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Maintaining memories by reactiv
ationBjorn Rasch and Jan BornAccording 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
Current Opinion in Neurobiology 2007, 17:698–703
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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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
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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��].
Current Opinion in Neurobiology 2007, 17:698–703
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.
Current Opinion in Neurobiology 2007, 17:698–703
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-
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Maintaining memories by reactivation Rasch and Born 701
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
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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’’.
Current Opinion in Neurobiology 2007, 17:698–703
702 Neurobiology of behaviour
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An outstanding study investigating the influence of schemas pre-existingin memory on the time course of system consolidation for newly acquiredinformation. Rats learned flavor-place associations. Learning and, initi-ally, retrieval rely on the hippocampus. However, retrieval becomesgradually independent of the hippocampus over longer time periods.When rats had acquired a scheme of flavor-place association in which anew association could be integrated, retrieval of this newly acquiredknowledge became hippocampus-independent after only 48 hours, indi-cating that system consolidation (probably during sleep) occurs fairlyrapidly when new information can be readily integrated within pre-existingmemories.
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Current Opinion in Neurobiology 2007, 17:698–703