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Diekelmann S, Born J. The memory function of sleep. Nat Rev Neurosci 11: 114-126

February 2010
Nature Reviews Neuroscience 11(2):114-26

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PubMed

Authors:

University of Tübingen

Sleep has been identified as a state that optimizes the consolidation of newly acquired information in memory, depending on the specific conditions of learning and the timing of sleep. Consolidation during sleep promotes both quantitative and qualitative changes of memory representations. Through specific patterns of neuromodulatory activity and electric field potential oscillations, slow-wave sleep (SWS) and rapid eye movement (REM) sleep support system consolidation and synaptic consolidation, respectively. During SWS, slow oscillations, spindles and ripples - at minimum cholinergic activity - coordinate the re-activation and redistribution of hippocampus-dependent memories to neocortical sites, whereas during REM sleep, local increases in plasticity-related immediate-early gene activity - at high cholinergic and theta activity - might favour the subsequent synaptic consolidation of memories in the cortex.

| Memory re-activation during slow wave sleep (sWs). a | In awake rats running on a circular track (Run), neurons in the sensory cortex and hippocampus fire in a characteristic sequential pattern. Each row represents an individual cell and each mark in the upper parts of the diagrams indicates a spike; the curves in the lower parts indicate the respective average firing patterns of the cells. During subsequent slow wave sleep (SWS) (Sleep), temporal firing sequences observed in the cell assemblies during running re-appear both in the cortex and in the hippocampus 72 . b | Human subjects learned a two-dimensional object location task on a computer while an odour was presented as a context stimulus. Re-exposure to the odour specifically during subsequent SWS enhanced retention performance (recalled card locations) when tested the next day. There was no enhancement in retention when no association was formed between object locations and odour (that is, odour presentation during SWS but not during learning) or when odour re-exposure occurred during rapid eye movement (REM) sleep or waking 15 . c | When participants slept in an fMRI scanner after learning in the presence of odour, re-exposure to the odour during SWS activated the left anterior hippocampus (left) and neocortical regions like the retrosplenial cortex (right), which was not observed without odour presentation during prior learning 7 . Part a is modified, with permission, from Ref. 72 © 2007 Macmillan Publishers Ltd. All rights reserved; part b is modified, with permission, from Ref. 15 © 2007 American Association for the Advancement of Science; part c modified, with permission, from Ref. 7 © 2007 Elsevier.

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Although sleep is a systems-level process that affects

the whole organism, its most distinctive features are the

loss of behavioural control and consciousness. Among

the multiple functions of sleep1, its role in the establish-

ment of memories seems to be particularly important:

as it seems to be incompatible with the brain’s normal

processing of stimuli during waking, it might explain the

loss of consciousness in sleep. Sleep promotes primarily

the consolidation of memory, whereas memory encoding

and retrieval take place most effectively during waking.

Consolidation refers to a process that transforms new

and initially labile memories encoded in the awake state

into more stable representations that become integrated

into the network of pre-existing long-term memories.

Consolidation involves the active re-processing of ‘fresh’

memories within the neuronal networks that were used

for encoding them. It seems to occur most effectively

off-line, i.e. during sleep, so that encoding and consoli-

dation cannot disturb each other and the brain does not

‘hallucinate’ during consolidation2.

The hypothesis that sleep favours memory consolida-

tion has been around for a long time3. Recent research

in this field has provided important insights into the

underlying mechanisms through which sleep serves

memory consolidation4–7. In this Review, we first discuss

findings from behavioural studies regarding the specific

conditions that determine the access of a freshly encoded

memory to sleep-dependent consolidation, and regard-

ing the way in which sleep quantitatively and qualitatively

changes new memory representations. We then consider

the role of slow-wave sleep (SWS) and rapid eye move-

ment (REM) sleep in memory consolidation (BOX 1). We

finish by comparing two hypotheses that might explain

sleep-dependent memory consolidation on a mechanis-

tic level, that is, the synaptic homeostasis hypothesis and

the active system consolidation hypothesis.

Behavioural studies

Numerous studies have confirmed the beneficial effect

of sleep on declarative and procedural memory in various

tasks8–10, with practically no evidence for the opposite

effect (sleep promoting forgetting)11. Compared with a

wake interval of equal length, a period of post-learning

sleep enhances retention of declarative information3,12–16

and improves performance in procedural skills13,17–24.

Sleep likewise supports the consolidation of emotional

information25–27. Effects of a 3-hour period of sleep on

emotional memory were even detectable 4 years later28.

However, the consolidating effect of sleep is not revealed

under all circumstances and seems to be associated with

specific conditions29 (see below).

Sleep duration and timing. Significant sleep benefits

on memory are observed after an 8-hour night of sleep,

but also after shorter naps of 1–2 hours14,19,23,30, and even

an ultra-short nap of 6 minutes can improve memory

retention16. However, longer sleep durations yield greater

improvements, particularly for procedural memo-

ries18,21,31. The optimal amount of sleep needed to benefit

memory and how this might generalize across species

showing different sleep durations is unclear at present.

Some data suggest that a short delay between

learning and sleep optimizes the benefits of sleep on

memory consolidation. For example, for declarative

University of Lübeck,

Department of

Neuroendocrinology,

Haus 50, 2. OG, Ratzeburger

Allee 160, 23538 Lübeck,

Germany.

Correspondence to J. B.

e‑mail:

born@kfg.uni‑luebeck.de

doi:10.1038/nrn2762

Published online

4 January 2010

Declarative memory

Memories that are accessible

to conscious recollection

including memories for facts

and episodes, for example,

learning vocabulary or

remembering events.

Declarative memories rely on

the hippocampus and

associated medial temporal

lobe structures, together with

neocortical regions for

long-term storage.

Procedural memory

Memories for skills that result

from repeated practice and

are not necessarily available

for conscious recollection, for

example, riding a bike or

playing the piano. Procedural

memories rely on the striatum

and cerebellum, although

recent studies indicate that the

hippocampus can also be

implicated in procedural learning.

The memory function of sleep

Susanne Diekelmann and Jan Born

Abstract | Sleep has been identified as a state that optimizes the consolidation of newly

acquired information in memory, depending on the specific conditions of learning and the

timing of sleep. Consolidation during sleep promotes both quantitative and qualitative

changes of memory representations. Through specific patterns of neuromodulatory activity

and electric field potential oscillations, slow-wave sleep (SWS) and rapid eye movement

(REM) sleep support system consolidation and synaptic consolidation, respectively. During

SWS, slow oscillations, spindles and ripples — at minimum cholinergic activity — coordinate

the re-activation and redistribution of hippocampus-dependent memories to neocortical

sites, whereas during REM sleep, local increases in plasticity-related immediate-early gene

activity — at high cholinergic and theta activity — might favour the subsequent synaptic

consolidation of memories in the cortex.

SLEEP

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AOP, published online 4 January 2010; doi:10.1038/nrn2762

REM sleep

Nature Reviews | Neuroscience

Slow oscillation Spindle Sharp wave-ripple PGO wave Theta activity

Field potential oscillations

Neuromodulators

Slow oscillations

SWS

Stage 4

Stage 3

Stage 2

Stage 1

REM

Wake

23:00 0:00 1:00 2:00 3:00 4:00 5:00 6:00 7:00

Late sleep

Early sleep

Hours

Acetylcholine Acetylcholine

Noradrenaline/

serotonin

Noradrenaline/

serotonin

Cortisol Cortisol

Field potential

Single cell

recording

1 s

Up-state

Down-state

Serial reaction time task

A task in which subjects are

required to rapidly respond to

different spatial cues by

pressing corresponding

buttons. This task can be

performed implicitly (that is,

without knowledge that there is

a regularity underlying the

sequence of cue positions) or

explicitly (by informing the

subject about this underlying

regularity).

information, sleep occurring 3 hours after learning

was more effective than sleep delayed by more than

10 hours32,33. However, these studies did not control for

the confounding effects of forgetting during the wake

interval before the onset of sleep. For optimal benefit

on procedural memory consolidation, sleep does not

need to occur immediately18,19 but should happen on

the same day as initial training17,22,24.

Explicit versus implicit encoding. Whether memories

gain access to sleep-dependent consolidation depends

on the conditions of encoding. Encoding of declara-

tive memories is typically explicit, whereas proce-

dural memory encoding can involve both implicit

and explicit processes. Most robust and reliable sleep-

dependent gains in speed have been revealed for the

finger sequence tapping task, which involves explicit

procedural memory17–19,24. For the serial reaction time

task (SRTT), which can be learnt implicitly or explicitly,

the sleep-induced speeding of performance was more

robust when people learnt the task explicitly than

after implicit learning34. These observations suggest

that explicit encoding of a memory favours access to

sleep-dependent consolidation.

The benefit of sleep is greater for memories formed

from explicitly encoded information that was more dif-

ficult to encode or that was only weakly encoded35,36, a n d

it is greater for memories that were behaviourally relevant.

Thus, sleep enhances the consolidation of memories for

intended future actions and plans (D. S., I. Wilhelm, U.

Wagner, J. B., unpublished observations). Notably, this

enhancement could be nullified by letting the subject

Box 1 | Sleep architecture and neurophysiological characteristics of sleep stages

Sleep is characterized by the cyclic occurrence of rapid

eye movement (REM) sleep and non-REM sleep, which

includes slow wave sleep (SWS, stages 3 and 4) and lighter

sleep stages 1 and 2 (see the figure, part a). In humans, the

first part of the night (early sleep) is characterized by high

amounts of SWS, whereas REM sleep prevails during the

second half (late sleep). SWS and REM sleep are

characterized by specific patterns of electrical field

potential oscillations (part b) and neuromodulator activity

(part c, BOX 3).

The most prominent field potential oscillations during SWS

are the slow oscillations, spindles and sharp wave-ripples,

whereas REM sleep is characterized by ponto-geniculo-

occipital (PGO) waves and theta activity. The slow oscillations

originate in the neocortex with a peak frequency (in humans)

of ~0.8 Hz130,164. They synchronize neuronal activity into

down-states of widespread hyperpolarization and neuronal

silence and subsequent up-states, which are associated with

depolarization and strongly increased, wake-like neuronal

firing132,165,166 (part d). The hyperpolarization results from

activation of a Ca2+-dependent K+ current and inactivation of

a persistent Na+ current, which dampens excitability165,167,168.

The depolarizing up-state might be triggered by summation

of miniature EPSPs (from residual activity from encoding

information) and is formed by activation of T-type Ca2+ and

persistent Na+ currents.

Spindle activity refers to regular electroencephalographic

oscillations of ~10–15 Hz, which are observed in human sleep

stage 2 as discrete waxing and waning spindles, but are present

at a similar level during SWS (although here they form less

discrete spindles)169. Spindles originate in the thalamus from an

interaction between GABAergic neurons of the nucleus

reticularis, which function as pacemakers, and glutamatergic

thalamo-cortical projections that mediate their synchronized

and widespread propagation to cortical regions132,168,169.

Hippocampal sharp waves are fast depolarizing events, generated in the CA3, on which

high-frequency oscillations (100–300 Hz) originating from an interaction between inhibitory

interneurons and pyramidal cells in CA1 (so-called ripples) are superimposed104,121. Sharp

wave-ripples occur during SWS and also during waking, and accompany the re-activation

of neuron ensembles that are active during a preceding wake experience70,71,121,122,170.

PGO-waves are driven by intense bursts of synchronized activity that propagate from the pontine

brainstem mainly to the lateral geniculate nucleus and visual cortex. They occur in temporal association

with REM in rats and cats but are not reliably identified in humans. Theta oscillations (4–8 Hz) hallmark

tonic REM sleep in rats and predominate in the hippocampus141. In humans, theta activity is less

coherent144,145.

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Implicit learning

Learning without being aware

that something is being

learned.

Explicit learning

Learning while being aware

that something is being

learned.

Memory systems

Different types of memory,

such as declarative and

non-declarative memory, are

thought to be mediated by

distinct neural systems, the

organization of which is still a

topic of debate.

execute the intended behaviour before sleep. Similarly,

subjects who had been trained on two different finger-

tapping sequences showed greater sleep-dependent gains

in performance for the sequence for which they expected

to be rewarded for optimal performance at re-testing after

sleep37. Thus, a motivational tagging of memories, which

probably relies on the function of the prefrontal cortex38,

might signal behavioural effort and relevance and mediate

the preferential consolidation of these memories.

In summary, a great number of studies indicate that

sleep supports the consolidation of memory in all major

memory systems, but preferentially those that are explicitly

encoded and that have behavioural relevance to the indi-

vidual. There is growing evidence that explicit encoding,

even in procedural tasks, involves a dialogue between

the prefrontal cortex and the hippocampus38–40, which

also integrates intentional and motivational aspects of

the task. Activity of this circuit may be crucial in mak-

ing a memory susceptible to sleep-dependent memory

consolidation.

Sleep changes memory representations quantitatively

and qualitatively. Consolidation of memory during

sleep can produce a strengthening of associations as

well as qualitative changes in memory representations.

Strengthening of a memory behaviourally expresses itself

as resistance to interference from another similar task

(‘stabilization’) and as an improvement of performance

(‘enhancement’) that occurs at re-testing, in the absence

of additional practice during the retention interval.

The stabilizing effects of sleep have been observed in

declarative41 and procedural19 memory tasks. Similarly,

enhancements in performance after sleep have been

shown for declarative information13,14,20 and in proce-

dural tasks13,17,18,21,22,31. However, it is still controversial

to what extent these improvements reflect actual per-

formance ‘gains’ induced by sleep, because the measured

gains depend on the pre-sleep performance used as a

reference, which itself can be subject to rapid changes

after training42,43.

There is a long-standing debate about whether sleep

passively protects memories from decay and interfer-

ence or actively consolidates fresh memory represen-

tations44 (for a review see REF. 45). Importantly, a lack

of enhancement of memory performance after sleep

does not preclude an active role of sleep in memory

consolidation. There is strong evidence for an active con-

solidating influence of sleep from behavioural studies,

which indicate that sleep can lead to qualitative changes

in memory46–48. For example, in one study, subjects

learned single relations between different objects which,

unknown to the subject, relied on an embedded hierar-

chy47. When learning was followed by sleep, subjects at a

re-test were better at inferring the relationship between

the most distant objects, which had not been learned

before. Likewise, after sleep subjects more easily solved

a logical calculus problem that they were unable to solve

before sleep or after corresponding intervals of wakeful-

ness46. Of note, sleep facilitated the gain of insight into

the problem only if adequate encoding of the task was

ensured before sleep.

Interacting or competing memory systems? The behav-

ioural findings described above show that sleep can

‘re-organize’ newly encoded memory representations,

enabling the generation of new associations and the

extraction of invariant features from complex stimuli,

and thereby eventually easing novel inferences and

insights. Re-organization of memory representations

during sleep also promotes the transformation of

implicit into explicit knowledge, as was shown in an

SRTT which was implicitly trained but in which explicit

knowledge about the underlying sequence was exam-

ined during the re-test48. Following post-training sleep,

subjects were better at explicitly generating the SRTT

sequence. Interestingly, subjects who developed explicit

sequence knowledge no longer showed the improve-

ment in implicit procedural skill (that is, faster reaction

times) that is normally observed after sleep, suggesting

that procedural and declarative memory systems interact

during sleep-dependent consolidation.

Contrasting with this view of interacting memory

systems, it has also been proposed that disengagement

of memory systems is an essential characteristic of sleep-

dependent consolidation49. This idea derives mainly

from experiments showing that declarative learning of

words immediately after training of a procedural skill

can block off-line improvement in that skill if the subject

does not sleep between learning and re-testing, but not if

the subject sleeps between learning and re-testing50. This

suggests that memory systems compete and reciprocally

interfere during waking, but disengage during sleep,

allowing for the independent consolidation of memories

in different systems. The two views might be reconciled

by assuming a sequential contribution of interaction and

disengagement processes to consolidation, which might

be associated with different sleep stages (REM sleep and

SWS), as discussed below.

Influence of sleep stages on consolidation

Early studies in rats and humans investigating whether

different sleep stages have different roles in memory

consolidation mainly focused on REM sleep and the

consequences of REM sleep deprivation (REMD) by

repeatedly waking subjects at the first signs of REM

sleep. However, this approach is of limited value for logi-

cal reasons and because the repeated awakenings cause

stress, which itself influences memory function51,52.

Overall, these studies have provided mixed results52–55.

Of note is a recent study showing that pharmacologi-

cal suppression of REM sleep by administration of anti-

depressant drugs (selective noradrenaline or serotonin

re-uptake inhibitors) did not impair consolidation of

procedural memory56, which is in agreement with clini-

cal observations that antidepressant treatment does not

affect memory function57. However, such substances also

exert direct effects on synaptic plasticity and synaptic

forms of consolidation that could compensate for a loss

of REM sleep58.

Some studies performed in rats showed that REMD

is only effective during specific periods after learning

— the so-called ‘REM sleep windows’54. During post-

learning sleep, increases in the amount and intensity

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Transitory sleep

Short transitory periods of

sleep in rats that, based on

EEG criteria, can neither be

classified as REM sleep or

SWS.

of REM sleep occur several hours or even days after

learning, depending on the kind of task and amount of

initial training54, and memory is particularly impaired if

REMD coincides with these periods. Of note, the mem-

ory tasks used in rats are typically emotionally loaded. As

there is evidence that REM sleep preferentially benefits

the consolidation of emotional aspects of a memory25,27,

this could partly account for the strong REMD effect

observed in many animal studies53,55.

Studies in humans have compared the effects on

consolidation between sleep periods with different

proportions of SWS and REM sleep. In humans, SWS

and REM sleep dominate the early and late part of noc-

turnal sleep, respectively (BOX 1). SWS-rich, early sleep

consistently benefits the consolidation of declarative

memories12,13,59, whereas REM-rich sleep benefits non-

declarative types of memory (that is, procedural and

emotional aspects of memory)13,25,59. These results are con-

sistent with the ‘dual-process hypothesis’, which assumes

that SWS facilitates declarative, hippocampus-depend-

ent memory and REM sleep supports non-declarative,

hippocampus-independent memory6.

Other studies have shown that SWS can also

improve procedural skill (that is, non-declarative)

memories31,60,61 and that REM sleep can also improve

declarative memory62,63. Although these divergent find-

ings could reflect that stimuli used in memory tasks are

often not of one type of memory system, they agree

with the ‘sequential hypothesis’, which argues that the

optimum benefits of sleep on the consolidation of both

declarative and non-declarative memory occur when

SWS and REM sleep take place in succession31,64. Thus,

overnight improvements in visual texture discrimina-

tion correlated with both the amount of SWS in the

first quarter of sleep and the amount of REM sleep in

the last quarter21. Texture discrimination also improved

following a short midday nap of 60–90 minutes con-

taining solely SWS, but more so if the nap included

both SWS and REM sleep23. Also, memory consolida-

tion seems to be impaired by disruptions of the natural

SWS–REM sleep cycle that left the time spent in these

sleep stages unchanged65.

Intermediate sleep stages (non-REM sleep stage 2 in

humans, transitory sleep in rats) can also contribute to

memory consolidation66,67. For example, pharmaco-

logical suppression of REM sleep in humans produced

an unexpected overnight improvement in procedural

skill that was correlated with increased non-REM sleep

stage 2 spindle activity (see below)56. Such findings high-

light the fact that it is not a particular sleep stage per se

that mediates memory consolidation, but rather the

neuro physiological mechanisms associated with those

sleep stages, and that some of these mechanisms are

shared by different sleep stages.

Core features of off-line consolidation

Since the publication of Hebb’s seminal book68, memory

formation has been conceptualized as a process in which

neuronal activity reverberating in specific circuits pro-

motes enduring synaptic changes. Building on this, it is

widely accepted that the consolidation process that takes

place off-line after encoding relies on the re-activation

of neuronal circuits that were implicated in the encod-

ing of the information. This would promote both the

gradual redistribution and re-organization of memory

representations to sites for long-term storage (that is,

system consolidation; BOX 2) and the enduring synaptic

changes that are necessary to stabilize memories (syn-

aptic consolidation). The conditions that enable these

two processes during sleep differ strongly between SWS

and REM sleep.

Re-activation of memory traces during sleep. The finding

that in rats the spatio-temporal patterns of neuronal

firing that occur in the hippocampus during explora-

tion of a novel environment or simple spatial tasks are

re-activated in the same order during subsequent sleep

was an important breakthrough in memory research69–74

(FIG. 1a, see REF. 75 for methodological considerations

on the identification of neuronal re-activations). Such

neuronal re-activation of ensemble activity mostly

occurs during SWS (it is rarely observed during REM

sleep76,77) and during the first hours after learning (but

see REF. 78), and typically only in a minority of recorded

neurons69–74. Moreover, unlike re-activations that occur

during wakefulness, re-activations during SWS almost

always occur in the order in which they were expe-

rienced79. Compared with activity during encoding

phases, re-activations during SWS seem to be noisier,

less accurate and often happen at a faster firing rate71.

They are also observed in the thalamus, the striatum

and the neocortex72–74,78. Sleep-dependent signs of re-

activation in brain regions implicated in prior learning

were also shown in human neuroimaging studies80,81.

The first evidence for a causal role of re-activation

during SWS in memory consolidation came from a study

in humans learning spatial locations in the presence of an

odour15. Re-exposure to the odour during SWS, but not

REM sleep, enhanced the spatial memories (FIG. 1b) and

induced stronger hippocampal activation than during

wakefulness, indicating that during SWS hippocampal

networks are particularly sensitive to inputs that can

re-activate memories (FIG. 1c). It is assumed that the re-

activations during system consolidation stimulate the

redistribution of hippocampal memories to neocorti-

cal storage sites, although this has not been directly

demonstrated yet82,83.

Synaptic consolidation. In addition to system consoli-

dation (BOX 2), consolidation involves the strengthening

of memory representations at the synaptic level (syn-

aptic consolidation)84,85. Long-term potentiation (LTP)

is considered a key mechanism of synaptic consolida-

tion, but it is unclear whether memory re-activation

during sleep promotes the redistribution of memories

by inducing new LTP (at long-term storage sites not

involved at encoding) or whether re-activation merely

enhances the maintenance of LTP that was induced

during encoding.

LTP can be induced in the hippocampus during

REM sleep but less reliably so during SWS86. LTP induc-

tion in the hippocampus or neocortex during SWS is

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Long-term store (slow learning)

Encoding

Encoding Consolidation

Temporary store (fast learning)

Immediate early genes

Genes that encode

transcription factors that are

induced within minutes of

raised neuronal activity without

requiring a protein signal.

Immediate-early gene

activation is, therefore, used as

an indirect marker of neuronal

activation. The immediate

early genes Arc and Egr1

(zif268) are associated with

synaptic plasticity.

Hebbian plasticity

Refers to the functional

changes at synapses that

increase the efficacy of

synaptic transmission and

occurs when the presynaptic

neuron repeatedly and

persistently stimulates the

postsynaptic neuron.

Spike-time dependent

plasticity

Refers to the functional

changes at synapses that alter

the efficacy of synaptic

transmission depending on the

relative timing of pre- and

postsynaptic firing (‘spiking’).

The synaptic connection is

strengthened if the presynaptic

neuron fires shortly before the

postsynaptic neuron, but is

weakened if the sequence of

firing is reversed. probably temporally restricted to the up-states of the

slow oscillation and its concurrent phenomena of rip-

ples and spindles87,88 (see BOX 1 and below). Indeed, in

neocortical slices, stimulation that mimicked neuronal

activity during SWS could induce long-term depression

(LTD)89 or LTP87 depending on the pattern of stimula-

tion (rhythmic bursts or spindle-like trains, respectively).

LTP maintenance in the rat hippocampus, but not in the

medial prefrontal cortex, was impaired if induction was

followed by REMD90. In humans, sleep strengthened

LTP-like plasticity that had been induced in the neocor-

tex by transcranial magnetic stimulation (TMS) prior

to sleeping91.

Globally (meaning measured in whole-brain or large

cortical samples) sleep suppresses the molecular sig-

nals that mediate LTP-related synaptic remodelling but

enhances LTD-related signalling, and this effect seems

to be mediated by SWS92–95. This observation, however,

does not preclude that LTP occurs during sleep (during

SWS or REM sleep) in specific regions, for example in

those that were engaged in memory encoding prior to

sleeping. In rats, both induction of hippocampal LTP

and exposure to a novel tactile experience during wak-

ing increased the expression of the plasticity-related

immediate early genes (IEGs) Arc and Egr1 (which are

implicated in LTP) during subsequent sleep, mainly in

cortical areas that were the most activated by the novel

experience, and this effect seemed to be mediated by

REM sleep96–98. Investigations in visual cortex in cats

and humans have demonstrated that sleep-dependent

plasticity depends on the activation of glutamatergic

NMDA (N-methyl--aspartate) receptors and associ-

ated cAMP-dependent protein kinase A (PKA), and

on AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole

propionic acid) receptor activation, that is, the post-

synaptic machinery that is crucial for the induction and

maintenance of LTP99–102. These findings indicate that

local, off-line re-activation of specific glutamatergic

circuits supports both LTP induction and maintenance,

and the molecular processes underlying synaptic con-

solidation. Moreover, these processes probably occur

preferentially during REM sleep, although they are

likely to be triggered by the re-activations that occur

during prior SWS (see below). Evidence about how LTP

induction and maintenance is linked to specific sleep

stages is presently scarce, but based on the available

data it is tempting to speculate that SWS supports the

re-activation of new memories (system consolidation)

and thus, could initialize LTP and prime the relevant

networks for synaptic consolidation during subsequent

REM sleep. This idea seems to be supported by elec-

troencephalographic (EEG) rhythms that characterize

these sleep stages.

Sleep-specific field potential oscillations

Sleep stages are characterized by specific electrical

field potential rhythms that temporally coordinate

information transfer between brain regions and

might support Hebbian and spike-time-dependent

plasticity103,104.

Box 2 | The two-stage model of memory consolidation

A key issue of long-term memory formation, the

so-called stability–plasticity dilemma, is the problem

of how the brain’s neuronal networks can acquire new

information (plasticity) without overriding older

knowledge (stability). Many aspects of events

experienced during waking represent unique and

irrelevant information that does not need to be stored

long term. The two-stage model of memory offers a

widely accepted solution to this dilemma2,7,85,152 (see

the figure). The model assumes two separate memory

stores: one store allows learning at a fast rate and

serves as an intermediate buffer that holds the

information only temporarily; the other store learns at

a slower rate and serves as the long-term store.

Initially, new events are encoded in parallel in both

stores. In subsequent periods of consolidation, the

newly encoded memory traces are repeatedly

re-activated in the fast-learning store, which drives

concurrent re-activation in the slow-learning store,

and thereby new memories become gradually

redistributed such that representations in the slow-learning, long-term store are strengthened. Through the

repeated re-activation of new memories, in conjunction with related and similar older memories, the fast-learning

store acts like an internal ‘trainer’ of the slow-learning store to gradually adapt the new memories to the

pre-existing network of long-term memories. This process also promotes the extraction of invariant repeating

features from the new memories. As both stores are used for encoding information, in order to prevent interference,

the re-activation and redistribution of memories take place off-line (during sleep) when no encoding occurs.

Because in this model consolidation involves the redistribution of representations between different neuronal

systems that is, the fast- and slow-learning stores, it has been termed ‘system consolidation’. For declarative

memories, the fast- and slow-learning stores are represented by the hippocampus and neocortex, respectively.

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x = 11 y = -15

3.5

6.0

t21

Run Sleep Run Sleep

Sleep RetrievalLearning

Cortex Hippocampus

Cell number

1 s

0.5 s 0.2 s

1 s

Wake

REM

Stage 1

Stage 2

Stage 3

Stage 4

During SWS

Recalled card locations

No odour Odour No odour OdourNo odour Odour

100

20:00 24:0004:00 08:00

During REM During waking

100

***

Odour/vehicle

Odour

Odour re-exposure

Retrieval

performance

Odour

Time of day

Field potentials associated with SWS. Neocortical slow

oscillations, thalamo-cortical spindles and hippocampal

ripples have been associated with memory consolidation

during SWS (BOX 1). The neocortical slow oscillations (of

<1 Hz), by globally inducing up- and down-states of neu-

ronal activity, are thought to provide a supra-ordinate

temporal frame for the dialogue between the neocortex

and subcortical structures that is necessary for redistrib-

uting memories for long-term storage8,105,106. The ampli-

tude and slope of the slow oscillations are increased

when SWS is preceded by specific learning experi-

ences60,107,108 and decreased when the encoding of infor-

mation was prevented109. These changes occur locally, in

the cortical regions that were involved in encoding, and

can also be induced in humans by potentiating synap-

tic circuits through TMS91,110,111. Inducing slow oscilla-

tions during non-REM sleep by transcranial electrical

stimulation using slow (0.75 Hz) but not fast (5 Hz)

oscillating potential fields improved the consolidation

of hippocampus-dependent but not hippocampus-

independent (procedural) memories112, indicating that

slow oscillations have a causal role in the consolidation

of hippocampus-dependent memories.

Thalamo-cortical spindles seem to prime cortical

networks for the long-term storage of memory repre-

sentations. Repeated spindle-associated spike discharges

can trigger LTP87 and synchronous spindle activity

occurs preferentially at synapses that were potentiated

during encoding113. Studies in rats and humans showed

increases in spindle density and activity during non-

REM sleep and SWS after learning of both declarative

tasks and procedural motor skills20,108,114–118. In some

studies these increases correlated with the post-sleep

memory improvement30,119,120 and were localized to the

cortical areas that were activated during encoding, for

example, in the prefrontal cortex after encoding of dif-

ficult word pairs117,119, the parietal cortex after a visuo-

spatial task120 and the contralateral motor cortex after

finger motor-skill learning30.

Hippocampal sharp wave-ripples accompany the

sleep-associated re-activation of hippocampal neuron

ensembles that were active during the preceding awake

experience70,71,121,122. The occurrence of sharp wave-

ripples is facilitated in previously potentiated synap-

tic circuits123 and sharp wave-ripples might promote

synaptic potentiation88,124. During an individual ripple

event only a small subpopulation of pyramidal cells fire

— the subpopulation varies between successive ripples,

indicating modulation of select neuronal circuits121,125.

In rats, learning of odour–reward associations pro-

duced a robust increase in the number and size of ripple

events for up to two hours during subsequent SWS126. In

humans (epileptic patients) the consolidation of picture

memories that were acquired before a nap correlated

with the number of ripples recorded from the peri- and

entorhinal cortex, which are important output regions

of the hippocampus127. Selective disruption of ripples

by electrical stimulation during the post-learning rest

periods in rats impaired formation of long-lasting spatial

memories128, suggesting that ripples have a causal role in

sleep-associated memory consolidation.

Figure 1 | Memory re-activation during slow wave sleep (SWS). a | In awake rats

running on a circular track (Run), neurons in the sensory cortex and hippocampus fire

in a characteristic sequential pattern. Each row represents an individual cell and each

mark in the upper parts of the diagrams indicates a spike; the curves in the lower parts

indicate the respective average firing patterns of the cells. During subsequent slow

wave sleep (SWS) (Sleep), temporal firing sequences observed in the cell assemblies

during running re-appear both in the cortex and in the hippocampus72. b | Human

subjects learned a two-dimensional object location task on a computer while an odour

was presented as a context stimulus. Re-exposure to the odour specifically during

subsequent SWS enhanced retention performance (recalled card locations) when

tested the next day. There was no enhancement in retention when no association was

formed between object locations and odour (that is, odour presentation during SWS

but not during learning) or when odour re-exposure occurred during rapid eye

movement (REM) sleep or waking15. c | When participants slept in an fMRI scanner after

learning in the presence of odour, re-exposure to the odour during SWS activated the

left anterior hippocampus (left) and neocortical regions like the retrosplenial cortex

(right), which was not observed without odour presentation during prior learning7. Part

Association for the Advancement of Science; part c modified, with permission, from

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Up- and down-states

The slow oscillations that

predominate EEG activity

during SWS are characterized

by alternating states of

neuronal silence with an

absence of spiking activity and

membrane hyperpolarization

in all cortical neurons

(‘down-state’) and strongly

increased wake-like firing of

large neuronal populations and

membrane depolarization

(‘up-state’).

Interestingly, there is a fine-tuned temporal relation-

ship between the occurrence of slow oscillations, spin-

dles and sharp wave-ripples during SWS that coordinates

the bidirectional information flow between the neocor-

tex and the hippocampus. With some exceptions (which

are probably due to methodological differences129) a

consistent finding in humans, cats, rats and mice is that

spindle activity and ripples increase during the up-state

and become suppressed during the down-state of a slow

oscillation105,129–132. The top–down control of neuronal

activity by neocortical slow oscillations probably extends

to activity in other brain regions that are also relevant to

memory consolidation, such as the noradrenergic

burst activity of the locus coeruleus133,134. Sharp wave-

ripple complexes are also temporally coupled to sleep

spindles105,135,136, with individual ripple events becom-

ing nested in individual spindle troughs135. It has been

suggested that such ripple-spindle events provide a

mechanism for a fined-tuned hippocampal-neocortical

information transfer, whereby ripples and associated

hippocampal memory re-activations feed exactly into

the excitatory phases of the spindle cycle8,105,137,138. In

this scenario, the feed-forward control of slow oscil-

lations over ripples and spindles enables transferred

information to reach the neocortex during widespread

depolarization (during the up-state), that is, a state that

favours the induction of persistent synaptic changes,

eventually resulting in the storage of the information in

the cortex. The extent to which the grouping effect of the

slow oscillation on hippocampal activity is associated

with transfer of memory-specific information in the

opposite direction (from cortex to hippocampus), is

currently unclear.

Field potentials associated with REM sleep. Ponto-

geniculo-occipital (PGO) waves and the EEG theta

rhythm seem to support REM sleep-dependent consoli-

dation processes (BOX 1). The significance of PGO-waves

for memory consolidation is indicated by findings in rats

of a robust increase in REM sleep PGO-wave density

for 3–4 hours following training on an active avoid-

ance task67,139,140. The increase was proportional to the

improvement in post-sleep task performance, and was

associated with increased activity of plasticity-related

IEGs and brain-derived neurotrophic factor (Bdnf)

in the dorsal hippocampus within 3 hours following

training140.

The theta (4–8 Hz) oscillations that characterize REM

sleep in rats are also thought to contribute to consolida-

tion, based mainly on the finding that theta activity during

waking occurs during the encoding of hippocampus-

dependent memories141. However, evidence for this

assumption is scarce. There is evidence of neuronal

re-play of memories in the hippocampus during REM

sleep-associated theta activity76,77. Place cells encoding a

familiar route were re-activated preferentially during the

troughs of theta oscillations during post-training REM

sleep, whereas cells encoding novel sites fired during the

peaks77. As LTP induction in hippocampal CA1 cells

during theta activity depends on the phase of burst activ-

ity142, this finding is consistent with the idea that REM

sleep de-potentiates synaptic circuits that encode famil-

iar events but potentiates synaptic circuits that encode

novel episodes77. In humans, neocortical theta activity

was enhanced during REM sleep following learning of

word pairs62. Theta activity specifically over the right

prefrontal cortex was correlated with the consolidation

of emotional memories27. By contrast, mice exhibited

reduced REM sleep theta activity after fear condition-

ing143. Thus, although overall there is some evidence for

an involvement of theta activity in memory processing

during sleep, its specific contribution to consolidation is

obscure at present.

Theta activity occurring in conjunction with activity

in other EEG frequencies points to another important

feature that is relevant to memory processing: during

REM sleep, EEG activity in a wide range of frequencies,

including theta, shows reduced coherence between lim-

bic-hippocampal and thalamo-cortical circuits than dur-

ing SWS or waking144,145. Likewise, >40 Hz gamma band

activity shows reduced coherence between CA3 and

CA1 during tonic REM sleep146. These findings suggest

that memory systems become disengaged during REM

sleep49, possibly as a pre-requisite for establishing effec-

tive local processes of synaptic consolidation in these

systems (see below).

Synaptic homeostasis versus system consolidation

There are currently two hypotheses for the mecha-

nisms underlying the consolidation of memory during

sleep (FIG. 2). The synaptic homeostasis hypothesis11,147

assumes that consolidation is a by-product of the glo-

bal synaptic downscaling that occurs during sleep. The

active system consolidation hypothesis proposes that

an active consolidation process results from selective

re-activation of memories during sleep2,8. The two

models are not mutually exclusive; indeed, the hypoth-

esized processes probably act in concert to optimize the

memory function of sleep.

Synaptic homeostasis. According to the synaptic home-

ostasis hypothesis, information encoding during wake-

fulness leads to a net increase in synaptic strength in the

brain. Sleep would serve to globally downscale synaptic

strength to a level that is sustainable in terms of energy

and tissue volume demands and that allows for the re-

use of synapses for future encoding92,94. Slow oscillations

are associated with downscaling: they show maximum

amplitudes at the beginning of sleep when overall syn-

aptic strength is high, due to information uptake dur-

ing encoding prior to sleep, and decrease in amplitude

across SWS cycles as a result of the gradual synaptic de-

potentiation. Memories become relatively enhanced as

downscaling is assumed to be proportional in all syn-

apses, nullifying weak potentiation and thus improv-

ing the signal-to-noise ratio for the synapses that were

strongly potentiated during prior waking147 (FIG. 2a).

However, there is no clear evidence on how slow

oscillations might induce synaptic downscaling. The

low levels of excitatory neurotransmitters during SWS

(BOX 3) and the sequence of depolarization (up-states)

and hyperpolarization (down-states) of slow oscillations

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Waking – Synaptic potentiation

SWS REM

Sleep – Synaptic downscaling

W=100

W=80

W=120

W=150

W=5

W=100

Time

Synaptic plasticity

Neocortex

Slow oscillations

Thalamus

Spindles

Hippocampus

Sharp wave-ripples

Ca2+

CaMKII

PKA

IEG

AMPAR

NMDAR

LTP

Synchronous

feedback

Synaptic strength

Synchronizing

feed-forward

effect

at a frequency of <1 Hz might specifically promote the de-

potentiation of synapses148. Indeed, slow oscillations and

the associated activation of T-type Ca2+ channels seem to

favour LTD over LTP89; however, thalamo-cortical spindles

and hippocampal ripples nesting in depolarizing up-states

of slow oscillations support LTP87,88,124.

In addition, although the expression of markers of

synaptic potentiation (such as plasticity-related IEGs) is

globally reduced after a period of sleep, it is increased in

specific regions, particularly if sleep was preceded by a

learning experience78,96,98, indicating that synaptic poten-

tiation might still take place during sleep. Consistent

with downscaling, some neuroimaging studies (which

measure relative changes in brain activation) have shown

reduced task-related activity in cortical regions after sleep

(e.g. REF. 149), but these reductions were accompanied by

increases in activity in other regions82,83,149,150. Also, glo-

bal synaptic downscaling implicates that weakly encoded

memories are forgotten, which contrasts with behav-

ioural evidence indicating either no or, under certain

conditions, a greater benefit from sleep for weakly than

strongly encoded memories35,36. Therefore, downscaling

per se does not explain key features of sleep-dependent

consolidation. However, the synaptic downscaling

model explains a second memory-related function

of sleep, namely that sleep pro-actively facilitates the

encoding of new information during subsequent wake-

fulness through the de-potentiation of synapses that had

become saturated during preceding wakefulness (this

topic is beyond the scope of this Review)151.

Active system consolidation. This concept originated

from the standard two-stage model of consolidation pro-

posed for declarative memory2,7,85,121,152 (BOX 2; FIG. 2b), but

might also account for consolidation in other memory

systems8. It is assumed that in the waking brain events

are initially encoded in parallel in neocortical networks

and in the hippocampus. During subsequent periods of

SWS the newly acquired memory traces are repeatedly

re-activated and thereby become gradually redistributed

such that connections within the neocortex are strength-

ened, forming more persistent memory representations.

Re-activation of the new representations gradually adapt

them to pre-existing neocortical ‘knowledge networks’,

Figure 2 | Synaptic homeostasis versus active system consolidation. The synaptic homeostasis hypothesis (a)

proposes that due to encoding of information during waking, synapses become widely potentiated (large yellow nerve

ending), resulting in a net increase in synaptic strength (W = synaptic weight). The small nerve ending represents a new

synapse and the unfilled nerve ending is not activated and therefore does not increase in weight. The slow oscillations

during subsequent SWS serve to globally downscale synaptic strength (burgundy nerve endings). Thereby, weak

connections are eliminated, whereas the relative strength of the remaining connections is preserved. Thus, a memory is

enhanced as a consequence of an improved signal-to-noise ratio after downscaling. The active system consolidation

model (b) assumes that events during waking are encoded in both neocortical and hippocampal networks. During

subsequent slow wave sleep (SWS), slow oscillations drive the repeated re-activation of these representations in the

hippocampus, in synchrony with sharp wave-ripples and thalamo-cortical spindles (synchronizing feed-forward effect of

the slow oscillation up-state). By synchronizing these events the slow oscillations support the formation of ripple-spindle

events, which enable an effective hippocampus-to-neocortex transfer of the re-activated information. Arrival of the

hippocampal memory output at cortical networks, coinciding with spindle activity during the depolarizing slow oscillation

up-state predisposes these networks to persisting synaptic plastic changes (for example, expression of immediate early

genes (IEG) through Ca2+/calmodulin-dependent protein kinase II (CaMKII) and protein kinase A (PKA) activation) that are

supported primarily by subsequent rapid eye movement (REM) sleep. AMPAR, α-amino-3-hydroxy-5-methyl-4-isoxazole

propionic acid receptor; LTP, long-term potentiation; NMDAR, N-methyl-d-aspartate receptor. Part a is modified, with

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thereby promoting the extraction of invariant repeat-

ing features and qualitative changes in the memory

representations2,7.

Corroborating this concept, studies showed that

memory re-activation during post-learning SWS and

hippocampal ripples accompanying this re-activation

have a causal role in consolidation15,128. Re-activation in

hippocampal networks seems to be enabled by the low

cholinergic tone that characterizes SWS153–155 (BOX 3).

Moreover, there is evidence that the re-activation and

redistribution of memories during SWS is regulated

by a dialogue between the neocortex and the hippoc-

ampus that is essentially under feed-forward control of

the slow oscillations, which provide a temporal frame.

The depolarizing cortical up-states repetitively drive the

re-activation of memory traces in hippocampal circuits

in parallel with thalamo-cortical spindles and activity

from other regions (for example, noradrenergic locus

coeruleus bursts, see BOX 3). This enables synchronous

feedback from these structures to the neocortex during

the slow oscillation up-state, which is probably a pre-

requisite for the formation of more persistent traces in

neocortical networks8,106. Consistent with this concept,

neuronal re-activations in the timeframe of cortical slow

oscillations have been demonstrated, in which hippocam-

pal re-play leads re-activation in the neocortex72,122 (and

also in other structures like the striatum156). Moreover,

slow oscillations drive the ripples that accompany hip-

pocampal re-activation, thus allowing for the formation

of spindle-ripple events as a mechanism for effective

hippocampus-to-neocortex information transfer105,137,138

(FIG. 2b). Spindles reaching the neocortex during slow

oscillation up-states probably act to prime specific neu-

ronal networks, for example, by stimulating Ca2+ influx,

for subsequent synaptic plastic processes87,157.

The concept of active system consolidation during

SWS integrates a central finding from behavioural stud-

ies, namely that post-learning sleep not only strength-

ens memories but also induces qualitative changes in

their representations and so enables the extraction of

invariant features from complex stimulus materials, the

forming of new associations and, eventually, insights

into hidden rules46–48. The concept of a redistribution

of memories during sleep has been corroborated by

human brain imaging studies82,83,149,150,158. Interestingly, in

these studies, hippocampus-dependent memories were

particularly redistributed to medial prefrontal cortex

regions82,83,122 that also contribute to the generation of

slow oscillations159,160. These regions not only have a key

role in the recall and binding of these memories once

they are stored for the long term85, but also, together

with the hippocampus, form a loop that supports the

explicit encoding of information. As mentioned above,

behavioural data indicate that sleep does not benefit all

memories equally, but seems to preferentially consoli-

date explicitly encoded information34. In this context, the

prefrontal–hippocampal system might provide a selec-

tion mechanism that determines which memory enters

sleep-dependent consolidation.

A role for REM sleep in synaptic consolidation

The active system consolidation hypothesis leaves open

one challenging issue: although it explains a re-activation-

dependent temporary enhancement and integration

of newly encoded memories into the network of pre-

existing long-term memories, active system consoli-

dation alone does not explain how post-learning sleep

strengthens memory traces and stabilizes underlying

synaptic connections in the long term. Hence, sleep pre-

sumably also supports a synaptic form of consolidation

for stabilizing memories and this could be the function

of REM sleep.

The view that synaptic consolidation is promoted

by REM sleep is supported by the molecular and elec-

trophysiological events that characterize this stage.

Box 3 | Neuromodulators

The specific neurochemical milieu of neurotransmitters and hormones differs strongly

between slow wave sleep (SWS) and rapid eye movement (REM) sleep. Some of these

neuromodulators contribute to memory consolidation. Interestingly, the most

prominent contributions to memory processing seem to originate from the cholinergic

and monoaminergic brainstem systems that are also involved in the basic regulation of

sleep171.

SWS

Cholinergic activity is at a minimum during SWS; this is thought to enable the

spontaneous re-activation of hippocampal memory traces and information transfer to

the neocortex by reducing the tonic inhibition of hippocampal CA3 and CA1 feedback

neurons8,154,155. Accordingly, increasing cholinergic tone during SWS-rich sleep (using

physostigmine) blocked the sleep-dependent consolidation of hippocampus-dependent

word-pair memories153. Conversely, blocking the high cholinergic tone in awake

subjects improved consolidation but impaired the encoding of new information172,

suggesting that acetylcholine serves as a switch between modes of brain activity, from

encoding during wakefulness to consolidation during SWS154,155. This dual function of

acetylcholine seems to be complemented by glucocorticoids (cortisol in humans), the

release of which is also at a minimum during SWS. Glucocorticoids block the

hippocampal information flow to the neocortex, and if the level of glucocorticoids

is artificially increased during SWS, the consolidation of declarative memories is

blocked173,174.

Noradrenergic activity is at an intermediate level during SWS, and seems to be

related to slow oscillations. In rats, phasic burst firing in the locus coeruleus (the brain’s

main source of noradrenaline) can be entrained by slow oscillations in the frontal

cortex, with a phase-delay of ~300 ms133. It is possible that such bursts enforce

plasticity-related immediate early gene (IEG) activity in the neocortex93,95, and thereby

support at the synaptic level the stabilization of newly formed memory

representations. In humans, the consolidation of odour memories was impaired after

pharmacological suppression of noradrenergic activity during SWS-rich sleep and

improved after increasing noradrenaline availability (S. Gais, B. Rasch, J.C. Dahmen, S.J.

Sara and J. B., unpublished observations).

REM sleep

Cholinergic activity during REM sleep is similar or higher than during waking. This high

cholinergic activity might promote synaptic consolidation by supporting

plasticity-related IEG activity162 and the maintenance of long-term potentiation163.

Accordingly, blocking muscarinic receptors in rats by scopolamine during REM sleep

impaired memory in a radial arm maze task175. In humans, blocking cholinergic

transmission during REM-rich sleep prevented gains in finger motor skill176. Conversely,

enhancing cholinergic tone during post-training REM-rich sleep improved

consolidation of a visuo-motor skill177.

Noradrenergic and serotonergic activity reaches a minimum during REM sleep, but it

is unclear whether this contributes to consolidation. It has been proposed that the

release from inhibitory noradrenergic activity during REM sleep enables the

re-activation of procedural and emotional aspects of memory (in cortico-striatal and

amygdalar networks, respectively), thus supporting memory consolidation154,178.

However, enhancing noradrenergic activity during post-learning REM sleep in humans

failed to impair procedural memory consolidation56.

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Waking SWS REM sleep

Sequential

Time

Long-term store

Encoding

Temporary store

Active system

consolidation

Synaptic

consolidation

Although any links between sleep phases of short dura-

tion and gene expression are difficult to demonstrate

for methodological reasons, several studies suggest that

REM sleep, unlike SWS, is associated with an upregu-

lation of plasticity-related IEG activity (REFS 97,98,139).

The upregulation depends on learning experience dur-

ing prior wakefulness and is localized to brain regions

involved in prior learning97,98,139. Interestingly, this IEG

activity is correlated with EEG spindle activity during

preceding SWS98. Spindles (which, as discussed above,

represent a candidate mechanism that tags networks for

the neocortical storage of memories during system con-

solidation) per se do not induce IEG activity, but might

prime particular brain areas for it, possibly by enhanc-

ing Ca2+ concentrations in select subgroups of cortical

neurons87,157. The activity of plasticity-related early genes

depends on cholinergic tone161,162, which is enhanced to

wake-like levels during REM sleep (BOX 3). Cholinergic

activation strengthens the maintenance of LTP in the hip-

pocampus-medial prefrontal cortex pathway163, a main

route for transferring memories during SWS-dependent

system consolidation82,83,122,136. Electrophysiological sig-

natures of REM sleep, such as PGO waves, are increased

during post-learning sleep and might promote IEG

activity and memory consolidation140. EEG recordings

indicate that during REM sleep brain activation is as

high as during waking, but less coherent between differ-

ent regions and noisier144–146. This high level of activation

could act non-specifically to amplify local synaptic plas-

ticity in an environment that, compared with the awake

state, is almost entirely unbiased by external stimulus

inputs. The disentangled, localized nature of synaptic

consolidation might also explain why REM sleep alone

fails to improve declarative memory consolidation: this

process essentially relies on the integration of features

from different memories in different memory sys-

tems and corresponding information transfer between

widespread brain areas, that is, SWS-dependent system

consolidation.

Conclusions and future directions

SWS and REM sleep have complementary functions to

optimize memory consolidation (FIG. 3). During SWS —

characterized by slow oscillation-induced widespread

synchronization of neuronal activity — active system

consolidation integrates newly encoded memories with

pre-existing long-term memories, thereby inducing con-

formational changes in the respective representations.

System consolidation (which preferentially affects explic-

itly encoded, behaviourally relevant information) acts in

Figure 3 | Sequential contributions of SWS and REM sleep to memory consolidation in a two-stage memory

system. During waking, memory traces are encoded in both the fast-learning, temporary store and the slow-learning,

long-term store (in the case of declarative memory these are represented by the hippocampus and neocortex,

respectively). During subsequent slow wave sleep (SWS), active system consolidation involves the repeated re-activation

of the memories newly encoded in the temporary store, which drives concurrent re-activation of respective

representations in the long-term store together with similar associated representations (dotted lines). This process

promotes the re-organization and integration of the new memories in the network of pre-existing long-term memories.

System consolidation during SWS acts on the background of a global synaptic downscaling process (not illustrated) that

prevents saturation of synapses during re-activation (or during encoding in the subsequent wake-phase). During ensuing

rapid eye movement (REM) sleep, brain systems act in a ‘disentangled’ mode that is also associated with a disconnection

between long-term and temporary stores. This allows for locally encapsulated processes of synaptic consolidation, which

strengthen the memory representations that underwent system consolidation (that is, re-organization) during prior SWS

(thicker lines). In general, memory benefits optimally from the sequence of SWS and REM sleep. However, declarative

memory, because of its integrative nature (it binds features from different memories in different memory systems),

benefits more from SWS-associated system consolidation, whereas procedural memories, because of their specificity

and discrete nature, might benefit more from REM sleep-associated synaptic consolidation in localized brain circuits.

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concert with global synaptic downscaling, which serves

mainly to preclude the saturation of synaptic networks.

Ensuing REM sleep — characterized by de-synchroniza-

tion of neuronal networks, which possibly reflects a disen-

gagement of memory systems — might act to stabilize the

transformed memories by enabling undisturbed synaptic

consolidation. Although REM sleep has been suspected

for a long time to have a key role in memory consolida-

tion, research has paid little attention to the fact that REM

sleep naturally follows SWS. This points to complementing

contributions of sequential SWS and REM sleep to mem-

ory consolidation — an idea that was originally proposed

in the sequential hypothesis64. This Review revives this

idea by indicating an essential role of SWS in system con-

solidation that might be complemented by the synaptic

consolidation taking place during REM sleep. However,

direct evidence of this is scarce at present65. Specifying the

role of REM sleep, as an integral part of this sequence, in

synaptic consolidation will undoubtedly pose a particular

challenge to future research.

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Acknowledgments

We apologize to those whose work was not cited because of

space constraints. We thank Drs. B. Rasch, L. Marshall, I.

Wilhelm, M. Hallschmid, E. Robertson and S. Ribeiro for help-

ful discussions and comments on earlier drafts. This work was

supported by a grant from the Deutsche Forschungsgemeinschaft

(SFB 654 ‘Plasticity and Sleep’).

Competing interests statement

The authors declare no competing financial interests.

DATABASES

Entrez Gene: http://www.ncbi.nlm.nih.gov/gene

Arc | Egr1

UniProtKB: http://www.uniprot.org

Bdnf |

FURTHER INFORMATION

Jan Born’s homepage: http://www.kfg.uni-luebeck.de

ALL LINKS ARE ACTIVE IN THE ONLINE PDF

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