memory consolidation - cbmm · 2017-12-21 · memory consolidation comes from studies of...

Memory Consolidation

Larry R. Squire1,2,3, Lisa Genzel4, John T. Wixted3, and Richard G. Morris4

1VA San Diego Healthcare System, San Diego, California 921612Departments of Psychiatry and Neurosciences, University of California, San Diego, La Jolla, California 920933Department of Psychology, University of California, San Diego, La Jolla, California 920934Centre for Cognitive and Neural Systems, The University of Edinburgh, Edinburgh EH8 9JZ, United Kingdom

Correspondence: [email protected]

Conscious memory for a new experience is initially dependent on information stored in boththe hippocampus and neocortex. Systems consolidation is the process by which the hippo-campus guides the reorganization of the information stored in the neocortex such that iteventually becomes independent of the hippocampus. Early evidence for systems consoli-dation was provided by studies of retrograde amnesia, which found that damage to thehippocampus-impaired memories formed in the recent past, but typically spared memoriesformed in the more remote past. Systems consolidation has been found to occur for bothepisodic and semantic memories and for both spatial and nonspatial memories, althoughempirical inconsistencies and theoretical disagreements remain about these issues. Recentwork has begun to characterize the neural mechanisms that underlie the dialogue betweenthe hippocampus and neocortex (e.g., “neural replay,” which occurs during sharp waveripple activity). New work has also identified variables, such as the amount of preexistingknowledge, that affect the rate of consolidation. The increasing use of molecular genetic tools(e.g., optogenetics) can be expected to further improve understanding of the neural mech-anisms underlying consolidation.

Memory consolidation refers to the processby which a temporary, labile memory is

transformed into a more stable, long-lastingform. Memory consolidation was first proposedin 1900 (Muller and Pilzecker 1900; Lechneret al. 1999) to account for the phenomenon ofretroactive interference in humans, that is, thefinding that learned material remains vulnera-ble to interference for a period of time afterlearning. Support for consolidation was alreadyavailable in the facts of retrograde amnesia, es-pecially as outlined in the earlier writings of

Ribot (1881). The key observation was that re-cent memories are more vulnerable to injury ordisease than remote memories, and the signifi-cance of this finding for consolidation was im-mediately appreciated.

In normal memory a process of organization iscontinually going on—a physical process of or-ganization and a psychological process of repe-tition and association. In order that ideas maybecome a part of permanent memory, time mustelapse for these processes of organization to becompleted. (Burnham 1903, p. 132)

Editors: Eric R. Kandel, Yadin Dudai, and Mark R. Mayford

Additional Perspectives on Learning and Memory available at www.cshperspectives.org

Copyright # 2015 Cold Spring Harbor Laboratory Press; all rights reserved; doi: 10.1101/cshperspect.a021766

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It is useful to note that the term consolidationhas different contemporary usages that derivefrom the same historical sources. For example,the term is commonly used to describe events atthe synaptic/cellular level (e.g., protein synthe-sis), which stabilize synaptic plasticity withinhours after learning. In contrast, systems con-solidation, which is the primary focus of thisreview, refers to gradual reorganization of thebrain systems that support memory, a processthat occurs within long-term memory itself(Squire and Alvarez 1995; Dudai and Morris2000; Dudai 2012).

Systems consolidation is typically, and accu-rately, described as the process by which mem-ories, initially dependent on the hippocampus,are reorganized as time passes. By this process,the hippocampus gradually becomes less im-portant for storage and retrieval, and a morepermanent memory develops in distributed re-gions of the neocortex. The idea is not thatmemory is literally transferred from the hippo-campus to the neocortex, for information is en-coded in the neocortex as well as in hippocam-pus at the time of learning. The idea is thatgradual changes in the neocortex, beginning atthe time of learning, establish stable long-termmemory by increasing the complexity, distribu-tion, and connectivity among multiple corticalregions. Recent findings have enriched this per-spective by emphasizing the dynamic nature oflong-term memory (Dudai and Morris 2013).Memory is reconstructive and vulnerable toerror, as in false remembering (Schacter andDodson 2001). Also, under some conditions,long-term memory can transiently return to alabile state (and then gradually stabilize), a phe-nomenon termed reconsolidation (Nader et al.2000; Sara 2000; Alberini 2005). In addition, therate of consolidation can be influenced by theamount of prior knowledge that is availableabout the material to be learned (Tse et al.2007; van Kesteren et al. 2012).

Neurocomputational models of consolida-tion (McClelland et al. 1995; McClelland 2013)describe how the acquisition of new knowledgemight proceed and suggest a purpose for con-solidation. As originally described, elements ofinformation are first stored in a fast-learning

hippocampal system. This information directsthe training of a “slow learning” neocortex,whereby the hippocampus gradually guidesthe development of connections between themultiple cortical regions that are active at thetime of learning and that represent the memory.Training of the neocortex by the hippocampus(termed “interleaved” training) allows new in-formation to be assimilated into neocorticalnetworks with a minimum of interference. Insimulations (McClelland et al. 1995), rapidlearning of new information, which was incon-sistent with prior knowledge, was shown tocause interference and disrupt previously estab-lished representations (“catastrophic interfer-ence”). The gradual incorporation of informa-tion into the neocortex during consolidationavoids this problem. In a recent revision of thisframework (McClelland 2013), neocorticallearning is characterized, not so much as fastor slow, but as dependent on prior knowledge.If the information to be learned is consistentwith prior knowledge, neocortical learning canbe more rapid.

This review considers several types of evi-dence that illuminate the nature of the consol-idation process: studies of retrograde amnesia inmemory-impaired patients, studies of healthyvolunteers with neuroimaging, studies of sleepand memory, studies of experimental animals,both with lesions or other interventions, andstudies that track neural activity as time passesafter learning.

STUDIES OF RETROGRADE AMNESIAIN MEMORY-IMPAIRED PATIENTS

One useful source of information about mem-ory consolidation comes from studies in mem-ory-impaired patients of memory for past newsevents or other public facts. In an early studyof memory for television programs that hadbroadcast for only a single season, patients re-ceiving electroconvulsive therapy for depressiveillness showed temporally limited retrogradeamnesia extending back 1–3 years (Squireet al. 1975). This phenomenon was slow to berelated to neuroanatomy because of the need totest patients with well-characterized lesions who

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developed a memory impairment at a knowntime. In one of the first studies to meet theserequirements, six memory-impaired patientswith bilateral damage limited to the hippocam-pus were given a test of 250 news events cover-ing 50 years (Manns et al. 2003). The patientsshowed a similar graded memory loss extendingjust a few years into the premorbid period (fortwo additional patients, see Kapur and Brooks1999). Similar results have been obtained inneuroimaging studies of hippocampal activity,for example, when volunteers recalled past newsevents that had occurred 1–30 years ago (Smithand Squire 2009). These results suggest a con-solidation process whereby the human hippo-campus can be needed to support memory forfactual information (semantic memory) for aslong as a few years after learning, but is notneeded after that time.

Patients with damage that not only includesthe hippocampus but larger regions of the me-dial temporal (and sometimes lateral temporal)lobes as well can have severe retrograde memoryloss covering decades (Bayley et al. 2006; Brightet al. 2006). Nevertheless, patients with medialtemporal lobe lesions can have considerablesparing of premorbid memory (e.g., recogni-tion of famous faces: patient H.M. in Marslen-Wilson and Teuber 1975; spatial knowledge ofthe childhood environment: patient E.P. in Tengand Squire 1999). These findings show that thebrain regions damaged in such patients, for ex-ample, the entorhinal, perirhinal, and parahip-pocampal cortices, although important for newlearning, are not similarly important for recol-lecting the past. The implication is that infor-mation initially requires the integrity of medialtemporal lobe structures, but is reorganized astime passes so as to depend much less (or not atall) on these same structures.

Another useful source of evidence aboutmemory consolidation comes from studies ofautobiographical memory for past events (epi-sodic memory). The study of autobiographicalmemory presents unique challenges because itdepends on the analysis of spoken narrativesthat are often difficult to corroborate and onelaborate scoring methods that can be difficultto duplicate across laboratories. The findings

from studies of autobiographical memory aremixed. In several studies, patients with restrict-ed hippocampal lesions, or larger medial tem-poral lobe lesions, successfully recalled detailedmemories from early life (Eslinger 1998; Bayleyet al. 2003; Buchanan et al. 2005; Kirwan et al.2008; Kopelman and Bright 2012). Squire andBayley (2007) offer additional discussion of sin-gle-case reports. Whether assessed by countingthe details in tape-recorded narratives, ratingthe quality of narratives, or scoring responsesto a few standardized questions (on a 0–9scale), patients performed like controls (Fig.1). Recall of episodes from the recent past wasimpaired (see also Thaiss and Petrides 2008).Yet, other patients produced fewer details aboutpast events, even events from early life (Rosen-baum et al. 2005; Steinvorth et al. 2005; Raceet al. 2011).

Why are the findings mixed? A lingering andchallenging issue concerns the locus and extentof brain damage and the possibility that damageoutside the medial temporal lobe contributes toimpaired performance. Lesions that extend lat-eral to the medial temporal lobe, for example,

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Figure 1. Performance on the remote memory (child-hood) portion of the autobiographical memory in-terview (Kopelman et al. 1989; three questions; max-imum score ¼ 9) by controls (CON), patients withcircumscribed hippocampal (H) lesions, patientswith large medial temporal lobe (MTL) lesions, andpatients with medial temporal lobe lesions plus ad-ditional damage in the neocortex (MTLþ). Bracketsshow standard error of the mean. Patients with dam-age limited to the MTL have the capacity to recallremote events, but this capacity is diminished whenthe damage extends into the neocortex.


Cite this article as Cold Spring Harb Perspect Biol 2015;7:a021766 3

could impair remote memory by damaging re-gions thought to be repositories of long-termmemory. In one of the studies reporting anextensive deficit in autobiographical memory(Rosenbaum et al. 2005), all four patients hadsignificant damage to the posterior temporalcortex. Although the deficit was attributed tohippocampal damage, the data show that thebest predictor of retrograde memory perfor-mance was the volume of the posterior tempo-ral cortex and the cingulate cortex. The findingsseem as consistent with the idea that an extend-ed network of regions supports remote auto-biographical recollection (Svoboda et al. 2006)as with the idea that the medial temporal lobeitself is especially critical. In another study ofeight patients (Race et al. 2011), quantitativemagnetic resonance imaging (MRI) data wereavailable for only four and, of these, two haddamage to lateral temporal cortex.

The fate of past autobiographical memorieshas special significance for ideas about consol-idation. Multiple-trace theory (Moscovitchet al. 2006), later elaborated as the transfor-mation hypothesis (Winocur and Moscovitch2011), holds that memories retaining contextu-al details (such as episodic memories) remaindependent on the hippocampus so long as theypersist. The consolidation of memory into theneocortex is thought to involve a loss of timeand place, contextual information, and a tran-sition to more gist-based, fact-like semanticmemory. By this account, detailed context in-formation about past autobiographical eventsdoes not consolidate into the neocortex. Notethat, if the hippocampus supports the capacityfor episodic recollection during the full lifetimeof a memory, then hippocampal damage shouldnot only reduce the number of details that canbe produced (as has sometimes been reported),but should also result in fact-based narrativesthat reflect semantic knowledge and lack epi-sodic (time and place) information.

Tulving (1985) introduced a method thatcan be used to test this idea. He argued that itis possible to recover information about pastevents from either episodic or semantic memo-ry. In the former case, the phenomenal experi-ence is remembering (becoming aware of one’s

own past). In the latter case, the experience isknowing, as when one is simply convinced thatsomething is true without appreciating when orwhere the knowledge was acquired.

The method then involves asking peoplewhen they recall a past event whether they “re-member” the occurrence of the event, or wheth-er they simply “know” in some other way thatit occurred. The so-called “remember–know”procedure has been used extensively in studiesof learning and memory and has also been usedto assess the quality of retrieved memories fromthe past. This procedure is well suited to addressthe question of interest. When memory-im-paired patients with restricted medial temporallobe lesions recollect an event from the remotepast, do they report that they “remember” orthat they simply “know” about the event? Ittook a long time to test this question experi-mentally. In the first formal test, three patientswith hippocampal lesions and two with largemedial temporal lobe lesions recalled eventsfrom their early life and, then, were asked todecide whether they “remembered” the incidentor simply “knew” that it had happened (Bayleyet al. 2005). The patients produced as manydetails as controls and also rated most of theirmemories as “remember” (87.1% vs. 80.3% forcontrols). Thus, these patients reported thatthey were “remembering” and retrieving fromepisodic memory. The results suggest that epi-sodic retrieval from the remote past is possibleafter medial temporal lobe damage and thatsuch retrieval is independent of the medial tem-poral lobe.

There are patients who cannot “remember”the past at all, but these are not patients withdamage limited to the hippocampus. These arepatients with significant damage outside themedial temporal lobe whose narratives are notjust short on detail, but also lack any episodiccontent. Their knowledge of the past seems im-personal like their other knowledge of the world(patient S.S. in Cermak and O’Connor 1983;patient K.C. in Rosenbaum et al. 2005; patientG.T. in Bayley et al. 2005). They know a few factsabout their own past, but cannot recall a singleincident or event. For example, patient K.C. isdescribed as follows:

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The most striking fact about K.C.’s amnesia isthat he cannot recollect a single personal hap-pening or event from his life. He does not re-member any incidents from all the years preced-ing his accident, nor can he remember any of thenormally highly memorable things that havehappened to him. (Tulving et al. 1988, p. 9)

If episodic memory depends on the hippocam-pus for as long as memory persists, then patientswith restricted hippocampal lesions should beas empty of a personal past as patient K.C. Yet, acondition so severe has not, to our knowledge,been described for patients with restrictedhippocampal lesions. The available evidencesuggests that autobiographical memories con-solidate and ultimately depend on a distributednetwork of cortical regions.

NEUROIMAGING STUDIES OF NORMALMEMORY

Consolidation has also been explored in healthyvolunteers using neuroimaging methods likepositron emission tomography (PET) or func-tional magnetic resonance imaging (fMRI).Neuroimaging studies can establish whether ornot a particular structure (e.g., the hippocam-pus, medial prefrontal cortex, or a network ofstructures) is active when recent and remotememories are retrieved, but this method doesnot indicate whether a structure is necessary forretrieval. Thus, a temporal gradient of hippo-campal activation (e.g., greater activation forrecent than for remote memories) might reflecta decreasing dependence on the hippocampusas memories age, but such a result might alsoreflect differences in the extent to which mem-ories of different ages are relearned and re-encoded as they are recollected. Considerationssuch as these point to the complexities of inter-preting neuroimaging data and may help to ex-plain why the relevant neuroimaging literatureis decidedly mixed.

In neuroimaging studies, participants areoften tested for their semantic knowledge ofpublic events that occurred at various times inthe recent and remote past. With this approach,some studies have found greater activity in themedial temporal lobe during the recollection of

recent memories compared with remote mem-ories (Haist et al. 2001; Douville et al. 2005;Smith and Squire 2009), but other studieshave found no difference (e.g., Maguire et al.2001; Maguire and Frith 2003; Bernard et al.2004). The latter results (like all null results)are difficult to interpret and may reflect a failureto detect a true difference. If so, the availableresults may not be as contradictory as they ap-pear. More work is needed to settle this issue.

With respect to episodic (autobiographical)memories, several approaches have been used,and the literature is similarly mixed. In one typ-ical design, a prescan interview is conducted toelicit autobiographical memories from the re-cent and remote past, and these memories arethen queried during scanning (e.g., Niki andLuo 2002; Piefke et al. 2003; Bonnici et al.2012, 2013; Soderlund et al. 2012). Studies us-ing this design sometimes found greater medialtemporal lobe activity in association with recentrecollections compared with remote recollec-tions (i.e., evidence of a temporal gradient),but sometimes there was no evidence for a tem-poral gradient. However, a recognized limita-tion of the prescan interview is, that later inthe scanner, participants may retrieve whatthey had just recollected about their recentand remote memories. If so, all the memoriesare effectively recent, a circumstance that wouldwork against finding a temporal gradient (Ca-beza and St Jacques 2007).

An alternative design involves cueing sub-jects in the scanner for recent and remote auto-biographical memories without a prescan in-terview (e.g., Gilboa et al. 2004; Rekkas andConstable 2005; Viard et al. 2010). In one study(Rekkas and Constable 2005), volunteers took aprescan tour of a campus (to create recent mem-ories) and then, in the scanner, recalled eitherrecent events from the campus tour or remoteevents that had occurred during elementaryschool years. A temporal gradient of hippocam-pal activity was observed, but the level of activ-ity was “higher” for remote memories than forrecent memories (a result not anticipated by anyaccount of memory consolidation). In fMRIstudies, it is often difficult to know whethermeasured activity reflects reencoding or retriev-



al (Stark and Okado 2003). One possibility isthat interesting and personally significant mem-ories from the remote past might have stimulat-ed greater reencoding activity in the hippocam-pus than less interesting, and less significant,memories from the recent past.

A different approach is to use a prospectivedesign that affords experimental control overthe memories from different time periods. Inthis design, participants learn similar materialsat multiple different time points before scan-ning. A number of recent neuroimaging studieshave used this approach (Takashima et al. 2006,2009; Yamashita et al. 2009; Furman et al. 2012;Harand et al. 2012). For example, in one study(Takashima et al. 2009), participants memo-rized two sets of face-location associations;one was studied 24 h before testing (remotememories) and the other studied 15 min beforetesting (recent memories). Activity in the hip-pocampus decreased (and activity in the neo-cortex increased) as a function of time afterlearning. Concomitantly, functional connectiv-ity between the hippocampus and cortical areasdecreased over time, whereas connectivity with-in the cortical areas increased. This temporalgradient is shorter than what is typically ob-served in lesion studies, but the findings arenevertheless in agreement with the idea thatthe hippocampus becomes less important formemory as time passes. We shall consider thespeed of consolidation in more detail in a latersection on animal studies.

Furman et al. (2012), also using a prospec-tive design, tested memory of documentary filmclips. Hippocampal activity declined as timepassed over a period of months when memorywas tested by recognition (an indication ofmemory consolidation), but it remained stableacross time when memory was tested by recall.A complementary increase in activity in corticalareas as a function of time was not observed;instead, cortical activity decreased as well.

A concern that could be raised about pro-spective studies is that, by the time memory istested in the scanner, many older memories willhave been forgotten. As a result, the survivingremote memories are relatively durable and arebeing compared with a mixture of durable and

less durable recent memories. One elegant pro-spective memory study addressed this issue (Ya-mashita et al. 2009). Activity in the hippocam-pus and temporal neocortex was monitored asparticipants recalled two sets of paired-associatefigures (fractal images), which they had mem-orized at two different times. One set had beenstudied 8 weeks before testing (remote memo-ries), and the other had been studied just beforetesting (recent memories). Overall memory ac-curacy at the time of the test was equated forthese two conditions by providing more studytime for the items studied 8 weeks earlier. Theresults were that a region in the right hippocam-pus was more active during retrieval of newmemories than old memories, whereas in theleft temporal neocortex, the opposite patternwas observed. These results are consistent witha decreasing role of the hippocampus and anincreasing role of the neocortex as memoriesage across a period of 50 days.

Imaging studies have also been used to ex-plore how and under what conditions con-solidation occurs—a process that presumablyinvolves some relatively long-lasting communi-cation between the hippocampus and theneocortex. One proposal for how this couldbe accomplished is through the phenomenonof “neural replay,” which refers to the spontane-ous recurrence of hippocampal activity thatoccurred originally during learning. Neural re-play has most often been observed in rats during“non”–rapid eye movement [NREM]) slow-wave sleep (Wilson and McNaughton 1994),but something akin to neural replay seems tooccur in humans as well. For example, a studyof regional cerebral blood flow found that hip-pocampal areas that were active during routelearning in a virtual environment (a hippocam-pus-dependent, spatial learning task) were ac-tive again during subsequent slow-wave sleep(Peigneux et al. 2004). Moreover, the degree ofactivation during slow-wave sleep correlatedwith performance on the task the next day. In aconceptually related study (Rasch et al. 2007),cueing recently formed odor-card associationsby odor reexposure during slow-wave sleep, butnot during rapid eye movement (REM) sleep,increased hippocampal activity (as measured

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by fMRI), and resulted in less forgetting aftersleep. In both studies, hippocampal reactiva-tion, which presumably initiated hippocam-pal–neocortical dialogue, occurred withinhours of the learning episode.

Other studies have found that the replay-likeactivity observed during NREM sleep can alsooccur during quiet wakefulness, suggesting thatconsolidation-related processes may proceedwhenever the hippocampus is not otherwiseengaged in encoding activity (Karlsson andFrank 2009; Mednick et al. 2011). For example,following paired-associates learning (objects orscenes paired with faces), functional connectiv-ity between the hippocampus and a portion ofthe lateral occipital complex increased during apostlearning rest period (Tambini et al. 2010).Moreover, the strength of this effect predictedsubsequent memory performance. The specificpatterns of activity associated with encodingexperiences can also recur during subsequentoffline rest periods. In one study (Tambini andDavachi 2013), hippocampal activity patternspersisted into postencoding rest periods, andthe persistence of some of these patterns corre-lated with later memory performance for thematerial presented during the study. In relatedwork, an object-scene paired-associates learn-ing task was followed by a 2-min delay, followedby a cued-recall test (Staresina et al. 2013). Suc-cessful recall of individual study events waspredicted by the degree to which those eventselicited similar patterns of activation in the en-torhinal cortex during the encoding and delayperiods. Inasmuch as these studies have in-volved activity occurring rather soon after learn-ing, it will be useful to evaluate the possible roleof rehearsal, either intentional or spontaneous.

If neural replay is related to memory con-solidation, it should be possible to find evidenceof replay at longer time intervals after learning(i.e., across the portion of long-term memoryduring which consolidation is thought to oc-cur). In a study of trace eyeblink conditioningin rats, activity in the medial prefrontal cortex,selective for the acquired association, developedover a period of several weeks and in the absenceof continued training (Takehara-Nishiuchi andMcNaughton 2008). In this case, training initi-

ated gradual processes that developed withinlong-term memory. These findings are consis-tent with the idea that the encoding of a mem-ory can be followed by replay-like activity dur-ing subsequent offline periods. The extendedhippocampal–cortical communication result-ing from replay is thought to lead gradually toa memory that is represented in the neocortexand independent of the hippocampus.

ANIMAL STUDIES OF MEMORYCONSOLIDATION

Animal research on memory consolidationhas the same starting point as human work:establishing whether and how memory stabiliz-es with the passage of time. It differs in allowingfor invasive experiments using interventions,such as lesions, physiological monitoring andrecording, and molecular techniques. Key em-pirical issues include (1) Are temporal gradi-ents of retrograde amnesia reliably observed af-ter comparable experimental interventions?(2) Is there evidence of time-dependent changesin physiological function that relate to ormediate aspects of memory consolidation? (3)Can contemporary molecular-genetic tech-niques be used to shed new light on the systemsissues concerning hippocampal–neocorticaldialogue?

Are Temporal Gradients of RetrogradeAmnesia Reliably Observed in Animals?

Beginning more than 20 years ago, studies innonhuman primates, rodents, and other speciesconfirmed the existence of a temporal gradientof amnesia in animals. Thus, monkeys learnedmultiple object discrimination tasks at five dif-ferent intervals before surgery (Fig. 2A). Afterlesions of the hippocampal formation, theyremembered better the problems learned 12weeks before the lesion than problems learnedjust before the lesion (Zola-Morgan and Squire1990). A study of the social transmission of foodpreference task in rats yielded a similar butshorter temporal gradient (Winocur 1990). Incontext fear conditioning, rats given hippo-campal lesions 28 days after conditioning stilldisplayed fear of the chamber in which condi-



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Figure 2. Animal studies revealing temporal gradients and other characteristics of cortical memory measured ina variety of different tasks. (A) Object discrimination learning in monkeys shows a temporal gradient over aperiod of 12 weeks (based on Zola-Morgan and Squire 1990). (B) Context fear conditioning sometimes shows atemporal gradient, but does not always do so. In a study in which a temporal gradient was observed in animalstested during pharmacological inhibition of the hippocampus (left panel), animals that successfully discrim-inated two testing contexts show a loss of memory with hippocampal inhibition, whereas animals that gener-alized do not (right panel based on Figs. 2 and 5 of Wiltgen et al. 2010). (C) Glucose uptake measured usingradiolabeled 2-deoxyglucose shows a time-dependent increase in the cortex 25 days after radial-maze learningin mice (based on Bontempi et al. 1999). (Legend continues on following page.)

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tioning had occurred (indexed as “freezing”),whereas those trained only 1 day before the le-sion did not (Kim and Fanselow 1992). Simi-larly, in a within-subjects procedure, rats frozein the context in which fear conditioning hadoccurred 50 days before a hippocampal lesion,but not in a different context in which fear con-ditioning had occurred just before the lesion(Anagnostaras et al. 1999).

These studies made two important points.First, their prospective designs enabled behav-ioral training to be appropriately timed in rela-tion to lesions that could be both complete andlimited to a structure of interest. Second, thefindings indicated that it was not simply that alesion after training caused a deficit in memory.The key finding was that a group with a longtime interval between training and surgery per-formed paradoxically better than a group with ashorter training–surgery interval. Discussionsof retrograde amnesia have emphasized theimportance of this feature of the data (Squire1992). Indeed, the finding that remote memorycan be better than recent memory after a lesionis usually considered to be the gold standard forshowing memory consolidation.

However, not all studies of retrograde am-nesia in animals have yielded a gradient, forexample, in context fear conditioning. Thus,one group has repeatedly failed to find a tem-poral gradient (Lehmann et al. 2007; Suther-land et al. 2008; Sparks et al. 2011). Anothergroup found no temporal gradient despite sys-tematic manipulation of potentially relevantparameters: lesion method, lesion size, singletrial training, and massed and spaced multitrialtraining (Broadbent and Clark 2013).

Early studies in the water maze also did notfind a temporal gradient (Bolhuis 1994; Suth-erland et al. 2001). Our two groups investigatedthis in detail. Varying the task to a dry-landversion, called the “oasis” maze, revealed nosparing of remote memory after radio frequencylesions of the hippocampus (Clark et al, 2005a).Extended training of the water maze task beforethe lesion, in an effort to minimize floor effects,also did not reveal a gradient (Clark et al.2005b). One possibility was that this impair-ment in remote memory was a retrieval deficitrather than a true loss of consolidated memory.To address this, a reminder procedure was usedin two water maze studies involving neurotoxiclesions (de Hoz et al. 2004; Martin et al. 2005).The Atlantis platform procedure provided thereminder. The platform is near the bottom ofthe water maze during a probe trial, but be-comes available for escape after 60 sec. In thisway, a probe test can be performed and the an-imal is “reminded” of the correct location. Per-formance in a second probe test 1 h later wassignificantly better, indicating that remindingcan work. However, this effect occurred onlyin partially lesioned rats that had been trainedshortly before the lesion. Furthermore, success-ful reminding of memory was not observed inremote memory groups trained long before thelesion. Thus, a temporal gradient can appear inthe water maze once access to memory is im-proved but in the direction opposite to that pre-dicted by standard consolidation theory.

However, as navigation through space in-volves the hippocampal formation in rodents(O’Keefe and Nadel 1978; Moser et al. 2008),the failure to see intact memory could be be-

Figure 2. (Continued) (D) Detection and shutdown of hippocampal sharp-wave ripples (SWR), a candidatemediator of consolidation, slows learning of a spatial radial-arm maze task (based on Girardeau et al. 2009). (E)Comparison of short and prolonged optogenetic (halorhodopsin)-induced inhibition of the hippocampus.There is an unexpected effect of brief hippocampal inhibition after 28 days in a training paradigm that shows atemporal gradient with more prolonged inhibition (based on Goshen et al. 2011). (F) Optogenetic activation ofneurons in the retrosplenial cortex (RSC) labeled with channelrhodopsin via c-fos activation during context fearconditioning is sufficient to elicit a freezing response, bypassing the need for hippocampal binding during theearly stage of systems consolidation. Even when the hippocampus (HPC) was inactivated by tetrodotoxin (TTX)and 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), direct optogenetic activation of RSC elicited greater freez-ing 24 h after conditioning (middle) than during preconditioning (left). In the absence of optogenetic activation(right), hippocampal activity was essential to reactivate memory so soon after conditioning (based on Fig. 4E ofCowensage et al. 2014). MTL, medial temporal lobe.



cause of a secondary disruption of the expres-sion of memory, even for a memory that hadbeen consolidated in the cortex. It may be, forthis reason, that the reminding effect was ob-served in animals with partial neurotoxic le-sions with intact fibers of passage. If so, reduc-ing the navigational demands by arranging forswimming and escape within a circular corri-dor or “annulus” might reveal intact memoryin animals with larger lesions. However, sucha finding was also not observed (Clark et al.2007). Thus, something about allocentric spa-tial memory tasks, at least in the water maze,appears to be different from the tasks discussedearlier, possibly including some long-term stor-age of spatial information in the hippocampus.This difference has recently been driven homeby a study using a within-subjects design. In thesame experimental subjects, a temporal gradi-ent was found for context fear conditioning butnot for spatial memory (Winocur et al. 2013).Why the gradient is reliably seen in some studiesof context fear conditioning but not in others,nor in the water maze, is an issue of currentinterest (Winocur et al. 2013).

It has been shown that the hippocampushas to be active at the time of retrieval for theexpression of both recent and remote memoryin rodents (Liang et al. 1994; Broadbent et al.2006), and this fact points to the need for adifferent approach. One would like to inactivatethe hippocampus reversibly during the putativememory consolidation process, but allow it towork normally during learning and, later, at re-call. One relevant study used a chronic revers-ible blockade of GluR1-5 receptors in the dorsalhippocampus (for 7 days, beginning 1 or 5 daysafter learning), with blockade confirmed meta-bolically using 2-deoxyglucose (2-DG). Memo-ry retention was tested 16 days after trainingwith the hippocampus, once again, workingnormally (Riedel et al. 1999). A deficit in theconsolidation of memory was observed whetherthe inhibition was begun 1 day after training orafter a delay of 5 days. These findings suggestthat “turning off” the hippocampus for 7 daysafter learning, despite normal function duringencoding and retrieval, does cause retrogradeamnesia. Although this study lacked a long-

delay condition before the onset of hippocam-pal inhibition (which might then show spatialmemory to be intact), it confirms the idea thatwater maze learning may involve posttrain-ing consolidation just as the standard modelpredicts. However, it is unclear whether thepharmacological intervention affects only thedialogue between the hippocampus and neocor-tex for stabilization of cortical traces (Alvarezand Squire 1994), or might also affect memorytraces within the hippocampus itself (Nadel andMoscovitch 1997). A further difficulty is that astudy using continuous posttraining infusionsof either lidocaine or CNQX for 7 days did notreplicate the Riedel et al. (1999) findings (Broad-bent et al. 2010). However, a later study usingpostlearning transection of the temporoam-monic path from the entorhinal cortex to areaCA1 of the hippocampus did reveal poor mem-ory tested 28 days later (Remondes and Schu-man 2004), which was interpreted as interrupt-ing hippocampal–neocortical dialogue. Thatis, after learning, ongoing cortical input con-veyed by the temporoammonic path is requiredto consolidate long-term spatial memory. Fol-low-up studies need to be conducted that looknot only at the impact of sustained and revers-ible inactivation of the hippocampus, but alsoat relevant structures of the neocortex (retro-splenial, anterior cingulate, medial prefrontalcortex) that might be engaged in systems con-solidation.

For the present, it is clear that after appro-priately timed lesions, a temporal gradient fa-voring better remote memory is seen too oftento discount, including in a spatial paired-asso-ciate task to be discussed below (Tse et al. 2007),but it is unclear why it is not always observedwith either permanent lesions or temporary in-activation. The next section identifies some rel-evant factors.

Interpreting Behavioral Measuresand Cognitive Factors

Human studies are characterized by distinctways of measuring memory—from simple mea-sures of percent correct to more subjective mea-sures, such as the remember–know procedure.

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It is unclear how to apply such subtle qualitativedistinctions to animals who cannot verbally re-port a specific event. In a typical task, it is simplythe apparent strength of a memory that is beingtested. Recent animal research has endeavoredto determine whether different temporal gradi-ents of retrograde amnesia are associated withdifferent training protocols and/or whetherrepresentations in memory change qualitativelywith the passage of time. What is emerging isevidence that features of a test protocol can mat-ter and that the temporal gradient of retrogradeamnesia is not a fixed entity.

One important variable is whether the in-formation being learned is completely novel orcan be related to previously acquired knowl-edge. How easily new information can be assim-ilated into a neocortical knowledge structure,such as a “schema,” may depend on the extentto which subjects have an available frameworkof prior knowledge relevant to the new infor-mation being learned (Bransford 1979; McClel-land 2013; Ghosh and Gilboa 2014). Rapid as-similation of information into a schema shouldspeed up the time course of systems consolida-tion. This idea was investigated in rats by firsttraining them to learn multiple paired associ-ates. The associations involved the flavor/odorof a food reward buried in a sand well and thespatial location in an “event arena” where thefood could be found (Tse et al. 2007). The useof spatial location as one member of a pairedassociate enabled the animals to build a map or“schema” indicating what food was where.Learning was slow, �6 weeks, but the animalscould eventually use the taste or smell of thefood to direct their digging at the location wherethe corresponding food could be found. Theinitial learning of paired associates was im-paired by neurotoxic hippocampal lesions givenbefore training, indicating that this learningis “hippocampus dependent.” Critically, whennormal animals were trained and acquired aschema, and lesions were made at differenttimes after the introduction of new paired asso-ciates, a temporal gradient of retrograde amne-sia was observed. Specifically, when lesions weremade only 3 h after training, later memory waspoor. However, when lesions were made 2 days

after training, the animals showed good mem-ory. Thus, a rapid temporal gradient was ob-served (unlike in the water maze), reflectingthe apparent assimilation of new informationinto the previously trained neocortical schema.

These results raise the question: What is dif-ferent about context fear conditioning, the wa-ter maze, and the event arena? Temporal gradi-ents are seen in the first and third of these, butnot usually in the second. Spatial navigationis important in the water maze, but not in con-text fear conditioning, and not so importantin the event arena because the animal can decidewhether or not to dig for food at each sand wellafter it gets to it. Another difference betweenthese three tasks, to which Tse et al. (2007)drew particular attention, is that in studies todate, animals entering context fear conditioningand water maze experiments are “experimental-ly naıve.” That is, they have not been trained onother tasks, nor do they have a history of priorlearning like adult humans. The implicit sup-position has been that this exceptional degree ofcontrol is a desirable feature of animal proto-cols, but this may be incorrect. The results fromTse et al. (2007) raise the possibility that thetemporal parameters of consolidation are nota biological given (such as the interaction offast [hippocampal] and slow [cortical] learningsystems discussed by McClelland et al. 1995),but can be influenced by cognitive factors, thatis, the time course of consolidation is not fixed,and that this is the case is an important topicof current study (Tse et al. 2007). The paired-associate protocol may produce a relativelyshort temporal gradient of retrograde amnesiabecause the animals do not remember the in-dividual events associated with a paired-associ-ate learning trial, but can nevertheless modify apreexisting semantic memory in the cortex (Fig.3B). An additional justification for this secondpoint is that new computational modeling in-dicates that past experience may make the ex-traction of statistical regularities easier and fast-er (McClelland 2013).

It is possible that this same idea may illumi-nate context fear conditioning studies in somecircumstances. For example, following up earli-er work (Riccio et al. 1984), new studies of fear



conditioning have shown that the ability to dis-criminate between the training context (con-text A) and a novel context (context B) dimin-ishes over the course of a month (Wiltgen andSilva 2007; Wiltgen et al. 2010). Importantly,these studies revealed a temporal gradient ofretrograde amnesia when mice were tested inthe training context (context A) 1 or 28 daysafter training (hippocampal inactivation im-paired performance after 1 day, but not after28 days). What is the relationship between theloss of discriminability between contexts A andB across 28 days and the evidence for consoli-dation over the same time period? One possi-bility is that consolidation occurs against abackground of normal forgetting. Alternatively,the decline in discriminability might mean thatconsolidation is a time-dependent process that

gradually extracts statistical regularities whilepermitting details to be lost.

A study relevant to these issues assessed fearconditioning 14 days after training. A signifi-cant negative correlation was found betweenan individual animal’s discrimination ability(trained vs. novel context) and the extent towhich the animal showed freezing in the “novel”context (Wiltgen et al. 2010). There was no cor-relation between discrimination ability and theextent of freezing in the “trained” context. Inaddition, pharmacological inactivation of thehippocampus after 14 days impaired memoryfor the training context in animals that dis-criminated between contexts, but not in ani-mals that failed to discriminate (Fig. 2B). Oneinterpretation of this result is that, if a de-tailed contextual (“episodic-like”) memory is

Behavior

A Standard systems consolidation

B Systems consolidation with schema

Controls Networkdynamics

Cortical modules

Cortical modules

Hippocampus(hours)

Recent(hours)

Remote(weeks)

Recent(3 h)

Remote(48 h)

Mem

ory

scor

eM

emor

y sc

ore

Hippocampus(weeks)

Hippocampus(3 h)

Hippocampus(48 h)

Cortical modules

Cortical modulesmPFC mPFC

HPC lesion

Figure 3. Hypothetical models of hippocampal–neocortical interactions during memory consolidation. (A)The standard model supposes that information is stored simultaneously in the hippocampus and in multiplecortical modules during learning and that, after learning, the hippocampal formation guides a process by whichcortical modules are gradually bound together over time. This process is considered to be slow, occurring acrossweeks, months, or even longer (based on Frankland and Bontempi 2005). (B) In situations in which priorknowledge is available and, thus, cortical modules are already connected at the start of learning, a similarhippocampal–neocortical-binding process takes place. However, this process may involve the assimilation ofnew information into an existing “schema” rather than the slower process of creating intercortical connectivity(based on van Kesteren et al. 2012). HPC, hippocampus; mPFC, medial prefrontal cortex.

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available, whether immediately or long aftertraining, the hippocampus is engaged and re-quired. Moreover, if only a “semantic” or “gist”memory is available, which does not discrimi-nate between contexts, memory can be support-ed by the cortex alone.

An alternative way to understand these re-sults is that they may reflect group differences inthe rate of consolidation. Mice were separatedinto two groups based on their ability to dis-criminate context A from context B. According-ly, the two groups could have differed from eachother in many other ways as well (notwithstand-ing the finding that performance in context Awas similar for the two groups). Indeed, theamount of gist or detailed memory that wasavailable may not be relevant. The high-dis-crimination group might take longer to consol-idate than the low-discrimination group and,even after that point is reached, the animals inthe high-discrimination group might still beable to discriminate between contexts. This re-sult would imply that even memory for detailcan consolidate. This analysis predicts that if amuch longer period of posttraining consolida-tion were allowed, enabling the high-discrimi-nating group to fully consolidate, hippocampalinactivation would have no effect despite suc-cessful context discrimination.

Another study of how memory changes overtime involved use of the water maze (Richardset al. 2014). Mice were trained on a delayedmatching-to-place protocol in which the escapeplatform moved location each day. On each day,there was a rapid decline in escape latency as eachnew location was learned. In one version of thistask, the platform was located in various placesin the north quadrant of the pool twice as oftenas in various places in the east quadrant. Whentested 1 day after completing 8 days of training,mice searched primarily in the most recentlytrained location. However, when tested after30 days, mice tended to search twice as oftenin the north quadrant as in the east quadrant.That is, after 30 days, search was driven less byany single day’s training, or even by the last day’straining, but rather by the cumulative statisticaldistribution of training experience across days.When mice had to learn a new escape location

either 1 day or 30 days after training, they couldremember this new location better if it conflict-ed with the distribution of locations learned30 days earlier than if it conflicted with the dis-tribution of locations learned only 1 day earlier.

The nature of this stabilization of patternmemory or gist memory over time remains un-clear. The investigators propose that the findingis unlikely to be caused by the degradation ofmemories over time or to memory strength be-ing simply a function of relative recency. In-stead, like Wiltgen et al. (2010), they favor theview that consolidation entails an active processof extracting the gist or pattern from what waslearned, although forgetting individual instanc-es (including the most recent instance). Where-as this perspective does provide an accurate de-scription of the data, it is unclear whether aqualitative process/mechanism of gist extrac-tion is, in practice, actually required. Successivetraining days to platforms in distinct locationswill create multiple rapidly declining memorytraces whose residual strength over time maynot decline to zero. Instead, these traces couldgradually summate to result in particular areasof the water maze having different associativestrengths. This summation process could occurduring posttraining consolidation and result inthe time-dependent appearance of an apparentgist memory even in the absence of a specificpattern extraction process.

Taken together, the studies summarized inthis section indicate that temporal gradients ofretrograde amnesia can be observed, but thereis presently uncertainty about both the timecourse of the gradients and the factors that me-diate them. The possibility that there are qual-itative changes in the character of memory dur-ing consolidation is currently an active area ofresearch.

MONITORING METABOLIC, IMMEDIATEEARLY GENE, AND NEUROPHYSIOLOGICALSIGNATURES OF CONSOLIDATION ATVARIOUS TIMES AFTER TRAINING

Monitoring physiological changes over time of-fers a different window on consolidation pro-cesses. One strategy has been to look at region-



specific alterations of 2-DG uptake or immedi-ate early gene (IEG) activation in the hippocam-pus and neocortex at various times after train-ing. One study trained mice in an eight-armradial-maze task (Olton et al. 1979) in whichsome arms were rewarded and others were neverrewarded (Bontempi et al. 1999). Increased 2-DG uptake in the hippocampus was found whentesting occurred shortly after training. Impor-tantly, there was a time-dependent decrease inhippocampal uptake when testing was delayedfor several weeks, and there was a correspondingincrease in 2-DG uptake in the neocortex (Fig.2C). Follow-up work found similar temporalpatterns in the expression levels of IEGs, suchas c-fos (Frankland et al. 2004; Maviel et al.2004). Direct transfer of information from thehippocampus to the cortex is not thought tooccur in consolidation. However, the processof cortical stabilization may require guidance,whether the stabilization involves synaptogene-sis or persistent changes in synaptic strength inthe cortex. One suggestion for this process is theidea of a “tagging” process at neocortical syn-apses (Lesburgueres et al. 2011). Tagging refersto a local, posttranslational change in corticalneurons that occurs in parallel with memoryencoding.

Using a social transmission of food-prefer-ence paradigm in which a demonstrator ani-mal “teaches” an observer animal which foodsare safe to eat, these investigators explored theidea that neurons might undergo a “taggingprocess” in the orbitofrontal cortex at the timeof memory encoding. This process would helpto ensure that the gradual, hippocampus-drivenrewiring of cortical networks, which ultimate-ly support long-term memory, is directed ap-propriately. Using a combination of lesionsand pharmacological interventions, these stud-ies established that tagging was amino-3-(5-methyl-3-oxo-1,2-oxazol-4-yl) propanoic acid(AMPA)- and N-methyl-D-aspartate receptor–dependent, information-specific, and capableof modulating remote memory persistence byaffecting the temporal dynamics of hippocam-pal–cortical interactions. The concept emerg-ing from these studies is in line with standardconsolidation theory. Specifically, the concept is

that neocortical tags are set early at the time ofmemory encoding and time-dependent changesdevelop across time as dynamic interactions oc-cur between the hippocampus and neocortex.

When animals were tested for their memoryof context fear conditioning at 1 and 30 daysafter training, correlations in the expression ofthe IEG c-fos were observed across brain areas(Wheeler et al. 2013). Specifically, the absolutelevels of IEG expression in up to 80 brain areasrevealed a striking change in the correlationmatrix between brain areas 1 and 30 days aftertraining. These results indicate time-dependentchanges in cortical networks over this time pe-riod. This “functional connectome” is stronglysuggestive of a time-dependent reorganiza-tion and stabilization of neocortical networks.However, given the uncertainty about whichfactors influence temporal gradients of be-havioral memory (Broadbent and Clark 2013),caution is also appropriate in the case of IEGmeasures. That time-dependent changes areobserved in IEG expression is clear. Less clearis what these changes correspond to in termsof underlying memory processes. For example,c-fos activation likely reflects increased neuralactivity at the time of retrieval, but this acti-vation does not necessarily measure retrievalitself. Although there was no opportunity for“new” fear learning during the retrieval tests(because reexposure to the training contextwas not accompanied by additional presenta-tions of the unconditional shock stimulus), itis nevertheless possible that retrieval could beassociated with new encoding (of the retrievaltest itself, for example). That is, what is proce-durally a retrieval paradigm (Wheeler et al.2013) might reflect gene expression associatedwith retrieval-related encoding.

IEG expression in the hippocampus andcortex has also been measured as animals ex-press a learned schema in the event arena orare required to assimilate new information(Tse et al. 2011). In that study, two IEGs, zif-268 and Arc, were measured and found to be up-regulated throughout consolidation-relevantmidline regions of the neocortex at the time ofmemory encoding, broadly similar to the areasidentified in earlier work at long time periods

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after learning (Frankland and Bontempi 2005).The magnitude of the increase for these IEGswas related to how readily the new informationwould later be expressed, that is, how easily itwould be assimilated into the existing and acti-vated knowledge structure if the full period ofconsolidation had been allowed to take place.These findings support the possibility, raisedearlier (Lesburgueres et al. 2011), that corticaltagging helps promote the neocortical consoli-dation process. They are also consistent with theidea, derived from studies of amygdala-depen-dent fear conditioning, that neurons are recruit-ed into a memory trace as a function of neuro-nal excitability (Yiu et al. 2014).

Another and distinct window onto putativeconsolidation mechanisms comes from neuro-physiological recordings from relevant neuronalensembles of the hippocampus and neocortexduring sleep. It has been proposed that con-solidation occurs specifically during NREMsleep (Jenkins and Dallenbach 1924; Marr1971; Smith 1996). Two mechanisms have sincebeen proposed. One is “replay,” the reactivationof patterns of network activity that had oc-curred during previous experience and thatare thought to lead to potentiation of relevantsynaptic connections in the cortex. Replay startsin the hippocampus and propagates to the cor-tex, with reprocessing there to extract statisticaloverlap from different encoding episodes (Wil-son and McNaughton 1994; Diekelmann andBorn 2010; Battaglia et al. 2012; Genzel et al.2014). The other suggested mechanism forconsolidation during sleep is “downscaling”—“with sleep homeostatically but nonspecificallyregulating synaptic weights to improve the sig-nal-to-noise ratio of memory traces” (Tononiand Cirelli 2006, 2014). The combined “push–pull” action of replay on the one hand (“push”equals potentiating “important” traces) anddownscaling on the other (“pull” equals weak-ening irrelevant traces) may together aid theconstruction and updating of memory networksin the cortex (Diekelmann and Born 2010;Lewis and Durrant 2011; Genzel et al. 2014).Sleep replay seems to be a widespread phenom-enon requiring participation and cooperationamong many different brain areas, whereas

downscaling is thought to be a more local pro-cess, which is locally initiated and regulated.

What mechanisms are responsible for mem-ory traces becoming consolidated during sleep?To initiate replay in the hippocampus, a slowoscillation starts in the prefrontal cortex, con-sisting of an alternation between states of gen-eralized cortical excitation and depolarizedmembrane potentials (UP states) and general-ized states of relative neuronal silence (DOWNstates). This oscillation, as seen in intracranialrecordings of patients being evaluated for epi-leptic surgery, travels across the brain to themedial temporal lobe (Nir et al. 2011), whereit is followed by sharp wave ripples in the hip-pocampus. During sharp wave ripples, 30% ofhippocampal neurons increase their firing rate,and the replay of sequential firing of neuronsthat encode, for example, previous spatial expe-riences occurs in a temporally compressed form(Wilson and McNaughton 1994). Hippocampalreplay was first observed in the rat when placecells were seen to fire during sleep in the samesequence as they fired on a linear track whenthe rat was actually running (Wilson and Mc-Naughton 1994). Since then, many other inter-esting attributes of sharp wave ripples and re-play have been reported. Replay occurs 7–10times faster than the original experience (Eu-ston et al. 2007) and seems to be homeostati-cally regulated. The increased appearance ofsharp wave ripples after their disruption isseen only after a significant learning period (Gi-rardeau et al. 2014). Further, the type of neuralnetwork being activated during replay, that is,the specific memory, can be recognized by thetypical morphology of the ripple (Reichinneket al. 2010), and longer memories seem to bereplayed across multiple sharp wave ripples(Davidson et al. 2009). By recording neuronalfiring patterns in the prefrontal cortex at choicepoints in a maze and during sleep, it has beenshown that hippocampal replay during sleep(but not during the awake state) is directly com-municated to the prefrontal cortex. As a result,there is simultaneous expression in the hippo-campus and prefrontal cortex of learning-as-sociated neural firing patterns (Peyrache et al.2009). Evidence for replay has also been found



in other brain areas, including the striatum,motor cortex, and visual cortex (Euston et al.2007; Ji and Wilson 2007; Aton et al. 2009; Lan-sink et al. 2009; Yang et al. 2014). Additionally,if sharp-wave ripples are followed by neocorticalspindles, secondary larger waves of increasedfiring rates can be observed in the cortex (Wier-zynski et al. 2009). At the same time, by com-paring unit firing in the cortex and hippocam-pus during spindles, it was observed in onestudy that the cortex became functionally de-afferented from hippocampal inputs duringsleep spindles (Peyrache et al. 2011). Spindlesmay also play an additional but separate role inlocal cortical processing during sleep, which isindependent of the hippocampal replay mech-anism (Andrillon et al. 2011).

As discussed earlier, recent studies in hu-mans have tried to increase the probability ofreplay during sleep by cueing recently learnedmemories via smell or sound associations(Rasch et al. 2007; Rudoy et al. 2009). In a relat-ed study in rats, two running tracks were asso-ciated with distinct sounds. In this case, cueingreplay during sleep did not increase the absoluteamount of replay. Instead, cueing biased replaytoward the cued content at the cost of thenoncued content (Bendor and Wilson 2012).

Interestingly, replay is observed not onlyduring sleep, but can occur during waking aswell. Intervention studies have addressed wheth-er there are different functions of replay in sleepversus awake states by interrupting sharp waveripples with electrical stimulation wheneverthey occur (Fig. 2D). This work has hinted atthe possibility that replay during sleep is im-portant for consolidation processes, whereasawake replay is more associated with spatialworking memory and navigational planning(Girardeau et al. 2009; Ego-Stengel and Wilson2010; Jadhav et al. 2012; Pfeiffer and Foster2013). However, both awake and sleep replaydo seem to contribute to later memory perfor-mance (Dupret et al. 2010), with awake replay,perhaps, serving to initially stabilize memorybut with sleep replay operating in associationwith systems consolidation.

To summarize, there are time-dependentchanges in physiological function that relate to

or mediate aspects of systems memory consol-idation, as now shown with 2-DG, immediateearly gene mapping, and electrophysiologicalrecordings. New technologies, notably opticalrecording, offer the opportunity to study thesechanges dynamically in large numbers of neu-rons. This approach might require a head-fixed,virtual-reality paradigm that could be used overthe time periods after learning when consolida-tion occurs.

THE USE OF MOLECULAR–GENETICTECHNIQUES TO ILLUMINATEMECHANISMS OF HIPPOCAMPAL–NEOCORTICAL DIALOGUE

New approaches are starting to use elegant in-ducible and reversible genetic interventions toexamine systems consolidation. The focus hereis not on the specific molecular mechanismsof consolidation (discussed elsewhere in thiscollection), but on the use of molecular engi-neering approaches to illuminate the dynamicsof systems consolidation. Two studies illustratethe approach.

In one study, optogenetic inhibition of thehippocampus was deployed to examine the in-terplay of the hippocampus and neocortex,emphasizing the opportunity that this tech-nique offers for precise temporal intervention(Goshen et al. 2011). Halorhodopsin-inducedinhibition of area CA1 of the hippocampus re-duced the frequency of cell firing and blockedthe acquisition and retrieval of contextual fearconditioning. Brief optogenetic inhibition (for5 min) of hippocampus consistently interferedwith retrieval (after 28 days, 9 weeks, and 12weeks). In contrast, more extended pharma-cological and optogenetic inhibition spared re-mote memory, but impaired recent memory,revealing a temporal gradient (Fig. 2E). Briefinhibition of CA1 resulted in a decreased c-fosexpression at recall in both CA1 and the anteriorcingulate cortex (ACC), whereas extended in-hibition decreased expression in CA1, but in-creased expression in ACC. These results couldmean that prolonged inhibition allows forcompensatory activity to develop and that thiscompensatory activity supports remote memo-

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ry performance. An alternative is that pro-longed inhibition allows nonspecific effects ofthe inhibition to wear off and remote memoryto be successfully expressed.

The concept of rapid cortical tagging (Les-burgueres et al. 2011; Tse et al. 2011) suggeststhat, even if the hippocampus is normally en-gaged for a short period for “binding” disparatecortical networks during memory encodingand the early stages of consolidation, a memorytrace of some kind is rapidly formed in the cor-tex. The cortical trace in this case correspondsto the episodic memory-like trace that wasformed during the initial experience and notto a gist-memory trace. This trace may ordinar-ily require co-occurrent activity in the hippo-campus for behavioral expression during theconsolidation period, but this involvement ofthe hippocampus might be mimicked optoge-netically. That is, if the role of the hippocampusduring the consolidation period is to engagecortical neurons selectively during the stabiliza-tion process, this function of the hippocampusmight be achieved optogenetically by selectivelyactivating those cortical neurons that are in-volved in the memory.

A relevant step forward has used context fearconditioning and tet-TAG mice in which c-fosis used to drive the insertion of a channelrho-dopsin-like protein into learning-activated cells(Cowensage et al. 2014). A subset of neurons inthe retrosplenial cortex (RSC) was tagged in thisway during context fear conditioning. Subse-quently, it was possible to activate just this sub-set of RSC cells optogenetically (despite diffuselight activation of all cells) because only thoseneurons were activated that had been firing atthe time of cortical memory encoding and had,therefore, expressed c-fos. The mice showed el-evated freezing in response to the light, an ob-servation made even more secure through theuse of a context discrimination procedure (rem-iniscent of Wiltgen’s work cited earlier). In-creased freezing was also observed in responseto light activation of the RSC network whenthe hippocampus was simultaneously inactivat-ed with lidocaine (Fig. 2F). Thus, although thehippocampus may ordinarily serve to guide theprocess of neocortical stabilization, its role can

be bypassed if another (exogeneous) method isused to activate the appropriate subset of neo-cortical neurons. Whereas the method of by-passing the hippocampus is artificial, this is animportant proof-of-principle study establishingthat memory traces in the cortex are sufficientfor memory expression.

CONCLUSIONS

Evidence for memory consolidation has accu-mulated in the laboratory and the clinic formore than 100 years. Yet, quantitative studiesof retrograde amnesia began only in the 1970s,and the idea that consolidation involves a dia-logue between the hippocampus and neocor-tex is even more recent. Information is storedinitially in both the hippocampus and neo-cortex, and the hippocampus then guides agradual process of reorganization and stabili-zation whereby information in the neocortexeventually becomes independent of the hippo-campus. This is the so-called standard model ofmemory consolidation depicted in Figure 3A.It is now known that the rate of this process de-pends on the extent to which new informationcan be related to preexisting knowledge, such asnetworks of connected neurons called “sche-mas” (Fig. 3B). Consolidation occurs for bothfacts and events and for both spatial and non-spatial information, although it appears to bemasked in tasks that depend prominently onspatial navigation (e.g., the water maze in ro-dents), as the integrity of the hippocampal for-mation is required for memory expression. Mo-lecular genetic tools, including optogenetics andmetabolic markers, are now being used to ex-plore further the mechanisms by which consol-idation occurs.

ACKNOWLEDGMENTS

This work is supported by the Medical ResearchService of the Department of Veterans Affairs(L.R.S.), The National Institute of MentalHealth (NIMH) Grant 24600 (L.R.S.), an Ad-vanced Investigator Grant (Project 268800-NEUROSCHEMA) from the European Re-search Council (R.G.M.), and a postdoctoralfellowship from Society-in-Science (L.G.).



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