for protein synthesis following memory reactivationrdquoNeuron vol 36 no 3 pp 521ndash525 2002

[10] A Suzuki S A Josselyn P W Frankland S Masushige AJ Silva and S Kida ldquoMemory reconsolidation and extinctionhave distinct temporal and biochemical signaturesrdquoThe Journalof Neuroscience vol 24 no 20 pp 4787ndash4795 2004

[11] J Debiec J E LeDoux and K Nader ldquoCellular and systemsreconsolidation in the hippocampusrdquoNeuron vol 36 no 3 pp527ndash538 2002

[12] I Goshen M Brodsky R Prakash et al ldquoDynamics of retrievalstrategies for remote memoriesrdquo Cell vol 147 no 3 pp 678ndash689 2011

[13] Y Dudai ldquoThe neurobiology of consolidations or how stable isthe engramrdquo Annual Review of Psychology vol 55 pp 51ndash862004

[14] L R Squire and P Alvarez ldquoRetrograde amnesia and memoryconsolidation a neurobiological perspectiverdquo Current Opinionin Neurobiology vol 5 no 2 pp 169ndash177 1995

[15] L Restivo F S Roman M Ammassari-Teule and E MarchettildquoSimultaneous olfactory discrimination elicits a strain-specificincrease in dendritic spines in the hippocampus of inbredmicerdquoHippocampus vol 16 no 5 pp 472ndash479 2006

[16] L Restivo G Vetere B Bontempi and M Ammassari-TeuleldquoThe formation of recent and remote memory is associatedwith time-dependent formation of dendritic spines in thehippocampus and anterior cingulate cortexrdquo The Journal ofNeuroscience vol 29 no 25 pp 8206ndash8214 2009

[17] G Vetere L Restivo C J Cole et al ldquoSpine growth in theanterior cingulate cortex is necessary for the consolidation ofcontextual fear memoryrdquo Proceedings of the National Academyof Sciences of the United States of America vol 108 no 20 pp8456ndash8460 2011

[18] E R Kandel ldquoThe molecular biology of memory storage adialogue between genes and synapsesrdquo Science vol 294 no5544 pp 1030ndash1038 2001

[19] A J Silva Y Zhou T Rogerson J Shobe and J BalajildquoMolecular and cellular approaches to memory allocation inneural circuitsrdquo Science vol 326 pp 391ndash395 2009

[20] J-H Han S A Kushner A P Yiu et al ldquoNeuronal competitionand selection during memory formationrdquo Science vol 316 no5823 pp 457ndash460 2007

[21] J-H Han S A Kushner A P Yiu et al ldquoSelective erasure of afear memoryrdquo Science vol 323 no 5920 pp 1492ndash1496 2009

[22] Y Zhou J Won M G Karlsson et al ldquoCREB regulatesexcitability and the allocation of memory to subsets of neuronsin the amygdalardquo Nature Neuroscience vol 12 no 11 pp 1438ndash1443 2009

[23] A J Silva J H Kogan PW Frankland and S Kida ldquoCREB andmemoryrdquo Annual Review of Neuroscience vol 21 pp 127ndash1481998

[24] S Maren and G J Quirk ldquoNeuronal signalling of fear memoryrdquoNature Reviews Neuroscience vol 5 no 11 pp 844ndash852 2004

[25] EA Phelps and J E LeDoux ldquoContributions of the amygdala toemotion processing from animal models to human behaviorrdquoNeuron vol 48 no 2 pp 175ndash187 2005

[26] A V Tzingounis and R A Nicoll ldquoArcArg31 linking geneexpression to synaptic plasticity and memoryrdquo Neuron vol 52no 3 pp 403ndash407 2006

[27] T Miyashita S Kubik G Lewandowski and J F GuzowskildquoNetworks of neurons networks of genes an integrated view ofmemory consolidationrdquoNeurobiology of Learning andMemoryvol 89 no 3 pp 269ndash284 2008

10 Neural Plasticity

[28] N Kee C M Teixeira A H Wang and P W FranklandldquoPreferential incorporation of adult-generated granule cellsinto spatial memory networks in the dentate gyrusrdquo NatureNeuroscience vol 10 no 3 pp 355ndash362 2007

[29] S Ge K A Sailor G-L Ming and H Song ldquoSynaptic integra-tion and plasticity of new neurons in the adult hippocampusrdquoJournal of Physiology vol 586 no 16 pp 3759ndash3765 2008

[30] W Penfield and B Milner ldquoMemory deficit produced bybilateral lesions in the hippocampal zonerdquoArchives of Neurologyamp Psychiatry vol 79 no 5 pp 475ndash497 1958

[31] W B Scoville and BMilner ldquoLoss of recent memory after bilat-eral hippocampal lesionsrdquo Journal of Neurology Neurosurgeryand Psychiatry vol 20 no 1 pp 11ndash21 1957

[32] J J Kim and M S Fanselow ldquoModality-specific retrogradeamnesia of fearrdquo Science vol 256 no 5057 pp 675ndash677 1992

[33] E Shimizu Y-P Tang C Rampon and J Z Tsien ldquoNMDAreceptor-dependent synaptic reinforcement as a crucial processformemory consolidationrdquo Science vol 290 no 5494 pp 1170ndash1174 2000

[34] H Wang E Shimizu Y-P Tang et al ldquoInducible proteinknockout reveals temporal requirement of CaMKII reactivationfor memory consolidation in the brainrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 100 no 7 pp 4287ndash4292 2003

[35] J D Sweatt ldquoToward a molecular explanation for long-termpotentiationrdquo Learning and Memory vol 6 no 5 pp 399ndash4161999

[36] M-G Zhao H Toyoda Y-S Lee et al ldquoRoles of NMDANR2B subtype receptor in prefrontal long-term potentiationand contextual fear memoryrdquo Neuron vol 47 no 6 pp 859ndash872 2005

[37] D Tse T Takeuchi M Kakeyama et al ldquoSchema-dependentgene activation and memory encoding in neocortexrdquo Sciencevol 333 no 6044 pp 891ndash895 2011

[38] A W Bero J Meng S Cho et al ldquoEarly remodeling of theneocortex upon episodic memory encodingrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 111 no 32 pp 11852ndash11857 2014

[39] K K Cowansage T Shuman B C Dillingham A Chang PGolshani and M Mayford ldquoDirect reactivation of a coherentneocortical memory of contextrdquoNeuron vol 84 no 2 pp 432ndash441 2014

[40] L G Reijmers B L Perkins N Matsuo and M MayfordldquoLocalization of a stable neural correlate of associativememoryrdquoScience vol 317 no 5842 pp 1230ndash1233 2007

[41] J P Aggleton ldquoUnderstanding retrosplenial amnesia Insightsfrom animal studiesrdquoNeuropsychologia vol 48 no 8 pp 2328ndash2338 2010

[42] C Katche G Dorman C Gonzalez et al ldquoOn the role of retro-splenial cortex in long-lasting memory storagerdquo Hippocampusvol 23 no 4 pp 295ndash302 2013

[43] C S Keene and D J Bucci ldquoNeurotoxic lesions of retrosplenialcortex disrupt signaled and unsignaled contextual fear condi-tioningrdquo Behavioral Neuroscience vol 122 no 5 pp 1070ndash10772008

[44] C S Keene and D J Bucci ldquoContributions of the retrosplenialand posterior parietal cortices to cue-specific and contextualfear conditioningrdquo Behavioral Neuroscience vol 122 no 1 pp89ndash97 2008

[45] E Lesburgueres O L Gobbo S Alaux-Cantin A HambuckenP Trifilieff and B Bontempi ldquoEarly tagging of cortical networks

is required for the formation of enduring associative memoryrdquoScience vol 331 no 6019 pp 924ndash928 2011

[46] P W Frankland B Bontempi L E Talton L Kaczmarek andA J Silva ldquoThe involvement of the anterior cingulate cortex inremote contextual fear memoryrdquo Science vol 304 no 5672 pp881ndash883 2004

[47] T Maviel T P Durkin F Menzaghi and B Bontempi ldquoSites ofneocortical reorganization critical for remote spatial memoryrdquoScience vol 305 no 5680 pp 96ndash99 2004

[48] B Bontempi C Laurent-Demir C Destrade and R JaffardldquoTime-dependent reorganization of brain circuitry underlyinglong-termmemory storagerdquoNature vol 400 no 6745 pp 671ndash675 1999

[49] E O Einarsson and K Nader ldquoInvolvement of the anterior cin-gulate cortex in formation consolidation and reconsolidationof recent and remote contextual fear memoryrdquo Learning andMemory vol 19 no 10 pp 449ndash452 2012

[50] J Bourne and K M Harris ldquoDo thin spines learn to be mush-room spines that rememberrdquoCurrent Opinion in Neurobiologyvol 17 no 3 pp 381ndash386 2007

[51] H Kasai M Matsuzaki J Noguchi N Yasumatsu and HNakahara ldquoStructure-stability-function relationships of den-dritic spinesrdquo Trends in Neurosciences vol 26 no 7 pp 360ndash368 2003

[52] A Attardo J E Fitzgerald andM J Schnitzer ldquoImpermanenceof dendritic spines in live adult CA1 hippocampusrdquoNature vol523 no 7562 pp 592ndash596 2015

[53] T J Ryan D S Roy M Pignatelli A Arons and S TonegawaldquoEngram cells retain memory under retrograde amnesiardquo Sci-ence vol 348 no 6238 pp 1007ndash1013 2015

[54] T Xu X Yu A J Perlik et al ldquoRapid formation and selectivestabilization of synapses for enduringmotormemoriesrdquoNaturevol 462 no 7275 pp 915ndash919 2009

[55] P W Frankland and B Bontempi ldquoThe organization of recentand remote memoriesrdquoNature Reviews Neuroscience vol 6 no2 pp 119ndash130 2005

[56] P Rajasethupathy I Antonov R Sheridan et al ldquoA role forneuronal piRNAs in the epigenetic control of memory-relatedsynaptic plasticityrdquo Cell vol 149 no 3 pp 693ndash707 2012

[57] F Crick ldquoMemory andmolecular turnoverrdquoNature vol 312 no5990 p 101 1984

[58] R Holliday ldquoIs there an epigenetic component in long-termmemoryrdquo Journal ofTheoretical Biology vol 200 no 3 pp 339ndash341 1999

[59] K L Arney and A G Fisher ldquoEpigenetic aspects of differen-tiationrdquo Journal of Cell Science vol 117 no 19 pp 4355ndash43632004

[60] I Djupedal andK Ekwall ldquoEpigenetics heterochromatinmeetsRNAirdquo Cell Research vol 19 no 3 pp 282ndash295 2009

[61] N L Vastenhouw K Brunschwig K L Okihara F Muller MTijsterman and R H A Plasterk ldquoGene expression long-termgene silencing by RNAirdquo Nature vol 442 article 882 2006

[62] FMuhlbacher H Schiessel and C Holm ldquoTail-induced attrac-tion between nucleosome core particlesrdquo Physical Review E vol74 no 3 Article ID 031919 2006

[63] R Y Tweedie-Cullen J M Reck and I M Mansuy ldquoCom-prehensive mapping of post-translational modifications onsynaptic nuclear and histone proteins in the adult mousebrainrdquo Journal of Proteome Research vol 8 no 11 pp 4966ndash4982 2009

Neural Plasticity 11

[64] C A Miller and J D Sweatt ldquoCovalent modification of DNAregulates memory formationrdquo Neuron vol 53 no 6 pp 857ndash869 2007

[65] D Genoux U Haditsch M Knobloch A Michalon D Stormand I M Mansuy ldquoProtein phosphatase 1 is a molecularconstraint on learning and memoryrdquo Nature vol 418 no 6901pp 970ndash975 2002

[66] E J Weeber U Beffert C Jones et al ldquoReelin and ApoEreceptors cooperate to enhance hippocampal synaptic plasticityand learningrdquo Journal of Biological Chemistry vol 277 no 42pp 39944ndash39952 2002

[67] U Beffert E J Weeber A Durudas et al ldquoModulation ofsynaptic plasticity and memory by Reelin involves differentialsplicing of the lipoprotein receptor Apoer2rdquoNeuron vol 47 no4 pp 567ndash579 2005

[68] C A Miller C F Gavin J A White et al ldquoCortical DNAmethylation maintains remote memoryrdquo Nature Neurosciencevol 13 no 6 pp 664ndash666 2010

[69] M W Jung E H Baeg M J Kim Y B Kim and J J KimldquoPlasticity and memory in the prefrontal cortexrdquo Reviews in theNeurosciences vol 19 no 1 pp 29ndash46 2008

[70] I L C Nieuwenhuis and A Takashima ldquoThe role of theventromedial prefrontal cortex in memory consolidationrdquoBehavioural Brain Research vol 218 no 2 pp 325ndash334 2011

[71] J Graff B T Woldemichael D Berchtold G Dewarrat and IM Mansuy ldquoDynamic histone marks in the hippocampus andcortex facilitate memory consolidationrdquo Nature Communica-tions vol 3 article 991 2012

[72] S Davis B Bozon and S Laroche ldquoHow necessary is theactivation of the immediate early gene zif268 in synapticplasticity and learningrdquo Behavioural Brain Research vol 142no 1-2 pp 17ndash30 2003

[73] I B Zovkic B S Paulukaitis J J Day D M Etikala and J DSweatt ldquoHistone H2AZ subunit exchange controls consolida-tion of recent and remote memoryrdquo Nature vol 515 no 7528pp 582ndash586 2014

[74] R Bargaje M P Alam A Patowary et al ldquoProximity of H2AZcontaining nucleosome to the transcription start site influencesgene expression levels in the mammalian liver and brainrdquoNucleic Acids Research vol 40 no 18 pp 8965ndash8978 2012

[75] P Rajasethupathy S Sankaran J H Marshel et al ldquoProjec-tions from neocortex mediate top-down control of memoryretrievalrdquo Nature vol 526 no 7575 pp 653ndash659 2015

[76] P W Frankland H-K Ding E Takahashi A Suzuki S Kidaand A J Silva ldquoStability of recent and remote contextual fearmemoryrdquo Learning and Memory vol 13 no 4 pp 451ndash4572006

[77] S G Bustos M Giachero H Maldonado and V A MolinaldquoPrevious stress attenuates the susceptibility to Midazolamrsquosdisruptive effect on fear memory reconsolidation influenceof pre-reactivation D-cycloserine administrationrdquo Neuropsy-chopharmacology vol 35 no 5 pp 1097ndash1108 2010

[78] G Vetere L Restivo G Novembre M Aceti M Lumaca andM Ammassari-Teule ldquoExtinction partially reverts structuralchanges associated with remote fear memoryrdquo Learning andMemory vol 18 no 9 pp 554ndash557 2011

[79] C SW Lai T F Franke andW-BGan ldquoOpposite effects of fearconditioning and extinction on dendritic spine remodellingrdquoNature vol 483 no 7387 pp 87ndash91 2012

[80] J Graff N F Joseph M E Horn et al ldquoEpigenetic priming ofmemory updating during reconsolidation to attenuate remotefear memoriesrdquo Cell vol 156 no 1-2 pp 261ndash276 2014

[81] R C Agis-Balboa D Arcos-Diaz J Wittnam et al ldquoA hippo-campal insulin-growth factor 2 pathway regulates the extinctionof fear memoriesrdquoThe EMBO Journal vol 30 no 19 pp 4071ndash4083 2011

Submit your manuscripts athttpwwwhindawicom

Neurology Research International

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Alzheimerrsquos DiseaseHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

International Journal of

ScientificaHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Research and TreatmentSchizophrenia

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Neural Plasticity

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Parkinsonrsquos Disease

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Research and TreatmentAutism

Sleep DisordersHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Neuroscience Journal

Epilepsy Research and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Psychiatry Journal

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Computational and Mathematical Methods in Medicine

Depression Research and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Brain ScienceInternational Journal of

StrokeResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Neurodegenerative Diseases

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

Cardiovascular Psychiatry and NeurologyHindawi Publishing Corporationhttpwwwhindawicom Volume 2014