Maintaining memories by reactivation

Maintaining memories by reactiv
ationBjorn Rasch and Jan Born
According to a widely held concept, the formation of long-term

memories relies on a reactivation and redistribution of newly

acquired memory representations from temporary storage to

neuronal networks supporting long-term storage. Here, we

review evidence showing that this process of system

consolidation takes place preferentially during sleep as an

‘off-line’ period during which memories are spontaneously

reactivated and redistributed in the absence of interfering

external inputs. Moreover, postlearning sleep leads to a

reorganization of neuronal representations and qualitative

changes of memory content. We propose that memory

reactivations during sleep are accompanied by a transient

destabilization of memory traces. Unlike wake reactivations

that form part of an updating of memories with respect to

current perceptual input, reactivations during sleep allow for

gradually adapting newly acquired memories to pre-existing

long-term memories whereby invariants and certain other

features of these memories become extracted.

Addresses

University of Lubeck, Department of Neuroendocrinology, Haus 23a,

Ratzeburger Allee 160, 23538 Lubeck, Germany

Corresponding authors: Rasch, Bjorn ([email protected]) and

Born, Jan ([email protected])

Current Opinion in Neurobiology 2007, 17:698–703

This review comes from a themed issue on

Neurobiology of behaviour

Edited by Edvard Moser and Barry Dickson

Available online 28th January 2008

0959-4388/$ – see front matter

# 2007 Elsevier Ltd. All rights reserved.

DOI 10.1016/j.conb.2007.11.007

IntroductionFormation of long-term memories represents a core capa-

bility of the organism to adapt to a complex environment,

enabling to anticipate the future based on prior experi-

ences. During this process, the organism faces the problem

how to quickly acquire new information without over-

riding older knowledge. Furthermore, many newly

encountered pieces of information represent unique,

unstable, and temporary events and therefore are not

relevant for the long term. A possible solution to this

problem proposed by Marr [1] is the assumption of two

separate memory stores, each working at a different learn-

ing rate, which has now become the standard model of

long-term memory consolidation with regard to declarative

memories of events and facts [2,3]. In this model, certain


features of the new information encoded by neocortical

neuronal networks are initially bound together and stored

by fast learning regions of the temporal lobe, mainly the

hippocampus. During off-line periods without encoding

demands, the newly acquired memory traces are gradually

redistributed to neocortical regions by strengthening cor-

tico-cortical connections, thereby rendering the memories

increasingly independent from the integrity of hippo-

campal regions. This process of so-called system consoli-

dation originates from the repeated reactivation of memory

traces, during which the fast learning temporary store acts

as internal ‘trainer’ of the slowly learning long-term store.

Reactivation of the new information, occurring in conjunc-

tion with reactivations of related and elder information, are

thought to gradually adapt in an interleaved learning

process the new memories to the pre-existing network

of long-term memories, thereby promoting the extraction

of invariant features and qualitative changes in the respect-

ive memory representations [4]. Although the standard

model of consolidation was formulated originally for

declarative memories, its basic principles have been suc-

cessfully applied to nondeclarative learning systems [5],

suggesting that the off-line reactivation of recent mem-

ories together with the redistribution of memories from a

fast learning temporary storage system to a slow learning

permanent store could be general features of long-term

memory formation.

Memory consolidation during off-lineperiodsIn support of the basic principles of the standard model of

long-term memory consolidation, evidence for memory

consolidation during off-line periods has been provided

by numerous studies showing that sleep improves mem-

ory formation of declarative and nondeclarative memories

[6,7]. In certain tasks of motor and visuomotor skill

learning, improvements in performance between sessions

occur only when sleep occurs within some hours (less than

�16 hours) after training [6]. These performance gains are

accompanied by characteristic sleep-dependent changes

in retrieval-associated brain activity [8,9] suggesting that

the underlying neuronal substrates of the memory

become redistributed during sleep [10]. Using a declara-

tive word-pair learning task, Gais et al. [11��] showed that

sleep after learning as compared to wakefulness increased

functional connectivity between medial prefrontal cortex

and hippocampus at retrieval tested 48 hours later, and

enhanced activity in prefrontal cortex at retrieval 6

months later, consistent with the view of a sleep-de-

pendent shift towards an enhanced neocortical contri-

bution to memory representations (for related findings,

see [12]). In addition, there is behavioral evidence that

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http://dx.doi.org/10.1016/j.conb.2007.11.007

Maintaining memories by reactivation Rasch and Born 699

memory representations undergo qualitative changes

during postlearning sleep, resulting in a facilitated gain

of insight into an arithmetic problem [13��] and of explicit

knowledge about hidden structures and invariants

embedded in tasks performed before sleep [14�,15�].These findings fit well with the notion that memory

consolidation during sleep involves a redistribution of

neuronal representations, which is accompanied by the

extraction of invariants in the newly acquired information

thereby promoting distinct qualitative changes of the

memory representation and gains of explicit knowledge.

Reactivation of memories during off-lineperiodsIn parallel with behavioral evidence for gains in memory

during sleep, evidence has accumulated mainly from

recordings of neuronal activity in rodents suggesting that

newly acquired memories become reactivated during off-

line periods. Especially during slow wave sleep (SWS),

firing patterns within hippocampal assemblies of place

Figure 1

Neuronal reactivation of memory during slow wave sleep (SWS) in rats and

in the sensory cortex and the hippocampus fire in a characteristic sequentia

upper parts of the diagrams indicates a spike, while the curves in the lower

subsequent SWS (Sleep), temporal firing sequences observed in the cell as

hippocampus. The reactivation during SWS of pattern activity during prior w

hippocampus to reflect the same wake experience, thus forming a hippoca

memories during sleep. (b) Human subjects learned a two-dimensional obje

exposure to the odor specifically during subsequent SWS enhanced retentio

participants slept in an fMRI-scanner after learning in the presence of odor,

whereas no hippocampal activation was observed when odor presentation

statistical comparison of the two conditions confirmed distinctly higher activ

neocortical regions like the retrosplenial cortex (right panel) to odor re-expo

than in the absence of odor. Panels indicate differences between BOLD-res

the two conditions, thresholded at P < 0.001 uncorrected. Adapted from [26


cells (coding the position in space) express a striking

similarity to firing patterns that were present during

learning and exploratory behaviors before sleep [16–

19]. Experience-dependent reactivations have also been

observed in other brain regions including the thalamus,

putamen, ventral striatum, and neocortex [20,21] as well

as in other species-like monkeys [22] and birds [23].

Several authors suggested that the learned information

is ‘replayed’ during sleep, though probably at a faster time

scale [24,25], because the temporal order of spike trains is

maintained during sleep. Neuronal reactivations occur in

a temporally coordinate fashion, with first hints

suggesting that reactivations in hippocampal networks

lead reactivations in visual cortex, consistent with the

notion of a hippocampo-to-neocortical transfer of the

replayed information during sleep [26��] (Figure 1a).

Studies of memory reactivation during sleep have been

criticized along several lines. Reactivations were often

observed in highly trained animals after repeated runs

humans. (a) In awake rats running on a circular track (Run), neurons

l pattern. Each row represents an individual cell and each tick in the

parts indicate respective average firing patterns of the cells. During

semblies during running re-emerge in the cortex as well as in the

aking experience is temporally coordinated between cortex and

mpo-neocortical dialog that could underly the redistribution of

ct location task while an odor was presented as context stimulus. Re-

n performance tested the next day (data not shown). When

the re-exposure to odor during SWS activated the left hippocampus,

during prior learning had been omitted (unpublished data). Direct

ation in the left anterior hippocampus (left panel) and also in

sure during SWS when subjects had learned in the presence of odor

ponses associated with ‘odor-on’ periods during SWS between��,37��].


700 Neurobiology of behaviour

through a maze, that is, conditions without an apparent

learning component [27]. In addition, recorded reactiva-

tions — though statistically significant — appear to be

extremely subtle and often decay within the first hour of

sleep, raising the question whether this phenomenon

could really act as repetitive ‘training signal’ for the

long-term store [28]. However, Ribeiro et al. [21] observed

signs of memory reverberation in hippocampus and other

regions during sleep that persisted up to 48 hours after

exploratory behavior (see [29] for a critical evaluation of

statistical methods of this study). Also, little decay has

been observed for reactivations in regions other than the

hippocampus like the striatum [30]. Generally, it is com-

pletely unknown which factors (e.g. emotional salience,

reward value) determine the selection of wake experience

replayed during sleep. In addition, the kind of infor-

mation replayed during sleep might change based on

interactions with pre-existing memories, raising the

possibility that the amount of ‘signal’ that is contained

in the neuronal firing patterns recorded during sleep is

underestimated with the current methods used.

In contrast to animal studies, human studies investigating

reactivation patterns during sleep always employed tasks

with a clear mnemonic component [31]. Using neuroima-

ging techniques, these studies showed that brain regions

activated during training of a nondeclarative memory task

(implicit sequence learning) are activated again during

subsequent rapid-eye movement (REM) sleep [32],

whereas learning a declarative task (spatial navigation)

reactivated the hippocampus during SWS [33��]. The

stronger the activity in the specific brain regions during

sleep the better was the performance during later retrie-

val testing, suggesting a functional role of the recorded

activity for processes of memory consolidation.

Reactivating memories during sleepenhances memory consolidationWhereas the studies discussed above demonstrate the

presence of memory reactivations during sleep, their func-

tional role for long-term memory formation can only be

derived from studies of memory retrieval after direct

manipulation of such reactivations during prior sleep. So

far no attempts have been made to block memory reactiva-

tions during sleep. However, a promising alternative

approach taken in several studies is to induce memory

reactivations by presenting a memory cue, that is, a ‘remin-

der’ during sleep. Hars et al. [34] trained rats in a fear-

conditioning paradigm, and presented the conditioned

stimulus (CS, weak ear shocks) at nonwaking levels again

repeatedly during subsequent REM sleep. Freezing to the

CS was enhanced at later re-testing. Similarly, Smith and

Weeden [35] reported that when human subjects were

trained on a complex rule-learning task in the presence of a

ticking alarm clock, the re-exposure of the clicks at times of

rapid-eye movements during subsequent sleep substan-

tially enhanced later performance on the task.


We used an olfactory stimulus to reactivate declarative

memories during sleep [37��] because shocks and clicks

presented during sleep acutely disturb sleep architecture

[36]. The impact of odors on sleep is negligible [38] and

odors are also known for their strong potency to activate

associated memories [39]. In our study, participants

learned a visual–spatial learning task under the presence

of an odor. Re-exposure to the odor during subsequent

SWS distinctly improved later retrieval of the task stimuli.

Control experiments specified that the memory enhance-

ment after odor-exposure during sleep depends crucially

on the presence of the odor during prior learning. Further

on, odor re-exposure was effective only during SWS, but

not during REM sleep or wakefulness. In an additional

experiment using functional magnetic resonance imaging

(fMRI), odor re-exposure during SWS activated the

hippocampus which also participates in the initial storage

of visuo-spatial memories [40]. Odor-induced reactivation

was seen only when the odor had been present during

prior learning (Figure 1b). In addition, hippocampal

activity during reactivation in SWS was significantly

stronger compared to odor re-exposure during wakeful-

ness after learning, pointing to an enhanced sensitivity of

the hippocampus during SWS to stimuli capable of reac-

tivating declarative memories. Together, these findings

of enhanced retrieval after induced reactivation of a

memory during sleep provide strong support for the

notion that reactivations occurring spontaneously during

sleep might serve in the same way to consolidate new

memories.

Sequential role of SWS and REM sleep formemory consolidationReactivations in hippocampal circuitry during SWS

benefit the consolidation of declarative memories

[33��,37��], whereas reactivation of memories during

REM sleep appear to improve particularly emotional

and procedural aspects of a memory [32,35]. As to declara-

tive memories, reactivations of hippocampal cell assem-

blies indeed occur mainly during SWS [19]. Paradoxically,

SWS is characterized by diminished activity of plasticity-

related early genes [41] and a greatly reduced ability to

induce synaptic long-term potentiation (LTP) [42], a

process believed to underlie neuronal encoding of new

information [43]. Induction and maintenance of LTP is

linked to activation of glutamatergic NMDA and AMPA

receptors, blocking of which inhibits sleep-dependent

memory consolidation (Gais et al., unpublished data;

[44]), corroborating the view that the consolidation pro-

cess during sleep leads to an involvement of new neuronal

circuitry for memory storage. REM sleep provides a more

adequate milieu of neurotransmitters and modulators for

synaptic plastic changes than SWS. Therefore, several

authors have proposed that memory reactivation during

SWS leads to a tagging of synapses which are strength-

ened during subsequent REM sleep [45,46]. A sequential

role of SWS and REM sleep stages in memory consolida-



tion is corroborated by findings indicating that optimal

memory benefits result from retention sleep containing

both undisturbed SWS and REM sleep [47–50], though

the role of memory reactivation observed during REM

sleep remains elusive in this context. Moreover, retrieval

improvements can occur after naps lacking any REM

sleep [51], tempting the speculation that synapses tagged

after memory reactivation during SWS can likewise be

strengthened during subsequent periods of wakefulness

which like REM sleep provides adequate resources for

synaptic plastic changes [52,53].

Reactivation of memories during wakefulnessNeuronal signs of reactivation of memories are not

restricted to sleep but have been revealed also during

postlearning periods of wakefulness, in animals while

resting quietly [18,22] and in humans while performing

an attention task unrelated to the preceding learning

experience [54]. Unlike reactivations during sleep,

sequential replay in hippocampal place cells during wake-

fulness can occur in a temporally reversed order [55,56].

In rats firing of place neurons on an elevated track

recurred in reverse order at the end of a run, but in

forward order in anticipation of the run. Bi-directional

wake reactivations might support the formation of higher

order episodic associations during learning [56]. However,

it is unknown whether these neuronal reactivations

during wakefulness are related to processes of memory

consolidation in the same way as reactivations during

sleep. In fact, studies of memory reconsolidation have

indicated that reactivation of memories during wakeful-

ness by cueing exerts a destabilizing rather than stabiliz-

ing influence on respective memory representations,

rendering already stored memories again susceptible to

interfering information and amnesic treatments [57,58].

However, although transiently disturbing processes of

consolidation, destabilization after memory reactivation

during wakefulness could provide the possibility to

modify and ‘update’ the existing memory trace with

reference to newly encountered information [59]. If the

newly encoded information matches the existing memory

trace, the memory is likely to be strengthened by a

process of ‘re-encoding’ [60] and to become more gener-

alized if reactivation occurs in a different environment

[61]. Still, any conflicting information encoded after

reactivation during wakefulness is expected to impair

subsequent consolidation.

In contrast to the wake state, no external information is

encoded or interferes with processes of memory consoli-

dation during sleep. Conceivably, memory reactivation

during sleep transiently destabilizes memory traces in the

same way as wake reactivations. However, due to the

lacking external input, memory traces undergo straight-

forward ‘reconsolidation’ without any danger of encoun-

tering conflicting information, resulting in strengthened

memory traces. Possible modifications to this process


would be restricted to internal information originating,

for example, from pre-existing knowledge, whereby sleep

provides optimal conditions for integrating newly

acquired information within these long-term memories.

ConclusionWe have argued here that the reactivation and sub-

sequent redistribution of newly acquired memory repres-

entations form general parts in a process of long-term

memory formation that is established most effectively

during off-line periods like sleep. Unlike others assuming

a role of sleep mainly in global processes of synaptic

downscaling precipitating forgetting of irrelevant infor-

mation [28], we consider sleep playing an active role in

memory consolidation by promoting particular processes

of system consolidation involving the redistribution of

memory representations to underlying neuronal net-

works. Although system consolidation usually refers to

remote memories whose retrieval becomes increasingly

independent from hippocampal circuitry over periods of

months and years, recent experiments indicate that the

redistribution from hippocampal to neocortical areas can

be accomplished in less than 48 hours if the newly

acquired information can be readily integrated into pre-

existing schemes [62��]. These findings suggest that

processes of system consolidation can occur very rapidly

which offers an explanation for the beneficial effects

observed in many studies of only one night of sleep on

memory consolidation [6,63].

Reactivation of a memory is most crucial for its mainten-

ance. In our view, it fulfils two different functions

depending on the brain state: In the wake state memory

reactivations are triggered by external information and, by

transiently destabilizing memories, serve to enable an

updating of memories. By contrast, during sleep, reacti-

vations are generated spontaneously in the absence of

interfering external inputs, thus allowing for a gradual

integration of the newly acquired information within pre-

existing long-term memories. This process of system

consolidation takes place off-line during sleep not only

to hold off interfering external inputs but also because the

spontaneous reactivation and redistribution of memories

would interfere with proper processing of external inputs

during wakefulness [64]. Unlike the reactivation of mem-

ories during sleep whose presence and function has been

compellingly demonstrated in recent research, the sleep-

dependent redistribution of memories is less well

examined both in terms of its psychological determinants

(i.e. which information is extracted in this process) and its

neuronal underpinnings (i.e. to which networks the infor-

mation is allocated).

AcknowledgementsWe thank Lisa Marshall and Susanne Diekelmann for critical comments andhelp in preparing the manuscript. Supported by the DeutscheForschungsgemeinschaft (DFG), SFB 654 ‘‘Plasticity and Sleep’’.


702 Neurobiology of behaviour

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Maintaining memories by reactivation