To appear in the Ken A. PallerNew Encyclopedia of Neuroscience kap@northwestern.edu

Memory Consolidation: Systems

The Consolidation of a MemoryAt the moment when we perceive an event, thejourney of memory storage begins. In a sense, thisevent may exist in its travels for many years beforefinally being remembered — where is it, what is it,and how does it manage to persist?

Whereas memory is revealed by an organism’sbehavior at the time of retrieval, neural substrates ofmemory storage assume some persistent formduring the entire retention interval. The ability toremember an event is made possible by changes inneurons and in networks of neurons — neuralplasticity. Yet, these changes are quite unlike whena liquid is poured into a mold and solidifies asplastic or when clay is shaped and fired to formpottery. A memory trace is not a static entity thatremains in a fixed state, as if waiting in a filedrawer until it is needed. Rather, numerous neuralchanges can transpire during the time periodbetween acquisition and retrieval as a memory isassociated with other stored information andpotentially becomes more stable.

What is the fate of the neural plasticity first set intomotion when an event is experienced? Anunderstanding of the concept of memoryconsolidation requires understanding the form ofmemory traces (engrams) both in neural andcognitive terms, as well as specifying how memorytraces change over time.

Memory DistinctionsMemory storage and retrieval mechanisms areknown to differ in fundamental ways according tothe type of memory in question. Likewise, memoryconsolidation proceeds differently for differenttypes of memory.

A long-standing distinction in research on humanmemory allows for separate mechanisms for short-term storage lasting seconds or minutes, perhapshours, and long-term storage lasting much longer.Donald Hebb’s seminal proposal was thatreverberating neural circuits can keep an experiencein mind for a short time, whereas structural changesin neuronal ensembles underlie storage that persistsover longer periods. Mental representations ofperceptual and conceptual information can beactively maintained through rehearsal. In this sense,

short-term storage cannot be defined by acharacteristic time span. Rehearsal can continue foran indefinite amount of time. The term immediatememory aptly draws attention to this aspect ofmemory, and is akin to what William James termedprimary memory. In contrast, Jamesian secondarymemory refers to information brought back to mindafter earlier leaving one’s awareness, rather thaninformation kept in mind through rehearsal. Thelength of the retention interval, short term versuslong term, is thus not a suitable way by itself todifferentiate between types of memory. Immediatememory (also known as working memory) belongsin a class by itself due to its dependence on thecontinuous rehearsal of information.

Aside from immediate memory, there are severaldistinct ways in which behavior comes under theinfluence of past experience. Of central relevancefor major territories of human cognition, declarativememory pertains to memory for complex facts andpersonally experienced events, and can bedistinguished from a diverse set of memoryphenomena collectively known as nondeclarativememory. Nondeclarative memory includes skilllearning, habit learning, simple forms ofconditioning, various types of priming that can bemeasured in implicit memory tests, andnonassociative forms of learning like habituationand sensitization.

Some of the molecular building blocks of memorystorage are common across these different types ofmemory. Elaborate layers of molecular machinerycan require some passage of time so as to completethe process of memory formation. In many cases,neural plasticity induced during learning can bemodulated by subsequent events. Release ofepinephrine and cortisol, for example, can allowemotional significance to regulate memory strength.Selective gene activation and protein synthesis alsoplay key roles in stabilizing synaptic changes.

These aspects of memory fall in a category calledsynaptic consolidation. Relevant molecular changescan require minutes to hours. On the other hand, thepresent discussion focuses on neural mechanisms ofsystems-level consolidation that are specific todeclarative memory and that tend to occur over amuch longer time scale.

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Consolidating Declarative Memories: Facts andEventsDeclarative memory concerns the ability to bringback to mind factual and episodic information. Eachof us maintains a colossal but changing record offacts and events to access when needed. Thisinformation can potentially stay with us so manyyears that one might say that declarative memoriescan last a lifetime. One general principle of memorystorage is that cortical networks specialized forprocessing specific types of information are thevery same networks involved in storing thatinformation as fragments of declarative memories.Importantly, those fragments must be linkedtogether in order for any particular declarativememory to exist. The tendency for declarativememory storage to be influenced by eventsintervening between initial acquisition and laterretrieval underscores the extreme malleability ofthese memories.

Pinpointing the exact neural substrates of any onespecific autobiographical event or fact is beyondcurrent technology. Nonetheless, there are a varietyof ways to assess this type of memory using recalland recognition tests, and we have learned muchabout the brain mechanisms responsible fordeclarative memory. Lively controversy surroundsquestions about how consolidation operates, theprecise length of time consolidation requires, andwhether these memories assume a labile form underspecial circumstances.

Empirical evidence that can be brought to bear ontheories of consolidation comes from multiplesources. Neuropsychological studies of patientswith amnesia, in particular, suggest that declarativememories can change to become resistant todisruption and that this change is a byproduct ofconsolidation. Critical brain damage in amnesiatends to include midline diencephalic or medialtemporal structures, including the hippocampus andadjacent cortical regions, though the distinctmemory functions presumably mediated by thesedifferent regions are currently unclear. Studies ofanimal models have also been designed to identifythe neuroanatomical basis of this criticalcontribution to memory.

Evidence from human memory disordersMemory impairment tends to comprise bothanterograde amnesia, a pronounced difficulty inlearning new information, and retrograde amnesia, a

disruption of the ability to remember informationthat had been learned prior to the onset ofsymptoms. In either case, patients experiencedifficulty remembering factual as well as eventinformation (though dissociations are possible, atleast in retrograde amnesia). Some amnesic patientsexhibit severe anterograde amnesia and severeretrograde amnesia; some exhibit mild anterogradeamnesia and mild retrograde amnesia. Given thatneurological insult can produce correlatedanterograde and retrograde amnesia in this manner(even though there are important exceptions),standard accounts sought to specify a singlemechanism that led to both effects. In particular,both types of impairment could hypotheticallyresult from a core defect in consolidation, given theassumptions that (a) new learning cannot beaccomplished in the absence of consolidation, and(b) old memories cannot be retrieved ifconsolidation does not run its course.

In analyses of retrograde amnesia, it is useful totake into account the age of memories that might beretrieved (i.e., the length of the retention interval)by distinguishing between recent memory andremote memory. Indeed, a prevalent characteristicof retrograde memory impairment, described in1882 by Theodore Ribot and known as Ribot’sLaw, states that the dissolution of memory isinversely related to the recency of the event.Numerous cases of retrograde amnesia have beendescribed in which the impairment was taken to belimited to recent memories, with preservation ofremote memories. Patterns of temporally gradedretrograde amnesia have been demonstrated using avariety of tests (Figure 1).

Implications of temporally graded retrogradeamnesiaThe notion that consolidation progresses over anextended period of time is consonant with evidencefrom retrograde amnesia, given the followingscenario. To the extent that memories were formedrecently, consolidation processes would have as yetbeen insufficient to produce a stabilized corticalmemory. These memories become inaccessible inthe absence of retrieval mechanisms that depend onhippocampal and related structures. This standardneuroanatomical account of consolidation thuscharacterizes recent memories as those that dependon both cortical and hippocampal networks.

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In contrast, to the extent that an old memory hasbeen subject to sufficient consolidation, it can beretrieved via cortical retrieval mechanisms.Whether hippocampal participation remains criticalfor some remote memories in some patients,however, is currently controversial.

The standard conceptualization of consolidation isas a process whereby declarative memories outgrowtheir dependence on cortico-hippocampal networksto become cortically self-reliant. Thismetamorphosis may involve increased connectivityamong the components of the memory in the cortex;accordingly, the process has sometimes beenreferred to as cross-cortical consolidation. Cross-cortical consolidation may also involve theformation of new cortical representations thatfunction to represent the gist or higher-ordermeaning of the memory while simultaneouslyenhancing the coherence of the set of neocorticalstorage sites (Figure 2).

Testing such speculations about how declarativememory representations change as a result ofconsolidation will require new sources ofneurophysiological and neuroanatomical evidence.Before delving into this sort of evidence, we must

examine doubts that have been raised about theevidence from retrograde amnesia.

Controversies and challenges in studies ofretrograde amnesiaThe extant literature on retrograde amnesia presentsa complicated story that does not uniformly supportthis standard account of consolidation. Temporallygraded retrograde amnesia has been observedreliably in patients with closed head injury,Korakoff’s syndrome, and other disorders ofmemory. Observations by Scoville and Milner in1957 of patient HM, who became amnesicfollowing bilateral medial temporal lobectomy formedically intractable epilepsy, showed retrogradeamnesia for autobiographical memory of roughly 2years duration. However, an insidious disease onset,as is likely in Korsakoff’s syndrome, or factors likeepilepsy or certain medications, could lead toapparent retrograde deficits that actually resultedfrom poor encoding during those years.

Conventional methods for assessing remotememory also have limitations. Whereas tests ofanterograde amnesia concern information deliveredsystematically to the patient under well-controlled

Figure 1. Forgetting curves showing temporally graded retrograde amnesia. A: Recall was tested using questions aboutnews events that occurred in preceding years (1950-2002) in 5 patients with damage limited primarily to thehippocampal region and 2-3 control subjects matched to each amnesic patient. The time period labeled AA (anterogradeamnesia) represents recall deficits for information acquired after the onset of amnesia. B: Recognition was tested for TVshows that were broadcast for only one season in preceding years (1957-1972) in 16 patients who were given a course ofelectroconvulsive therapy (ECT) as treatment for depressive illness. Subjects were required to select actual TV showtitles presented among fabricated titles, and the guessing rate was 25%. This test is advantageous because TV show titleswere learned in a specific year and were unlikely to be rehearsed repeatedly afterwards. ECT was given three times perweek and testing occurred before the first treatment and 1 hr after the fifth treatment. These memory deficits did notresult from medications or depressive illness per se. Memory abilities improved within a few weeks after ECT wascompleted. Figure adapted from Manns, J. R., Hopkins, R. O., & Squire L. R. (2003). Semantic memory and the humanhippocampus, Neuron 38, 127-133, and from Squire, L. R., Slater, P. C., & Chace, P. M. (1975). Retrograde amnesia:temporal gradient in very long term memory following electroconvulsive therapy. Science 187, 77-79.

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conditions, tests of retrograde amnesia tend to probeinformat ion acquired under unknowncircumstances. When testing memory for historicalevents or celebrities, for example, it can be difficultto determine the patient’s premorbid knowledge. Toattempt to overcome this problem, experimenterscan learn about important life events frominformants or create specialized tests for specificinformation.

In constructing retrograde tests, it can be helpful toselect test items such that various factors areequivalent across time periods. In this way, forexample, difficulty might be equated such that anobserved forgetting curve would reflect trueforgetting rather than greater difficulty for olderitems. However, equating difficulty may lead toother differences across items, as the most remoteitems may tend to concern factual rather thanepisodic knowledge. Interpretations of retrogradegradients thus require careful attention to the make-up of test materials.

Another interpretive limitation results because mostpeople show superior autobiographical retrieval forevents from their early adulthood. One explanationis that these years often include a person’s mostmomentous experiences and so have a powerfulinfluence on their life story and personality. Eventsfrom these times may also be extensivelyintertwined with other relevant information suchthat they are not easily lost.

Importantly, many reports of retrograde amnesiahave demonstrated impairments not limited to a fewyears, but spanning one or more decades. Somepatients lose essentially their whole life, in that theyare unable to retrieve many autobiographicalmemories from any past time period. Incontradistinction to the temporally graded period ofretrograde amnesia shown in Figure 1, thesepatients show no gradient. A process of gradualconsolidation does not seem to supply a viableexplanation for such extensive memory loss.Moreover, dense retrograde impairments have beenfound in some patients with minimal anterogradeamnesia, although this phenomenon is controversialand may be explained in some cases by otherfactors, such as psychogenic amnesia. Anothercomplication is that retrograde impairments candisproportionately affect episodic versus semanticknowledge. Some patients display poor memoryprimarily for remote autobiographical information,some primarily for remote factual information.

One theoretical view developed to account forextensive episodic memory loss is known asmultiple trace theory. By this view, thehippocampus contributes to episodic memoryretrieval for all time periods. This contributionprovides episodic retrieval with the contextualdetail that supports the ability to approximate re-living a past event. Memories for factualinformation do not include this contextual detailand become hippocampal-independent after

Neocortical ensemble Hippocampal network Coherence ensemble

Stage 2

Stage 1

Stage 3

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Figure 2. A speculative account of cross-cortical consolidation representedschematically. Initially (stage 1), a fact or event is encoded via representations inmultiple cortical regions with binding and cognitive control provided by prefrontalcortex. A selection of neocortical ensembles is figuratively shown in red (alliedsubcortical networks are omitted). At the same time, high-level features in thisdispersed representation involve hippocampal networks (stage 2). These hippocampalnetworks trigger pattern completion such that the set of dispersed cortical fragmentscan later be activated together. Over time (stage 3) and with the aid of hippocampalnetworks, coherence ensembles begin to form in various cortical regions such as medialtemporal cortex or other limbic-associated cortex (e.g., entorhinal, perirhinal,parahippocampal, posterior cingulate, and medial prefrontal cortex). These coherenceensembles ultimately become part of the memory representation, taking on asuperordinate role. Network connections become strengthened when the memory isretrieved and/or related to other stored information. By this account, a coherenceensemble is a cortical network that functions to maintain cohesiveness among thevarious parts of a declarative memory, and that ultimately (stage 4) takes over thebinding role of the hippocampus. Figure adapted from Paller, K. A. (2001).Neurocognitive foundations of human memory. In D. L. Medin (ed.). The Psychologyof Learning and Motivation, Vol. 40 (pp. 121-145). San Diego: Academic Press.

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sufficient consolidation. The idea that episodicmemories do not become independent of thehippocampus provides an explanation for retrogradeamnesia across all time periods.

Interpretations of these intriguing patterns ofretrograde impairment, however, must take intoaccount the fact that retrograde amnesia can arisefrom several fundamentally different causes.Although consolidation provides a viableexplanation for some instances of retrogradeamnesia, memories can also be lost when pathologydisrupts cortical areas responsible for the storage ofthis information. Whereas declarative memories aredispersed across multiple cortical regions, some ofthe multimodal and multidimensional knowledgecritical for retrieving certain memories may dependon the integrity of special convergence zones in thebrain, perhaps including medial temporal cortex(i.e., entorhinal, perirhinal, and parahippocampal),orbitofrontal cortex, medial prefrontal cortex,parietal cortex, and posterior cingulate cortex. Asdescribed above, a new representation formed inone of these regions may become part of thedeclarative engram by virtue of the consolidationprocess. Further research is needed to delineate thetype of information stored in such regions.Conceivably, decades of retrograde amnesia canarise when storage sites in these critical regions aredisrupted, in which case the evidence would haveno bearing on specifying the time-span ofconsolidation. Brain damage to some of theseregions could conceivably result in extensiveretrograde amnesia with minimal anterogradeamnesia if the hippocampus and some adjacentmedial temporal cortex remained intact.

Another alternative explanation for denseretrograde amnesia must also be considered. Cross-cortical consolidation may not be the culprit whenretrograde amnesia across all time periods resultsfrom a profound defect in retrieval. Indeed, varioussorts of evidence now point to a critical role of thefrontal lobes in orchestrating retrieval. Full-blownmemories of distinct autobiographical episodes canrequire extensive memory search. The planning,organization, and evaluation processes required forretrieval can become extremely challenging afterfrontal brain damage. Also, dissociations in the typeof information that can and cannot be retrievedcould arise from deficits based on either corruptedstorage sites or disabled retrieval.

The interpretation of long periods of remotememory loss must also be informed by evidence forsystematic relationships between the length of theretrograde loss and sites of brain damage. Moreevidence of this sort is needed, but results frompostmortem histological analysis for several casessuggest that partial hippocampal damage produceslimited retrograde impairment (1-2 years), whereasmore extensive damage to the hippocampus andentorhinal cortex produces broader retrogradeimpairment (15-25 years).

In sum, the literature includes an inconsistent mixof reports of retrograde amnesia that either extendsover decades or is limited to a recent period notlonger than a few years. In cases of temporallyextensive retrograde amnesia, storage and retrievalaccounts must be carefully evaluated. Perhaps allold memories in healthy people are subject tosteady reorganization. If so, an interesting butuntested possibility is that the longer a patient hasamnesia, the more dense their retrograde amnesiawill be. At any rate, further research will hopefullyexpand our understanding of the range of retrogradedeficits that can be observed and clarify when suchmemory disorders arise from a consolidation defect.

Problems with specifying the age of a memoryA further theoretical concern haunts the evaluationof all data on remote memory in amnesic patients.How should we conceptualize an episodic memorythat is 20 or more years old?

An episodic memory is defined with reference toone specific event that was experienced in a uniquetemporal and spatial context. If a person is capableof remembering an event from 20 years ago, it canreasonably be assumed that this memory has beenretrieved countless times in the intervening years.Nevertheless, researchers commonly refer to this asa 20-year-old memory. If intervening retrievalinfluences memory storage, it might be moreappropriate to regard the effective retention intervalas much shorter than 20 years. Although anindividual may recall an event from 20 years ago,the memory itself could be largely based onmodifications made more recently. Indeed, pastepisodes not retrieved and elaborated upon multipletimes over many years may be the ones we tend toforget.

Even younger memories are subject to concernsabout effects of intervening retrieval. Once weacknowledge that memories are accessed in sleep,

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which now seems undeniable, we cannot rule outthe idea that every instance of remote memoryretrieval is a function of storage events at multipletime points.

By the present account of consolidation, each time amemory for an episode is retrieved, there is apossibility that the information in question isassociated with other information so as to expandthe operative nature and meaning of the memory.Retrieved memories are regularly re-evaluated andrelated to new information in mind at the momentof retrieval, including the context of that retrievalepisode. Moreover, new events can provoke the re-interpretation of past events. Thus, the memorytrace should be conceived of as product of memorystorage operations engaged during various retrievalexperiences. Unless intervening retrieval can beruled out, it is problematic for the age of anepisodic memory to be defined simply on the basisof when the original event occurred.

This re-conceptualization of remote memoriesprovides an important point of contact betweenmultiple trace theory and the standard model ofconsolidation. A recalled episode may betantamount to a re-telling of prior re-tellings of thesame story, rather than a replay of an ancient storyset in stone long ago.

There are thus two reasons an amnesic patient’sretrograde impairment cannot be specified by asimple duration. First, consolidation for variousfactual and episodic memories may proceed at adifferent rate depending on the type of informationand the ways in which it is retrieved and associatedwith other information. Second, as underscored bythe preceding discussion, specifying a singleoperative age for a given memory is problematic.

Memory transformation due to consolidationConnections to the cortical storage sites thatcomprise a declarative memory may be formed viathe hippocampus at initial encoding, and then usedwhen that memory is subsequently retrieved. Bythis means, memories may be subject to continualhippocampal-dependent restructuring for sometime. Some remote memories may ultimately reacha state in which any further changes are relativelyminimal, even though these memories may retaintheir episodic quality.

Whereas consolidation can produce a hippocampal-independent memory, it can also change therepresentational quality of a memory. In some cases

of repeated retrieval of an event memory,contextual details are lost so that the event itselfcomes to be represented only abstractly. That is,specific episodic information can becomeex t r aneous t h rough a p roces s o fdecontextualization. Although these memories startout as contextually rich episodic memories, vividperceptual and contextual details gradually becomeunavailable — factual information about the eventbecomes the only part of the memory that can berecalled. In this manner, an episodic memory can besaid to have changed into a semantic memory.Decontextualization may produce an enduringsemantic memory in conjunction with a shift inmemory storage from neocortical/hippocampal toonly neocortical.

Computational models of consolidation haveimplemented procedures that theoretically couldlead to the formation of decontextualized memories.In the Complementary Learning Systemsframework, for example, hippocampal networksimplement fast links among neocorticalcomponents. Memory representation in theneocortex, in contrast, changes more slowly. Thisscheme keeps neocortical memories safe frominterference that would result if networks changedbased on each new piece of episodic information.Instead, slow neocortical changes can leadgradually to the build-up of semantic knowledge.The time-course of consolidation can then beconceived as a reflection of the time-consumingtraining of cortical networks by hippocampalnetworks.

Evidence from prospective studies,neuroimaging, and sleep researchMüller and Pilzecker introduced the termconsolidation (Konsolidierung) in 1900 andproposed that memories could change over timefrom a fragile, labile form to a fixed form. In 1903,Burnham took up consolidation in the context of theretrograde difficulties experienced by amnesicpatients and combined the notion of retrieval andassociation with the idea of neural reorganization.However, we have only limited opportunities toobserve these consolidation-based changes directly.Such opportunities will increase as we (a) begin tounderstand the physiological changes inscribed inbrain networks responsible for declarativememories, and (b) develop ways to overcome themethodological and interpretative limitationsdiscussed above.

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Prospective studies offer the opportunity to analyzewell-controlled memory storage over a certain timeperiod. Instead of relying on memory tests forretrospective information acquired under unknowncircumstances, the circumstances of encoding canbe controlled such that a range of retention intervalscan be systematically examined.

In animal studies of consolidation, a variety ofapproaches have been used in prospective studies,with lesions created surgically to encompassspecific regions (Figure 3). Many of these studieshave obtained results supporting the hypothesis thatmedial temporal damage produces temporallygraded retrograde amnesia (although there are alsosome exceptions). These observations of retrograde

amnesia in multiple species and with multiple typesof testing procedure also attest to the feasibility offuture efforts to delineate the precise causes ofretrograde memory impairment, and in this wayclarify how these memories are consolidated.

Human neuroimaging has also been used in studiesdesigned to examine how hippocampalcontributions to retrieval may change as a functionof the time since initial encoding. Interpretationsmust contend with many of the interpretive issuesdiscussed above. Hippocampal activity forretrospectively encoded recent and remotememories, in particular, can be engaged due toretrieval processing per se and/or due to encodingof the actual recollective experiences prompted by

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Figure 3. Several demonstrations of temporallygraded retrograde amnesia following damage to thehippocampal region. Learning took place at multipletimes before surgery. Two groups of animals weretested in each experiment, normal animals (N) andeither animals with lesions of the hippocampus (H),lesions of hippocampus plus surrounding cortex(H+), or lesions of entorhinal cortex (EC). Figureadapted from Eichenbaum, H. (2002). The cognitiveneuroscience of memory: an introduction. NewYork: Oxford University Press.A: Retention of 100 object discrimination problemsin monkeys. Data from Zola-Morgan, S. M., &Squire, L. R. (1990). The primate hippocampalformation: Evidence for a time-limited role inmemory storage. Science 250, 288-290.B : Retention of the social transmission of foodpreference in rats. Data from Clark, R. E., Broadbent,N. J., Zola, S. M., & Squire, L. R. (2002).Anterograde amnesia and temporally gradedretrograde amnesia for a nonspatial memory taskafter lesions of hippocampus and subiculum. JNeurosci 22, 4663-4669.C: Contextual fear conditioning in rats. Data fromKim, J. J., & Fanselow, M. S. (1992). Modality-specific retrograde amnesia of fear. Science 256,675-677.D: Trace eyeblink conditioning in rabbits. Data fromKim, J J., Clark, R. E., & Thompson, R. F. (1995).Hippocamectomy impairs the memory of recently,but not remotely, acquired trace eyeblink conditionedresponses. Behav Neurosci 109, 195-203.E: Retention of maze problems in mice. Data fromCho, Y. H., Beracochea, D., & Jaffard, R. (1993).Extended temporal gradient for the retrograde andanterograde amnesia produced by ibotenateentorhinal cortex lesions in mice. J Neurosci 13,1759-1766.

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retrieval cues. The possibility of superimposedencoding activity can thus pose difficulties forconclusive interpretations of the role of thehippocampus in recent versus remote memoryretrieval in these studies.

Prospective methods have also been used in someneuroimaging studies. In one such study, subjectsviewed a series of 320 landscape photographs andwere tested up to 90 days later. Brain activations forrecognized pictures were examined at four retentionintervals (Figure 4). Consolidation apparently led toa change in the anatomical basis of memorystorage, in line with predictions based ontemporally graded memory deficits due tohippocampal damage. The hippocampalcontribution appeared to decrease with time whilean anterior medial prefrontal contribution increasedwith time. Evidence from animal studies alsosupports the idea that this region of prefrontalcortex, which receives information from many othercortical regions, may play a key role in memoryreorganization.

Evidence from multiple sources supports the ideathat consolidation can occur both during wakingand during sleep. Hippocampal neurons in animalsshow evidence of memory replay during post-acquisition waking and sleep. Plasticity-relatedgene expression in medial temporal regions isaltered systematically during sleep. Hippocampaltheta during sleep may also index memoryprocessing, perhaps involving temporal couplingacross brain regions. Sleep spindles in cortical EEG

recordings at 12-15 Hz become more plentiful afterperiods of declarative memory encoding duringwaking, and together with hippocampal sharpwave/ripple EEG patterns may reflect hippocampal-neocortical dialogue. Depth EEG recordings havealso implicated interactions between hippocampusand medial temporal cortex in memory processingduring sleep. Various physiological events that haveyet to be deciphered may support memoryprocessing during multiple stages of sleep. Manydreams occur together with rapid eye movements,and these REM periods have some clear ties tomemory, perhaps emotional memories in particular.However, some evidence suggests that REM maynot be the only time, or even the foremost time, formemory reprocessing. Another stage, slow-wavesleep (SWS), which is prevalent early in the night,may play a vital role in hippocampal-neocorticalinteractions that promote declarative memoryconsolidation. During SWS, reduced cholinergicactivation and/or cortisol feedback in thehippocampus may promote hippocampalinformation flow to the neocortex. One possiblesign of the processing of declarative memoriesduring SWS is a build-up of slow negativepotentials over frontal cortex, and correlations havebeen observed between SWS and later performanceon declarative memory tests for information learnedprior to going to sleep. Although many questionsremain about memory processing during sleep, thisresearch area will undoubtedly be a source of muchnew thinking on consolidation in the coming years.

Figure 4. Results from an fMRI experiment in whichbrain activations for confident recognition responses werecompared as a function of whether initial encoding tookplace 1 , 2 , 30, or 90 days ear l ier .a: A region of ventral prefrontal cortex showed increasedactivity with increasing study-test delay. b: Bilateralhippocampal regions showed decreased activity withincreasing study-test delay. These findings suggest thathippocampal networks play a temporary role in memorystorage, and that this role may be transferred to corticalregions such as medial prefrontal cortex. This experimentalso included a rest period about 3 hrs after encoding,during which polysomnographic recordings were made,and those individuals who exhibited a greater amount ofslow-wave sleep during this period tended to demonstratesuperior memory for the photographs on later tests. Figureused with permission from Takashima, A., Petersson, K.M., Rutters, F., et al. (2006). Declarative memoryconsolidation in humans: a prospective functionalmagnetic resonance imaging study. Proc Natl Acad SciUSA 103, 756-761.

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Further ReadingAxmacher, N., Mormann, F., Fernández, G., et al.

(2006). Memory formation by neuronalsynchronization. Brain Research Reviews, inpress.

Buzsáki, G. (1998). Memory consolidation duringsleep: a neurophysiological perspective. J SleepRes 7, Suppl. 1, 17-23.

Burnham, W. H. (1903). Retroactive amnesia:illustrative cases and a tentative explanation.American Journal of Psychology 14, 382-396.

Dudai, Y. (2004). The neurobiology ofconsolidations, or, how stable is the engram?Annu Rev Psychol 55, 51–86.

Duncan, C. P. (1949). The retroactive effect ofelectroshock on learning. Journal of ComparativePhysiology and Psychology 42, 32-42.

Eichenbaum, H. (2002). The cognitive neuroscienceof memory: an introduction. New York: OxfordUniversity Press.

Frankland, P. W., & Bontempi, B. (2005). Theorganization of recent and remote memory.Nature Reviews Neuroscience 6, 119-130.

Gais, S., & Born, J. (2004). Declarative memoryconsolidation: mechanisms acting during humansleep. Learning & Memory 11, 679-685.

Hebb, D. O. (1949). The organization of behavior.New York: Wiley Press.

Kapur, N. (1993). Focal retrograde amnesia inneurological disease: a critical review. Cortex 29,217-234.

Kopelman, M. D. (2007, in press). Retrogradememory loss. In Miller, B. L., & Goldenberg, G.(eds.) Handbook of clinical neurology:neuropsychology and behavior. Elsevier.

McGaugh, J. L. (2000). Memory: a century ofconsolidation. Science 287, 248-251.

Meeter, M., & Murre, J.M. (2004). Consolidation oflong-term memory: evidence and alternatives.Psychol Bull 130,843-857.

Moscovitch, M, Rosenbaum, R. S., Gilboa, A. et al.(2005). Functional neuroanatomy of remoteepisodic, semantic and spatial memory: a unifiedaccount based on multiple trace theory. J Anat207, 35-66.

Müller, G. E. and Pilzecker, A. (1900).Experimentelle beitraege zur lehre vomgedaechtnis. Z. Psychol Ergaenzungband 1 , 1-300.

Paller, K. A. (1997). Consolidating dispersedneocortical memories: the missing link inamnesia. Memory 5, 73-88.

Paller, K. A., & Voss, J. L. (2004). Memoryreactivation and consolidation during sleep.Learning & Memory 11, 664-670.

Schacter, D. L., & Tulving, E. (eds.) (1994).Memory systems 1994. Cambridge, MA: MITPress.

Scoville, W.G., & Milner, B. (1957). Loss ofrecent memory after bilateral hippocampallesions. Journal of Neurology, Neurosurgery andPsychiatry 20, 11-21.

Squire, L. R. (1992). Memory and thehippocampus: a synthesis from findings with rats,monkeys, and humans. Psychological Review 99,195-231.

Squire, L. R., & Schacter, D. L. (eds.) (2002). Theneuropsychology of memory (3rd edn.). NewYork: Guilford Press.

Squire, L. R., Cohen, N. J., & Nadel, L. (1984). Themedial temporal region and memoryconsolidation: a new hypothesis. In Weingartner,H., & Parker, E. (eds.) Memory consolidation (pp.185-210). Hillsdale, NJ: Lawrence ErlbaumAssociates.

KeywordsCerebral cortex, declarative memory, episodicmemory, explicit memory, fact memory,familiarity, hippocampus, pattern completion.recognition, recollection, representation, sleep

SynopsisMemories for facts and events can last a lifetime,but neural substrates of these memories are notstatic. Hippocampal networks can conjointlyactivate a spatially distributed set of storagelocations in the cerebral cortex. Neuronalmodification and more effective storage may resultfrom hippocampal-cortical interactions duringwaking as well as during sleep. Whereas memoryretrieval initially depends on both hippocampal andcortical networks, following consolidationneocortical networks can be sufficient for memoryretrieval, though sometimes these memories aredevoid of contextual detail. Important questionsremain about how declarative memories arerepresented, how consolidation operates on theserepresentations, and how defective consolidationcan cause retrograde amnesia.