Sleep and Episodic Memory.

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Marion Inostroza1,2 and Jan Born1
by Pontificia Universidad Javeriana on 07/28/13. For personal use only.
1
Department of Medical Psychology and Behavioral Neurobiology and Centre for
Integrative Neuroscience (CIN), University of Tübingen, 72076 Tübingen, Germany;
email: jan.born@uni-tuebingen.de, marion.inostroza@uni-tuebingen.de
2
Departamento de Psicologı́a, Universidad de Chile, Santiago, Chile
Annu. Rev. Neurosci. 2013. 36:79–102 Keywords

First published online as a Review in Advance on slow-wave sleep, REM sleep, system consolidation, memory
April 29, 2013
reactivation, schema
The Annual Review of Neuroscience is online at
neuro.annualreviews.org Abstract
This article’s doi:
Sleep is known to support memory consolidation. Here we review ev-
10.1146/annurev-neuro-062012-170429
idence for an active system consolidation occurring during sleep. At
Copyright c 2013 by Annual Reviews.
the beginning of this process is sleep’s ability to preserve episodic ex-
All rights reserved
periences preferentially encoded in hippocampal networks. Repeated
neuronal reactivation of these representations during slow-wave sleep
transforms episodic representations into long-term memories, redis-
tributes them toward extrahippocampal networks, and qualitatively
changes them to decontextualized schema-like representations. Elec-
troencephalographic (EEG) oscillations regulate the underlying com-
munication: Hippocampal sharp-wave ripples coalescing with thalamic
spindles mediate the bottom-up transfer of reactivated memory infor-
mation to extrahippocampal regions. Neocortical slow oscillations exert
a supraordinate top-down control to synchronize hippocampal reacti-
vations of specific memories to their excitable up-phase, thus allowing
plastic changes in extrahippocampal regions. We propose that reactiva-
tions during sleep are a general mechanism underlying the abstraction of
temporally stable invariants from a flow of input that is solely structured
in time, thus representing a basic mechanism of memory formation.
79
With the accumulation of incoming informa-

Contents tion in a network of limited storage capacity, the
storage of new information tends to overwrite
INTRODUCTION . . . . . . . . . . . . . . . . . . 80
older memories (Marr 1971, McClelland et al.
A CONCEPT OF MEMORY
1995). How can the network keep stable older
FORMATION IN THE
representations and, simultaneously, provide
ADULT BRAIN . . . . . . . . . . . . . . . . . . 80
sufficient plasticity to incorporate new repre-
PROCESSING OF HIPPOCAMPAL
sentations? As a solution, the standard consol-
MEMORY DURING SLEEP. . . . . . 81
idation theory proposes a two-stage memory
DOES SLEEP PREFERENTIALLY
system by which the flow of incoming informa-
CONSOLIDATE EPISODIC
tion is acutely fed into a temporary store. From
MEMORY? . . . . . . . . . . . . . . . . . . . . . . . 83
these temporarily stored memories, some in-
Human Studies . . . . . . . . . . . . . . . . . . . . 84
formation is selected to be gradually integrated
Animal Studies . . . . . . . . . . . . . . . . . . . . . 86
with preexisting knowledge into a long-term
NEURONAL REACTIVATION
store, thereby leaving these older memories
OF REPRESENTATIONS
intact. Once a representation has been redis-

DURING SLEEP . . . . . . . . . . . . . . . . . 88
tributed to the long-term store, it is resistant
TRANSFORMATION OF MEMORY
to immediate interference from information
REPRESENTATIONS
continuously fed into the temporary store.
DURING SLEEP . . . . . . . . . . . . . . . . . 89
In the past two decades, major break-
Transformation Toward Increased
throughs in memory research indicate that
Executive Control . . . . . . . . . . . . . . 91
sleep plays a pivotal role in this consolidation
MECHANISMS UNDERLYING
process (Stickgold 2005, Diekelmann & Born
MEMORY
2010). Here, we do not comprehensively
TRANSFORMATION . . . . . . . . . . . . 91
review the vast amount of studies on the
Control of Communication During
link between memory and sleep but, instead,
Sleep-Dependent System
focus on evidence for a specific involvement
Consolidation . . . . . . . . . . . . . . . . . . 92
of sleep in system consolidation. We argue,
CONSOLIDATION OF
basically, that episodic memory during waking
HIPPOCAMPAL MEMORIES
hours is continuously encoded into temporary
IS SELECTIVE . . . . . . . . . . . . . . . . . . . 93
representations and is transformed by neuronal
PERSPECTIVE . . . . . . . . . . . . . . . . . . . . . . 94
reactivations during succeeding slow-wave
sleep (SWS) such that only the gist of this in-
formation becomes integrated with preexisting
INTRODUCTION memories without erasing them.
In our mind, the continuous flow of incoming
information is organized into representations
covering the dimensions of time and space. A CONCEPT OF MEMORY
Memory refers to the maintenance of these FORMATION IN THE
Consolidation: ADULT BRAIN
transforms a representations, or parts of them, over time.
temporary memory The consolidation of memory denotes a hypo- Episodic memory combines in a unique per-
representation into a thetical process that transforms newly encoded sonal experience what happened, where, and
more persistent representations from an initially labile into a when: Specific to episodic memory is that upon
long-term
more stable form that allows individuals to use its one-time occurrence, the experienced event
representation; unlike
encoding and retrieval, the acquired information for future behavior (item) becomes bound to the particular spatial
it occurs offline and plans (Müller & Pilzecker 1900, Dudai and temporal context in which it took place
SWS: slow-wave sleep 2012). A fundamental issue of consolidation (Tulving 2002). The episodic memory concept
theory refers to the stability–plasticity dilemma: arose from human research with particular
80 Inostroza · Born
reference to autonoetic consciousness during trahippocampal circuits. Consequently, based

recollection. Therefore, in animal studies, the on invariant overlapping activation and statis-
term episodic-like memory is preferably used. tical regularity, the gist from multiple episodes
System
In contrast with episodic memory, semantic is extracted to form a semantic representation consolidation: entails
memory stores knowledge about the world in that is independent of any specific context. the redistribution of
the broadest sense in the absence of contextual The TTT emphasizes the transformation that the (hippocampal)
information (e.g., objects, concepts, facts). an episodic representation undergoes with representation
toward different
Semantic memories can arise from the repeated repeated reactivations, resulting in abstract
(extrahippocampal)
encoding or activation of overlapping episodic semantic and schema-like representations, as neuronal networks and
memories. well as the dynamic interplay between episodic qualitative changes in
What kind of memory is processed during and semantic memories during the reactivation memory content and is
sleep? Standard consolidation theory was pro- process. Importantly, if a memory is retained sleep-dependent
posed with reference to declarative memories as a context-dependent episode, it will still re-
whose retrieval is explicit (i.e., “conscious”) quire the hippocampus, but the hippocampus is
and initially relies on the hippocampus as a basically dispensable when retrieving semantic
temporary store with fast encoding capabilities. memories. Which specific events are encoded
Over time, system consolidation is assumed into the hippocampal episodic memory system,
to stimulate a gradual redistribution of the as well as retrieval within this system, is
representation to extrahippocampal, prefer- essentially controlled by prefrontal cortical
entially neocortical and striatal structures that attention systems (Battaglia et al. 2011).
are slower to encode and serve as long-term Although research has experimentally
stores so that these memories eventually described the abstraction of semantic knowl-
become independent of hippocampal circuitry edge from episodic memories, mainly with
(McClelland et al. 1995, Frankland & Bontempi reference to perceived stimulus categories and
2005). Importantly, this theory assumes that schemata, some of the mechanisms underlying
the mechanism underlying consolidation is this extraction process may likewise contribute
equivalent for the two subtypes of declarative to procedural skill learning. An increasing
memory, i.e., episodic and semantic mem- number of studies shows that in the adult
ory. Standard consolidation theory has been brain, at least at an initial stage of training, the
challenged by evidence that some memories, acquisition of sequenced motor skills recruits
particularly those with a strong autobiograph- hippocampal circuitry, interacting with striatal
ical component, never become completely and motor cortical areas (Schendan et al.
independent from hippocampal function 2003, Albouy et al. 2008, Henke 2010). The
(Nadel & Moscovitch 1997). conscious practice of a motor skill represents
Unlike standard consolidation theory, the an episode featuring the repeated activation
trace transformation theory (TTT) and its of overlapping motor-related representations,
harbinger, i.e., the multiple trace theory, which eventually helps to shape a dominant skill
provide an account for the specific nature of representation that enables high performance
episodic memory (Nadel & Moscovitch 1997, on motor routines independent of contextual
Winocur et al. 2010). These theories posit stimuli and effector conditions. Motor skills can
that initially the hippocampus rapidly and also be acquired, however, independent of the
sparsely encodes key features of an experienced hippocampal system, although at a slower pace.
episode, whereby hippocampal neurons serve
as an index for extrahippocampal circuits that
encode semantic features of the episode. When PROCESSING OF HIPPOCAMPAL
these traces are later reactivated in an altered MEMORY DURING SLEEP
context, further new hippocampal traces are Sleep has been known for a long time to sup-
encoded, which in turn bind new traces in ex- port memory retention ( Jenkins & Dallenbach
www.annualreviews.org • Sleep and Episodic Memory 81

1924, Stickgold 2005). Initial studies ascribe strengthen the hippocampal episodic aspects
the effect to sleep’s passive protection of of the representation, but they also, via efferent
newly encoded memories from retroactive CA1 entorhinal pathways, simultaneously
SO: slow oscillation
interference, i.e., from being overwritten by feed reactivated memory information from
SW-R: sharp-wave
new information, because the encoding of new the hippocampus into neocortical and striatal
ripples
information is obviously hampered during networks. In these structures, the reactivations
Synaptic
sleep (Ellenbogen et al. 2006). Robust evidence spreading from the hippocampus initiate
consolidation:
stabilization of a from recent research, however, supports an plastic changes that mediate the formation of a
representation by active role of sleep in memory consolidation, transformed representation that preferentially
synaptic mechanisms in addition to the protection from interfer- resides in extrahippocampal networks and pre-
whereby the ence, which led us and others to posit an serves the decontextualized gist of the episode.
representation remains
active system consolidation view of memory The communication between hippocampal and
in the same neuronal
networks; it occurs formation during sleep (Born et al. 2006, extrahippocampal circuitry is regulated by elec-
Diekelmann & Born 2010, Payne & Kensinger troencephalographic (EEG) oscillations, pri-
during sleep and

wakefulness 2010, Lewis & Durrant 2011). This concept of marily by the neocortical slow oscillations (SOs)
REM sleep: rapid eye a sleep-dependent active system consolidation that hallmark SWS and drive memory reacti-
movement sleep process, which gradually integrates new mem- vations occurring conjointly with sharp-wave
ories relevant for an individual into preexisting ripples (SW-R) in the hippocampus. As the SOs
knowledge networks, is basically rooted in the concurrently drive spindles originating from
standard consolidation theory. Recent develop- thalamocortical circuits, they allow spindle-
ments connect the active system consolidation ripple events to form as a mechanism that trans-
view with the transformation of memory fers reactivated hippocampal memory informa-
representations as proposed by the TTT. tion to respective neocortical and striatal sites.
Key to the active system consolidation view The information arrives at these sites during the
on memory processing during sleep are findings highly excitable SO up-state and, by triggering
in rats of neuronal replay of activity occurring intracellular Ca2+ influx, can tag respective
in hippocampal place cell assemblies during networks for long-term synaptic changes
sleep, specifically during SWS (see Figure 1 (Sejnowski & Destexhe 2000) (Figure 2).
for the basic phenomenology of sleep), in the Whereas reactivations during SWS aid
same temporal order as during the encoding episodic memory transformation, synaptic
phase before the sleep period (Wilson & consolidation processes occurring during sub-
McNaughton 1994, Skaggs & McNaughton sequent REM sleep may help stabilize the newly
1996, O’Neill et al. 2010). The active system transformed representation (Diekelmann &
consolidation account proposes a dialogue Born 2010); this idea derived from the sequen-
between the hippocampus and extrahippocam- tial hypothesis assuming that the succession
pal, mainly neocortical and striatal, networks of SWS and REM sleep epochs serves a com-
that regulates the formation of long-term plementary function in memory processing
memory during waking and sleep (Buzsáki during sleep (Giuditta et al. 1995). Synaptic
1996, Diekelmann & Born 2010). During the consolidation mechanisms thus represent
wake phase, episodic information to be stored locally acting subroutines that support the
is initially encoded in both extrahippocampal system consolidation process specifically
and hippocampal networks; the hippocampal during REM sleep (Dudai 2012), i.e., a period
network encodes the binding aspects of the in which both external stimulus inputs as well
episodes, thus placing the experienced events as communication between brain regions are
into a spatiotemporal context. During sub- reduced to a minimum (Achermann & Borbely
sequent periods of SWS, the newly encoded 1998, Axmacher et al. 2008, Montgomery
hippocampal representations are repeatedly et al. 2008). Below, we discuss important
reactivated. These reactivations transiently experimental data relevant to this concept.
W REM sleep
REM
N1
N2
N3
Slow-wave sleep
23 0 1 2 3 4 5 6 7
Hours
b
Slow-wave sleep REM sleep
1s
Spindle
Theta
Surface EEG Slow-wave activity
(human)
Sharp
wave-ripple
0.5 s
Hippocampal EEG 50 ms Theta

(rat)
Figure 1
Physiological sleep. (a) Human nocturnal sleep profile. Sleep is determined mainly by continuous recordings of electroencephalogram
(EEG) complemented by electrooculogram and electromyogram, subsequent 30-s epochs of which are classified into wakefulness (W),
the non–rapid eye movement (non-REM) sleep stages N1, N2, N3, and REM sleep, according to standard criteria. The deepest
non-REM sleep stage, N3, defines slow-wave sleep (SWS). In rodents, classification of sleep stages concentrates on SWS and REM
sleep. An equivalent of N2 sleep is not discriminated. Non-REM and REM sleep periods alternate in cycles of ∼90 min, which, during
early nocturnal sleep, are dominated by SWS with little REM sleep and, during late sleep, by REM sleep with little SWS. (b) EEG
characteristics of SWS and REM sleep. During SWS, the surface EEG (upper trace) is hallmarked by high-amplitude slow-wave activity
in the frequency range between 0.5 and 4 Hz, whereby the <1 Hz range refers to the slow oscillation and the 1–4 Hz range to the delta
waves. SWS, and even more so N2 sleep, is also characterized by spindle activity (12–15 Hz). The rat hippocampal EEG (lower trace)
reveals sharp wave-ripples (SW-R); the sharp waves represent fast depolarizing events generated in CA3 that are superimposed on
(100–250 Hz) ripple activity originating in CA1. The enlarged detail (left) shows the ripple (upper trace) and sharp wave (lower trace)
components of a SW-R in separately filtered recordings at higher temporal resolution. During REM sleep, the surface EEG is
characterized by a low-amplitude EEG of mixed fast frequencies. Especially the rodent hippocampal EEG shows high (4–8 Hz) theta
activity.
DOES SLEEP PREFERENTIALLY is expected to affect episodic features more

CONSOLIDATE EPISODIC strongly than aspects of memories represented
MEMORY? in extrahippocampal networks. Nevertheless,
Assuming that reactivations during SWS the proposed transformation of the memory
originate from hippocampal representations, established during sleep implicates secondary
the sleep-associated consolidation process effects on extrahippocampal representations,

a b c
Neocortex I Neocortex II III Neocortex
Downscaling
Long-term Slow oscillations
Episodes store
Spindles
Thalamus
Downscaling
Reactivations
Temporary store in ripples
Hippocampus Hippocampus Hippocampus

Figure 2
Active system consolidation during sleep. (a) System consolidation relies on a dialogue between the hippocampus serving, for part of
the information, as temporary store, and extrahippocampal, mainly neocortical networks serving as long-term store. During the wake
phase, an episode is encoded in both hippocampal and extrahippocampal networks (dashed purple arrows), whereby the hippocampus
encodes aspects of the representation binding an experienced event into its unique spatiotemporal context. During subsequent
slow-wave sleep (SWS), repeated reactivations of the hippocampal representation (circular white arrows) support its redistribution such
that parts of it become preponderantly represented in extrahippocampal regions (dark yellow arrows). The redistribution of episodic
memory representations is accompanied by a transformation toward more decontextualized schema-like representations. (b) The
abstraction of a schema-like representation resulting from reactivations of episodic representations that overlap, i.e., share neuron
assemblies either (I) in the neocortex or (II) in the hippocampus. Reactivations originate in the hippocampus and spread to neocortical
networks. (III) Shared assemblies undergo stronger reactivation that, based on Hebbian learning, potentiates and strengthens (thick gray
lines) the connections between neurons contributing to the overlap. Concurrent global processes of synaptic downscaling generally
weaken and eventually erase connections (truncated dashed red, blue, and black lines) of the nonoverlapping portion of the representations
as these undergo less reactivation. Downscaling may be more effective in hippocampal networks, where it also counteracts the
persistence of potentiation in overlapping portions of a representation. Nonoverlapping areas preferentially represent idiosyncratic
details and specific context of an episode (modified from Lewis & Durrant 2011). (c) The communication between the hippocampus
and extrahippocampal circuitry during consolidation is regulated by EEG oscillations. During SWS, the depolarizing up-phases of slow
oscillations (SO, orange) originating preferentially from the prefrontal cortex act top-down repeatedly to drive neuronal reactivations of
representations in the hippocampus, where these reactivations occur simultaneously with sharp wave-ripples (SW-R, green). The
concurrent drive of the SO up-phase on thalamocortical spindles (blue) allows spindle-ripple events to form; ripples and enwrapped
reactivated memory information become nested into the excitatory phases, i.e., troughs, of the spindle oscillation (shown enlarged in
insert). Spindle-ripple events represent a mechanism mediating the bottom-up transfer of reactivated hippocampal memory information
to extrahippocampal (mainly neocortical) regions. Reactivated memory information nested in spindle troughs arrives at these regions
still during the excitable SO up-phase, which initiates Ca2+ -dependent intracellular processes of synaptic plasticity that mediate the
long-term storage of the information in these extrahippocampal regions.
i.e., semantic and procedural aspects of a proves the retention of these memories, which
memory, which might appear only with longer rely on hippocampal function (reviewed in
periods of intervening sleep. Overall there is Marshall & Born 2007). In fact, the first exper-
a paucity of studies directly dissociating effects imental work in this field relied exclusively on
of sleep on hippocampal and extrahippocampal the use of declarative tasks such as the learning
representations. of nonsense syllables, words, and paired
associate words, among others (e.g., Jenkins &
Dallenbach 1924), and the beneficial effects of
Human Studies postlearning sleep on memory retention seen
Numerous studies have demonstrated that in these early studies were confirmed in more
sleep after learning of declarative tasks im- recent studies (e.g., Yaroush et al. 1971, Fowler
et al. 1973). Compared with a postlearning wake control, showed significantly better memory
interval, sleep not only distinctly slowed the for the poster associated with a word, whereas
trajectory of forgetting over time, but also made recognition of the words per se did not differ.
the memory more resistant to interference The enhanced context memory was correlated
(Ellenbogen et al. 2006). Comparisons of sleep with the amount of non-REM sleep stage 2 and
periods rich in SWS, as they occur during the EEG spindles during the nap. However, while
early night, with those rich in REM sleep, as learning, subjects were instructed to form asso-
occurring during the late night, indicated that ciations between the words and the poster im-
SWS is much more relevant for strengthening ages, which may question whether the posters
declarative memory than is REM sleep (Plihal represented context in the strict sense. Sleep-
& Born 1997). REM-rich sleep appeared to dependent enhancements in context memory
strengthen preferentially procedural memories in the absence of changes in item memory were
considered less dependent on hippocam- likewise revealed with the what-where-when
pal function, although these findings were task, during which participants learned two lists
questioned by later studies using pharmaco- of nouns (items) one after the other (when),
logical REM-sleep suppression (Rasch et al. with the words written either on the top or
2009). However, although they differentiated on the bottom of a page (where) (Rauchs et al.
declarative from procedural memories, few 2004). The forgetting rate for temporal context
of these studies provided clues about which was lowest across SWS-rich sleep, whereas
type of declarative information is influenced memory for spatial context appeared to be
by sleep, i.e., semantic or episodic memory or relatively enhanced following late REM-rich
item versus spatiotemporal context aspects of sleep. Fittingly, sleep also enhanced temporal
episodic memory. order, as a principle underlying episodic mem-
Emerging evidence from recent studies ory, when memory for temporal sequences
supports preferential strengthening of context of word-triplets was studied in isolation by
over item (what) memory during sleep, if comparing retrieval of forward and backward
context is considered to refer more generally associations in these triplets (Drosopoulos
to relational features of an episode, comprising et al. 2007b). Sleep selectively strengthened
where (spatial) and when (temporal) an event the forward associations of the learned word
happened, as well as to background features triplets, matching the observation that mem-
and details of the event that are deemed more ory replay in hippocampal neuron assemblies
or less irrelevant in the context of learning during SWS exclusively occurs in a forward
(Aly & Moscovitch 2010). Indeed, “context” direction (Foster & Wilson 2006). Sleep also
often lacks a clear conceptual definition in rel- strengthened memory for temporal order in
evant studies. Neuroimaging and lesion studies picture sequences (Griessenberger et al. 2012),
indicate that contextual features of episodic and such effects were blocked by administration
memory critically depend on hippocampal of the stress hormone cortisol, which affects
function, whereas item memory is supported limbic-hippocampal circuitry in particular
by extrahippocampal structures, mainly the (Wilhelm et al. 2011b). Benefits of sleep on
perirhinal cortex (Davachi 2006, Eichenbaum context memory were enhanced by varying the
et al. 2007). Napping (maximally 120 min) emotionality of the context (Lewis et al. 2011).
was indeed revealed to selectively enhance Interestingly, contextual associations also
signs of context memory, leaving item memory strengthened sleep-dependent benefits for pro-
unaffected (van der Helm et al. 2011). In this cedural tasks that may not require hippocampal
study, participants learned two lists of words involvement per se. Comparing the effects
(defining item memory) while facing two dif- of sleep on implicitly trained noncontextual
ferent posters (contexts). At a delayed retrieval and contextual versions of a serial reaction
test, the nap group, compared with a no-nap time task (SRTT), Spencer et al. (2006)

revealed a sleep-dependent gain in response on episodic memory. The effect is preponder-

time only for the contextual but not for the antly seen on contextual aspects of episodic
noncontextual SRTT version. Rather than memory, where most consistent benefits of
responding directly to spatial cues, participants sleep were revealed for temporal contexts.
in the contextual version responded to the
color of the cues (again following a sequence of
spatial targets). Because the formation of such Animal Studies
contextual associations depends on the hip- Tasks examining the binding of item memory
pocampus, these observations strongly support to a spatiotemporal context also demonstrated
the view that gains in procedural skill from sleep the presence of episodic-like memory and
also represent a hippocampus-mediated pro- its genuine dependence on the hippocampus
cess. Presumably via amygdalar-hippocampal in animals (Kart-Teke et al. 2006, Devito
interactions, this process is subject to emotional & Eichenbaum 2010). Rats with lesions to
influences because sleep-dependent gains in dorsal CA3 and rats that, after kainate-induced
mirror tracing, a task in which hippocampal epilepsy, showed some minor cell loss restricted
involvement is also not mandatory, were to CA3, CA1, and ventral dentate gyrus per-
greater when the skill had been practiced with formed well on tasks separately testing what,
aversive than with neutral stimulus materials where, and when aspects but failed on a task re-
before sleep ( Javadi et al. 2011). quiring the binding of these three aspects into
Clues about sleep’s specific influence on an episodic-like representation, a result that
the episodic features of a memory can be also may be related to a disturbance in the coherent
obtained from the remember/know paradigm processing between these hippocampal areas
(Yonelinas 2001, Rugg & Yonelinas 2003). Re- of item and contextual information conveyed
membering is associated with the conscious rec- from lateral and medial entorhinal inputs,
ollection of the encoded event and thus reflects respectively (Li & Chao 2008, Inostroza et al.
episodic memory features, whereas knowing to 2010). Notably, this binding of an event into
have seen something but being unable to rec- the spatiotemporal context required sleep if rats
ollect the specific features of the encoded event needed to retain the episodic memory for more
merely invokes a sense of familiarity that is not than 80 min (Inostroza et al. 2013). This study
considered episodic in nature. Explicit recollec- compared memory retention across 80-min
tion critically relies on hippocampal function, postencoding intervals during which the rats
whereas familiarity-based implicit processes either had normal morning sleep or were sleep
of recognition can be achieved by extrahip- deprived. A third condition took place during
pocampal regions alone. In direct comparisons the evening hours when the rats were spon-
of explicit recollection and familiarity-based taneously awake during the retention interval.
judgments on memory for words and pictures, At retrieval testing, only in the sleep condition
postlearning sleep consistently enhanced the rats displayed significant memory for the
explicit recollection of memories, whereas episode, i.e., signs that the events experienced
familiarity-based judgments remained unaf- during encoding were remembered in correct
fected (Rauchs et al. 2004, Drosopoulos et al. temporal order and correct place. As an indica-
2005, Daurat et al. 2007, Atienza & Cantero tor of memory, the study used the rat’s natural
2008). Two of these studies (Rauchs et al. 2004, novelty preference, i.e., the tendency to explore
Daurat et al. 2007) also revealed a significant more intensely (a) objects that were placed at
link between enhanced recollection and the a novel rather than at the same location as that
occurrence of SWS during postlearning sleep. used during the encoding phase and (b) objects
Overall the picture emerging from these that were encountered earlier than objects en-
human studies suggests that sleep, in particular countered later in the encoding phase (Mitchell
SWS, exerts an immediate strengthening effect & Laiacona 1998, Kart-Teke et al. 2006). The
study also separately assessed memory for into hippocampus-based strategies. In another
the spatial and temporal contexts using an study, mice trained on a spatial maze shifted
object-place recognition task and a temporal from a hippocampus-dependent spatial strat-
memory task, respectively. Retention of both egy to a striatum-dependent response strategy
spatial and temporal memory critically relied when deprived from sleep (for 5 h) after each
on the occurrence of sleep during the 80-min daily training (Hagewoud et al. 2010).
retention interval. By contrast, item memory Fear conditioning, although stressful, bears
tested in a novel-object recognition task did not features of episodic memory because learning
require sleep but was retained in the wake and is achieved typically in a single trial, thus
sleep-deprivation conditions to virtually the avoiding confounding effects resulting from
same extent as was found in the sleep condition. repetitive stimulus presentations (Maren 2001).
Overall, this pattern corroborates the view that Contextual fear conditioning, a task that de-
sleep specifically supports the maintenance of pends on hippocampal function, was revealed
hippocampus-dependent memories because to be sensitive to sleep deprivation, whereas
novel-object recognition was the only task cued fear conditioning, which does not require
employed in the study which does not require hippocampal involvement, did not profit from
the integrity of this structure (Bussey et al. sleep (Graves et al. 2003). Only sleep in the 5-h
2000, Mumby et al. 2002). Of note, the tasks of interval immediately following conditioning
temporal and object-place memory used in this was effective; sleep occurring 5–10 h after con-
study to dissect the effects of sleep on memory ditioning was not effective. Later studies con-
for respective spatiotemporal context aspects, firmed the sensitivity of context fear memory
per se, also comprise clear episodic features; to sleep (Cai et al. 2009b) and identified cyclic
i.e., context-item binding, inasmuch as recall adenosine 3 ,5 -monophosphate (cAMP)-
of the contexts (i.e., the location and temporal protein kinase A (PKA)-dependent synaptic
order of the objects) implies that the rat also plasticity as a mechanism mediating this effect
correctly remembers the objects encountered in hippocampal circuitry (Vecsey et al. 2009,
during learning. Because as in a figure-ground Hagewoud et al. 2011), but studies were not
relationship context is, by definition, uniquely clear about the contributions of specific sleep
bound to an event, an isolated assessment of stages. In addition to SWS, contributions
context memory, in the absence of any item of REM sleep are likely due to the stressful
memory formation, is basically impossible. nature of the task. This notion is suggested
That the retention of spatial context over a by studies using the Morris water maze, in
short period of 2 h requires sleep has been con- which sleep (particularly REM sleep) benefited
firmed in a further study using the object-place spatial memory only in the hidden-platform
recognition task (Binder et al. 2012). The ef- version of the task, which requires hippocampal
fect was associated with high amounts of both functioning, but not in the visible-platform
SWS and spindles. However, in mice, differ- version, which does not require hippocampal
ent from rats, sleep also enhanced item mem- functioning (Smith & Rose 1996, 1997).
ory tested in a novel-object recognition task Altogether the reviewed studies in rodents
(Palchykova et al. 2006, Rolls et al. 2011). The rather consistently point to a preferential
reason for this divergence is not clear. Periods consolidation of episodic memory dur-
of sleep deprivation (>4 h) and retention in- ing sleep, although mostly they compared
tervals (24 h) in these studies were longer than hippocampus-dependent tasks with tasks
those used in the rat studies, which may increase that do not essentially rely on hippocampal
the likelihood for secondary memory effects function. By contrast, memories thought to
on extrahippocampal representations. The re- be represented primarily in extrahippocampal
lational features of the tasks may also have been circuitry do not require sleep to be maintained
more complex and demanding, forcing the mice in the short term, i.e., within the first couple

memory representations encoded during wak-

IS THERE SYSTEM CONSOLIDATION ing during subsequent periods of sleep (Pavlides
DURING WAKING SIMILAR TO THAT & Winson 1989; for reviews, see Sutherland
DURING SWS? & McNaughton 2000, O’Neill et al. 2010).
Recordings of spike activity in hippocampal
Assembly reactivations together with hippocampal sharp wave- CA1 place cells revealed patterns of correlated
ripples (SW-R) occur during quiet wakefulness as well, which has activity in these cell assemblies while the rat
stimulated the view that system consolidation would take place was running along a track for food reward, and
during waking in much the same way as it does during slow-wave these correlation patterns were reactivated dur-
sleep (SWS) (Mednick et al. 2011). However, this view neglects ing subsequent SWS (Wilson & McNaughton
that reactivations during SWS and waking occur in entirely 1994). Importantly, assembly reactivation dur-
different neurochemical milieus. Acetylcholinergic activity is ing SWS occurs, although at a faster speed, in
minimal during SWS but maximal in the wake state in which the same temporal order of place cell spiking
it mediates a tonic suppression of hippocampal CA1 outputs and in the same forward direction as that ob-
(Hasselmo & McGaughy 2004). Owing to minimal cholinergic served during wake encoding of the spatial task
activity, this inhibition is released during SWS, thus permitting (Skaggs & McNaughton 1996, Nadasdy et al.
reactivated memory information to spread to extrahippocampal 1999, Ji & Wilson 2007). Initially, investiga-
areas in this state. Other signals, e.g., low corticosteroid levels tors questioned the link between assembly re-
during SWS, add to this effect. In humans, consonant with reactivations during SWS and a one-time episodic
consolidation theory, wake reactivations transiently destabilized experience because in the first studies the rats
representations, whereas reactivations during SWS immediately were highly overtrained on the tasks; thus, the
strengthened them (Diekelmann et al. 2011). These findings tasks lacked any new learning. However, in later
suggest distinct functions of reactivations depending on the brain studies, reactivations during SWS were sim-
state: Wake reactivations and subsequent memory destabilization ilarly revealed after rats had engaged in ex-
may provide an acute opportunity to update a representation with ploring new environments (Ribeiro et al. 2004,
new information, whereas reactivations in SWS may essentially O’Neill et al. 2008). In these studies, neuron as-
serve to incorporate hippocampal memory information within semblies linked to place fields that were longer
preexisting extrahippocampal representations. or more frequently explored showed stronger
reactivation during succeeding sleep.
Assembly reactivations have been observed
of hours after learning, which does not exclude almost exclusively during SWS and rarely
secondary effects on such representations during REM sleep. In rats highly familiar with
occurring more gradually over time. Benefits a track, REM sleep–associated reactivations
for hippocampal representations appear to in the hippocampus were shifted in phases
be linked to SWS, but REM sleep may also toward the troughs of the EEG theta rhythm,
contribute in certain conditions, in particular suggesting that such reactivations help erase
when memories are emotional. Note, despite superfluous episodic memory information from
the evidence for preferential consolidation hippocampal circuitry once a task becomes
of hippocampus-dependent memory during familiar (Poe et al. 2000, Booth & Poe 2006).
Neuronal sleep, sleep, perhaps through different mecha- However, others failed to identify patterned
reactivation:
nisms, can also enhance memories that do not reactivations during REM sleep, questioning
temporally sequenced
replay of neuronal involve the hippocampus (e.g., Frank 2011). their existence (e.g., Kudrimoti et al. 1999).
firing patterns that During SWS, reactivations in the hippocampus
accompany episodic NEURONAL REACTIVATION typically co-occur with SW-R events (O’Neill
memory encoded OF REPRESENTATIONS et al. 2010) that also occur during quiet wake-
during subsequent DURING SLEEP
offline periods of sleep fulness but rarely occur during REM sleep
or wakefulness The active system consolidation view assumes (see sidebar, Is There System Consolidation
as a key mechanism the neuronal reactivation of During Waking Similar to that During SWS?).
Neuronal reactivations during SWS are (Girardeau et al. 2009, Bendor & Wilson 2012).
also observed in extrahippocampal regions, Diminished formation of spatial memory in
including frontal, parietal, and visual cor- old compared with young rats was associated
tical areas as well as the ventral striatum primarily with a disturbed temporal sequence
(Pennartz et al. 2004, Euston et al. 2007, Ji & in the reactivation patterns during sleep,
Wilson 2007, Lansink et al. 2009, Peyrache while patterns of mere coactivation persisted
et al. 2009). Assembly reactivations in these (Gerrard et al. 2008). Indeed, considering the
extrahippocampal areas slightly followed importance of temporal sequence in neuronal
(by less than 50 ms) signs of reactivation in replay activity during SWS and its origin from
hippocampal circuitry, which is consistent with hippocampal circuitry, it is tempting to con-
the notion that hippocampal reactivations play clude that these reactivations reflect primarily
a leading role for reactivations occurring in reprocessing of episodic memory aspects, al-
distributed representational networks outside though reactivations during sleep after strictly
the hippocampus. Reactivations originating episodic tasks have not been assessed so far.
from newly encoded hippocampal memories

and spreading to neocortical and striatal sites

may help strengthen these extrahippocampal TRANSFORMATION OF MEMORY
parts of the representation, thereby also fitting REPRESENTATIONS
them into preexisting knowledge networks. DURING SLEEP
Brain-imaging studies in humans confirmed The active system consolidation theory assumes
that reactivations occur during non-REM that, in addition to immediately enhancing the
sleep and SWS in hippocampal as well as memory representation per se, reactivations
extrahippocampal, i.e., neocortical, regions during sleep induce the transformation of
after learning of hippocampus-dependent memory representations. Specifically, reac-
declarative (spatial navigation, face-scene asso- tivations originating from the hippocampal
ciations; Peigneux et al. 2004, Bergmann et al. circuitry during SWS are expected to decontex-
2012) and procedural tasks (visual texture tualize episodic memory information, whereby
discrimination; Yotsumoto et al. 2009). semantic and skill representations are gener-
The causal role reactivations play for ated that can be applied independently from
memory consolidation has been demonstrated their specific spatiotemporal context during
in both humans and rats. In humans, olfactory acquisition. Such transformation implies that
and auditory cuing was used to experimentally memories change in quality during sleep, an
induce reactivations of newly encoded memo- aspect that has so far been less intensely stud-
ries during sleep (Rasch et al. 2007, Rudoy et al. ied, probably because persistence, rather than
2009). An odor presented while subjects learned its dynamic nature, is traditionally considered
place-object associations enhanced memories the hallmark of memory (Dudai 2012).
for the learned associations if it was presented Human functional magnetic imaging stud-
again during subsequent SWS but not when re- ies have consistently indicated that post-
exposed during REM sleep. Reexposure of the encoding sleep, aside from increased hip-
odor during SWS reactivated the hippocampus; pocampal activation, favors the redistribution
this reactivation was distinctly stronger than of declarative memory representations (for
that observed during wakefulness, suggesting word pairs, pictures, etc.) toward enhanced
that the hippocampus during SWS is particu- neocortical, mainly medial prefrontal corti-
larly sensitive to stimuli capable of reactivating cal involvement as well as increased func-
memories. In rats, conditions of diminished tional connectivity between medial frontal
pattern reactivation and accompanying SW-R cortical and hippocampal areas at delayed re-
were consistently associated with impaired retrieval (e.g., Gais et al. 2007, Sterpenich et al.
tention of hippocampus-dependent memories 2007, Takashima et al. 2009, Payne &

Kensinger 2011). For tasks with a strong pro- implicitly learned materials (Wagner et al.
cedural motor component, postencoding sleep 2004, Fischer et al. 2006, Drosopoulos et al.
appears to enhance the involvement of striatal 2011, Durrant et al. 2011). When asked to
Assimilation: process
in which newly regions and their functional connectivity with generate deliberately the sequence underlying
encoded memory the hippocampus (Fischer et al. 2005, Orban an SRTT trained under implicit conditions
information is et al. 2006). Yet, despite the obvious system- before a retention interval of sleep or wake-
integrated into level reorganization that memory represen- fulness, only after sleep had subjects developed
preexisting knowledge
tations undergo during sleep, the qualitative a significant amount of explicit sequence
and schema-like
representations changes in memory associated with such reor- knowledge (Fischer et al. 2006, Drosopoulos
ganization are presently not well characterized. et al. 2011). Postencoding sleep also improved
Abstraction: process
in which invariant Available evidence points to two major performance on transitive inference tasks
patterns are distilled processes that might be supported by system (Ellenbogen et al. 2007) and enhanced produc-
from multiple consolidation during sleep: assimilation and tion of false memories in the Deese-Roediger-
overlapping episodic abstraction (Lewis & Durrant 2011). As- McDermott (DRM) paradigm (Payne et al.
memory
similation refers to the integration of newly 2009, Diekelmann et al. 2010). In infants,
representations to
eventually form a encoded memory information into preexisting sleep promoted grammar-related abstraction
more generalized knowledge networks and schemas. In rats, processes in a language-learning task (Gomez
schema-like once an associative spatial schema represen- et al. 2006, Hupbach et al. 2009). In the infants
representation tation (of a large event arena) is established who had napped, memory for the words per
in neocortical long-term memory networks, se was worse than in the wake control infants,
newly learned additional locations in this arena suggesting that sleep acts primarily to trans-
can be incorporated into this schema within form rather than to enhance representations
48 h (Tse et al. 2007). As expected, memory directly.
for the new locations was impaired by lesions Hints at abstraction processes supported
to the hippocampus made 3 h after learning. by sleep were likewise obtained in studies of
However, it remained intact with lesions made procedural memory. On a finger-sequence
48 h after learning. Although not systematically tapping task, posttraining sleep favored the
explored in these experiments, sleep may have development of an effector-independent
been critical for this relatively fast assimilation representation, i.e., sleep benefited tapping
to extrahippocampal schemas, since only the the sequence of target keys independent of
48-h but not the 3-h interval contained sleep. whether tapping was performed with the same
In humans, sleep promoted the assimilation hand as during training or with the other hand
into existing knowledge networks of learned (Cohen et al. 2005, Witt et al. 2010). Sleep
spoken novel words that phonologically over- enhanced sequence finger-tapping perfor-
lapped with familiar words, as measured by mance when learning occurred by observation
a lexical competition task (Dumay & Gaskell (van der Werf et al. 2009b). Thus, sleep
2007), and this integration was associated with appears to transform skill representations such
increased spindle activity during postlearning that they become less dependent on a specific
sleep (Tamminen et al. 2010). stimulus context or effector system. Beyond
Abstraction refers to a process in which this decontextualization of memory by sleep,
rules and regularities are distilled from multiple the studies showed for the discussed declarative
episodic memory representations to eventually and procedural tasks that the transformation
form a more generalized schema in long-term of representations is linked to non-REM sleep
memory. Thus, in different tasks, such as and SWS and associated EEG oscillations (e.g.,
the number reduction task, the SRTT, and Yordanova et al. 2008, Tamminen et al. 2010,
statistical learning tasks, sleep consistently Durrant et al. 2011, Yordanova et al. 2012);
promoted the abstraction of explicit knowledge there were no consistent clues for additional
from hidden structures embedded in the contributions of REM sleep, although the
possibility cannot be excluded (Cai et al. 2009a, representations determines how memories are
Walker & Stickgold 2010). transformed during sleep-associated reactiva-
tions. However, it is not clear how hippocampus
and extrahippocampal areas in representing
Transformation Toward Increased episodic memories contribute to such over-
Executive Control lapping reactivation (Figure 2b). Overlap in
Findings that postencoding sleep facilitates in- spatial representations can already emerge
sight and awareness of rules hidden in implic- during encoding in hippocampal CA3 and CA1
itly learned materials suggest that the abstrac- as a result of experience on two tasks performed
tion process during sleep goes along with an in environments with graded dissimilarities
increased explicitness of memory in the sense (Guzowski et al. 2004, Lee et al. 2004, Leutgeb
that various effector systems (verbal, motor) et al. 2004). Reactivation of such generalized
can be flexibly used to express the memory mapping across episodes in CA1, as the major
in different stimulus conditions (Marshall & hippocampal output region, may then be
Born 2007). Sleep reorganizes representations considered a principal mechanism underlying

such that they become not only decontextual- the induction of abstract representations in ex-
ized but also more accessible via the prefrontal- trahippocampal networks. However, the exact
hippocampal system, i.e., the executive con- (spatial) conditions under which CA1, in the
trol system mediating explicit recollection. This course of encoding different episodes, forms
view could also explain that enhancing effects overlapping generalized or separated maps are
of sleep on memory are typically more robust not well understood. Alternatively, Buzsáki
when delayed retrieval is tested by free recall (2005) speculated that SW-R covering wider
rather than by a recognition procedure (see, areas of hippocampal circuitry create opportu-
for example, regarding the production of crit- nities to cross multiple separate episodes at the
ical lures in the DRM paradigm; Diekelmann timescale of synaptic plasticity, the resulting
et al. 2008, 2010; Payne et al. 2009). Against concordant reactivation of these representa-
this backdrop, it is tempting to speculate that tions allowing abstract representations to form
the transformation of memory representations in neocortical areas. In this case, overlap would
during SWS serves primarily to enhance their be acutely generated only in the course of redis-
accessibility to executive behavioral control by tributing representations to extrahippocampal
prefrontal cortex structures rather than to en- networks in a process that may also integrate
hance the content per se. Yet, such a distinction top-down inputs to the hippocampus originat-
is difficult to make on the basis of behavioral re- ing from preexisting knowledge networks.
trieval measures alone. The “information overlap to abstract”
concept proposed by Lewis & Durrant (2011)
provides a more theoretical account of how
MECHANISMS UNDERLYING neocortical overlap in representations could
MEMORY TRANSFORMATION contribute to the formation of abstract schema
The transformation of episodic memory that memories. The concept assumes that repeated
leads to the formation of decontextualized reactivations during SWS of newly encoded
schema-like representations is thought to be a representations that show overlapping cortical
gradual process originating from the repeated areas, based on Hebbian learning rules, lead
activation of multiple overlapping episodes that to the gradual strengthening, i.e., abstraction,
share common items, so that spatiotemporal of conceptual schemas representing those
context and idiosyncratic details of the episodic areas that, owing to the overlap, undergo the
representation attenuate and eventually strongest reactivation. Concurrently, global
completely disappear (Nadel & Moscovitch synaptic downscaling processes gradually erode
1997). Accordingly, overlap between episodic the more idiosyncratic aspects of each single

representation. The model receives preliminary of Hebbian and spike time-dependent synaptic
support from a study of interference learning plasticity underlying the formation of represen-
(Drosopoulos et al. 2007a), which compared tations in the receiving network (Benchenane
EEG coherence:
phase synchronization the effects of retention sleep and wakefulness et al. 2011). The spread of reactivated hip-
of field potential after subjects learned two-word pair lists pocampal memory information during SWS is
oscillations, that, according to an A-B, A-C paradigm, thought to be orchestrated by three different
coordinates the timing overlapped and thus produced retroactive oscillatory rhythms: the ∼0.75 Hz SO, the
of neuronal spiking
interference, or, according to an A-B, C-D classical 12–15 Hz spindles, and the SW-R
and resulting synaptic
plasticity across paradigm, did not overlap and thus did not (the ripples oscillate between 100 and 300 Hz)
distributed brain produce interference. Consistent with the (Figures 1 and 2c; Diekelmann & Born 2010).
regions information overlap to abstract concept, the SOs comprise highly synchronous al-
sleep-dependent improvement in recall of A-B terations of virtually every cortical neuron
associations was greater when these overlapped between periods of membrane depolarization
during learning with A-C associations, com- accompanied by sustained firing (up-state)
pared with the learning of nonoverlapping word and periods of hyperpolarization associated
lists. Related findings were reported by others with neuronal silence (down-state). The SO
for declarative (Ekstrand 1967) and also for thus provides a global time frame whereby the
procedural types of memories (Fenn et al. 2003, network is reset by the hyperpolarizing phase
Walker et al. 2003). However, the superior ben- and processing is limited to the subsequent
efit of sleep for A-B associations when learned depolarizing up-phase (Steriade 2006, Mölle
in the overlapping interference condition may & Born 2011). The SO is generated primarily
be due to their generally weaker strength when in neocortical networks; the depolarizing up-
entering sleep rather than resulting from reacti- states are presumably triggered by summation
vations of overlapping representations. In fact, of miniature excitatory postsynaptic potentials
some evidence indicates that profits from sleep as a residual synaptic activity in local synaptic
are greatest for memories with an intermediate circuits, which is increased after potentiation
presleep encoding strength (e.g., Tucker & of respective synapses, e.g., when information
Fishbein 2008, Wilhelm et al. 2012a). encodes in these circuits during prior waking
(Bazhenov et al. 2002). Spindles originate from
GABAergic thalamic networks; glutamatergic
Control of Communication During thalamocortical projections mediate their
Sleep-Dependent System widespread propagation to cortical regions
Consolidation (Gennaro & Ferrara 2003). In the neocortex,
The transformation of episodic representations spindles, independent of their synchronization
during sleep implicates the redistribution of with the central thalamic spindle generator,
reactivated hippocampal memory toward typically emerge as local phenomena that are
preponderant representations of the memory restricted to specific circuitry (Nir et al. 2011,
information in extrahippocampal regions, a Ayoub et al. 2012). SW-R accompany memory
process that entails a fine-tuned communica- reactivations in the hippocampus where they
tion between these regions. System communi- impact firing of discrete local circuits (Csicsvari
cation between brain regions is considered to be et al. 1999). Evidence indicates that all three
basically controlled by electrical field potential types of oscillations, SOs, spindles, and ripples,
rhythms (Buzsáki & Draguhn 2004). The EEG preferentially occur in previously potentiated
coherence, specifically the phase coherence in synaptic networks (e.g., Behrens et al. 2005,
these rhythms, provides a mechanism whereby Tononi & Cirelli 2006, Bergmann et al. 2008)
neuronal activity sent from one region can and, conversely, can support plastic synaptic
activate another network in a temporally coor- processes such as long-term potentiation (King
dinate manner, allowing also for the induction 1999, Rosanova & Ulrich 2005). For SOs and
ripples, studies have demonstrated a causal in the SO cycle (Mölle et al. 2011, Peyrache
involvement in consolidation of hippocampus- et al. 2011)]. Spindle-ripple events are a strong
dependent memories during sleep by directly candidate mechanism for the bottom-up
suppressing or enhancing them through transfer of memory information to neocortical
electrical stimulation (Marshall et al. 2006, and striatal regions (Sirota & Buzsáki 2005,
Girardeau et al. 2009, Marshall et al. 2011). Mölle & Born 2011), where they might induce
For spindle activity, studies have shown robust plastic processes to support specifically the
increases during postlearning sleep that pre- storage of semantic and procedural features in
dicted the retention of the acquired memories, episodic memories. Indeed, in humans signs of
including specifically episodic aspects in these conjoint reactivations in relevant neocortical
memories (e.g., Gais et al. 2002, Fogel & Smith and hippocampal regions occurred in temporal
2011, van der Helm et al. 2011). synchrony with spindles after subjects learned
The dialogue between the hippocampus and face-scene associations (Bergmann et al. 2012).
extrahippocampal regions underlying memory Also, spindles, in addition to ripples, phase-
transformation during SWS appears to be lock EEG gamma-band activity as an indicator

controlled mainly by the SOs that arise most of coherent information processing in local
powerfully from prefrontal circuitry engaged in neocortical networks (Ayoub et al. 2012).
information encoding during prior waking. SOs In rats, spindle activity following exposure
globally entrain neuronal activity not only in to a novel spatiotactile experience predicted
the neocortex but also in many other structures, immediate early gene (arc) expression in the
including the thalamus and the hippocampus, somatosensory cortex during subsequent REM
where spindle activity and SW-R together sleep, suggesting that, by facilitating Ca2+
with reactivated memory information likewise influx into pyramidal cells, spindles help tag
become synchronized with the SO up-state the newly formed neocortical representations
(Clemens et al. 2007, Csercsa et al. 2010). Prior for persistent synaptic strengthening during
learning strengthens the top-down control of subsequent REM sleep (Ribeiro et al. 2007).
SOs on spindles and ripples and also promotes
the occurrence of trains of several succeeding
SOs (Mölle & Born 2011, Ruch et al. 2012). In CONSOLIDATION OF
these SO trains, spindles appeared not only to HIPPOCAMPAL MEMORIES
be driven by the SO up-state but, conversely, IS SELECTIVE
to enforce also the succeeding SO, suggesting The brain’s capacity to store memories is lim-
a key role for spindles in maintaining memory ited. Even if the enhancing effect of sleep on
processing (Mölle et al. 2011). memory was restricted to the episodic memory
The synchronous drive of the SO up-state system, overflow would inevitably occur.
on the thalamus and the hippocampus allows Such considerations have stimulated concepts
spindle-ripple events to form during this de- that sleep entails processes counteracting any
polarizing period, when ripples and reactivated imminent overload resulting from encoding
memory information enwrapped in these of information during wakefulness. In this
ripples are nested into the succeeding troughs vein, the synaptic homeostasis hypothesis
of a spindle (Siapas & Wilson 1998, Clemens proposed that SWS via slow-wave activity
et al. 2011). Mutually stimulating influences induces a global and proportional downscaling
between spindles and ripples may add to the of synapses that were potentiated during
formation of spindle-ripple events (Mölle wakeful information encoding (Tononi &
et al. 2009, Wierzynski et al. 2009). [Note, Cirelli 2006). However, proportional synaptic
these relationships do not apply to the slow downscaling alone can explain neither why
10–12 Hz frontal spindles, which represent memories are enhanced by sleep nor why this
a separate type of spindles that occur later enhancing effect is selective. It is obvious that

some episodic memory content is strengthened encoding may also enable a top-down tagging
by sleep, whereas some other content is not of hippocampal memories as a prerequisite for
(Diekelmann & Born 2010). subsequent offline consolidation.
Selectivity of memory enhancement can A candidate mechanism conveying pre-
be adequately explained in the context of frontal tagging of memories for consolida-
memory transformation occurring during tion during sleep is the EEG theta rhythm
sleep, specifically in the context of abstracting (Benchenane et al. 2011). In a Y-maze task
and assimilating episodic memory information theta coherence between the prefrontal cor-
into schemas. Notwithstanding this theoretical tex and the hippocampus was increased at the
account, experimental work has revealed choice point of the maze as soon as the rats had
that sleep preferentially strengthens those learned to choose the correct arm (Benchenane
memories that are relevant for the individual’s et al. 2010). Notably, assembly pattern firing in
future plans. Sleep strongly supported the the prefrontal cortex present during increased
maintenance and delayed execution of plans theta coherence was likely reactivated during
in prospective memory paradigms (Scullin & subsequent SWS. In addition to prefrontal-

McDaniel 2010, Diekelmann et al. 2012). The hippocampal circuitry, the theta spanning net-
enhancing effect of sleep on declarative word- work includes regions such as the ventral
pair memories was distinctly greater in subjects tegmental area and the amygdala (Fujisawa &
who were informed (or merely suspected) that Buzsáki 2011, Lesting et al. 2011), which may
recall would be tested later as compared with help integrate reward-related and emotional
subjects who had no such expectations; only in aspects into the tagging process. Together
the informed subjects did later recall perfor- with studies of rhythmic electrical stimulation
mance correlate with slow-wave activity during (Marshall et al. 2006, Kirov et al. 2009), these
postlearning sleep (Wilhelm et al. 2011a). observations converge on the idea that the same
Comparable results were revealed for procedu- prefrontal-hippocampal network producing
ral skill memories (Cohen et al. 2005, Fischer & theta during wake encoding to tag memories
Born 2009). changes into the SO rhythm during subsequent
Processing of goal-directed anticipatory SWS to consolidate the tagged memories.
aspects of behavior and retrieval is strongly
associated with prefrontal cortex executive
functions (Miller & Cohen 2001, Polyn & PERSPECTIVE
Kahana 2008). In allocating relevance (for fu- A wealth of evidence now indicates that sleep
ture actions), the prefrontal structures may tag contributes to the formation of long-term
hippocampal memories to facilitate their access memories in an active system consolidation
to system consolidation during sleep. Indeed, process. Although the main features of this con-
growing experimental evidence supports the cept appear to be firmly anchored in human
notion that offline system consolidation is and rodent research, a number of questions
not only achieved in a bottom-up process, in are left unanswered. What exactly is the role
which reactivation of hippocampal represen- of prefrontal top-down control in this consol-
tations promotes the incorporation of some of idation process? Do neocortical SOs transfer
this information into preexisting neocortical schema-related information that supports the
knowledge networks, but also entails signifi- selection of representations to be reactivated
cant top-down processing (Morris 2006). Thus in the hippocampus? Do they moreover con-
during spatial learning, medial and limbic tribute to downscaling and erasing of super-
prefrontal regions can quickly (in a single trial) fluous memory information from hippocampal
encode associations that overlap with a preex- circuits (van der Werf et al. 2009a, Grosmark
isting spatial schema (Lesburgueres et al. 2011, et al. 2012)? How exactly do hippocampal reac-
Tse et al. 2011), and such rapid prefrontal tivations contribute in a bottom-up fashion to
transforming representations toward more ab- song areas in the absence of potentially disturb-
stract schema-like representations? What hap- ing acute feedback (Konishi 2004, Margoliash
pens when schemas are not readily available & Schmidt 2010). Indeed, offline neuronal re-
in long-term memory, i.e., during early de- activation during sleep may work as a principal
velopment? Sleep appears to play a pivotal mechanism to form any kind of memory, i.e., as
role for memory formation during develop- a mechanism that serves to abstract temporally
ment (Frank 2011, Wilhelm et al. 2012b). Thus, stable invariants from a complex stream of in-
sleep-dependent formation of song representa- puts that is dynamic and only structured in time.
tions in young birds has been conceptualized as Regardless of what answers we find for these
a bottom-up feedforward process in which sen- questions, the past research described here has
sory inputs that are too complex and dynamic firmly established a picture of sleep as a brain
to be integrated into song production online state most essential to the genuine understand-
are reactivated during sleep to program motor ing of memory.
DISCLOSURE STATEMENT
The authors are not aware of any affiliations, memberships, funding, or financial holdings that
might be perceived as affecting the objectivity of this review.
ACKNOWLEDGMENTS
We are grateful to Gordon Feld, Manfred Hallschmid, Edo Kelemen, and Hannes Noack for
comments and discussions. This work is supported by a grant from the Deutsche Forschungsge-
meinschaft, SFB 654 “Plasticity and Sleep.”
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NE36-FrontMatter ARI 12 June 2013 11:33
Annual Review of
Contents Neuroscience
Volume 36, 2013
Active Properties of Neocortical Pyramidal Neuron Dendrites

Guy Major, Matthew E. Larkum, and Jackie Schiller p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 1
Episodic Neurologic Disorders: Syndromes, Genes, and Mechanisms
Jonathan F. Russell, Ying-Hui Fu, and Louis J. Ptáček p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p25
Developmental Mechanisms of Topographic Map Formation

and Alignment
Jianhua Cang and David A. Feldheim p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p51

Sleep for Preserving and Transforming Episodic Memory
Marion Inostroza and Jan Born p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p79
Computational Identification of Receptive Fields
Tatyana O. Sharpee p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 103
The Evolution of Drosophila melanogaster as a Model
for Alcohol Research
Anita V. Devineni and Ulrike Heberlein p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 121
From Atomic Structures to Neuronal Functions
of G Protein–Coupled Receptors
Krzysztof Palczewski and Tivadar Orban p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 139
Superior Colliculus and Visual Spatial Attention
Richard J. Krauzlis, Lee P. Lovejoy, and Alexandre Zénon p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 165
Genetic Approaches to Neural Circuits in the Mouse
Z. Josh Huang and Hongkui Zeng p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 183
Early Olfactory Processing in Drosophila: Mechanisms and Principles
Rachel I. Wilson p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 217
RNA Protein Interaction in Neurons
Robert B. Darnell p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 243
Muscarinic Signaling in the Brain
Alexander Thiele p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 271
Mechanisms and Functions of Theta Rhythms
Laura Lee Colgin p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 295
Neural Basis of the Perception and Estimation of Time
Hugo Merchant, Deborah L. Harrington, and Warren H. Meck p p p p p p p p p p p p p p p p p p p p p p p 313
v
NE36-FrontMatter ARI 12 June 2013 11:33
Cortical Control of Arm Movements: A Dynamical

Systems Perspective
Krishna V. Shenoy, Maneesh Sahani, and Mark M. Churchland p p p p p p p p p p p p p p p p p p p p p p p 337
The Genetics of Hair Cell Development and Regeneration
Andrew K. Groves, Kaidi D. Zhang, and Donna M. Fekete p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 361
Neuronal Computations in the Olfactory System of Zebrafish
Rainer W. Friedrich p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 383
Transformation of Visual Signals by Inhibitory Interneurons in Retinal
Circuits
Pablo D. Jadzinsky and Stephen A. Baccus p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 403
Electrical Compartmentalization in Dendritic Spines
Rafael Yuste p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 429

Prefrontal Contributions to Visual Selective Attention

Ryan F. Squire, Behrad Noudoost, Robert J. Schafer, and Tirin Moore p p p p p p p p p p p p p p p p 451
Gene Therapy for Blindness
José-Alain Sahel and Botond Roska p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 467
Translating Birdsong: Songbirds as a Model for Basic and Applied
Medical Research
Michael S. Brainard and Allison J. Doupe p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 489
Transient Receptor Potential Channels and Mechanosensation
Niels Eijkelkamp, Kathryn Quick, and John N. Wood p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 519
The Molecular Basis of Self-Avoidance
S. Lawrence Zipursky and Wesley B. Grueber p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 547
Indexes
Cumulative Index of Contributing Authors, Volumes 27–36 p p p p p p p p p p p p p p p p p p p p p p p p p p p 569

Cumulative Index of Article Titles, Volumes 27–36 p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 573
Errata
An online log of corrections to Annual Review of Neuroscience articles may be found at

http://neuro.annualreviews.org/
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NE36CH04-Born ARI 7 June 2013 16:14

• Our comprehensive search

Annu. Rev. Neurosci. 2013. 36:79–102 Keywords

With the accumulation of incoming informa-

intact. Once a representation has been redis-

reference to autonoetic consciousness during trahippocampal circuits. Consequently, based

www.annualreviews.org • Sleep and Episodic Memory 81

during sleep and

Hippocampal EEG 50 ms Theta

DOES SLEEP PREFERENTIALLY is expected to affect episodic features more

www.annualreviews.org • Sleep and Episodic Memory 83

Hippocampus Hippocampus Hippocampus

www.annualreviews.org • Sleep and Episodic Memory 85

revealed a sleep-dependent gain in response on episodic memory. The effect is preponder-

www.annualreviews.org • Sleep and Episodic Memory 87

memory representations encoded during wak-

from newly encoded hippocampal memories

and spreading to neocortical and striatal sites

www.annualreviews.org • Sleep and Episodic Memory 89

Born 2007). Sleep reorganizes representations considered a principal mechanism underlying

www.annualreviews.org • Sleep and Episodic Memory 91

transformation during SWS appears to be lock EEG gamma-band activity as an indicator

www.annualreviews.org • Sleep and Episodic Memory 93

in prospective memory paradigms (Scullin & subsequent SWS. In addition to prefrontal-

www.annualreviews.org • Sleep and Episodic Memory 95

and sleep. Proc. Natl. Acad. Sci. USA 104(18):7723–28

www.annualreviews.org • Sleep and Episodic Memory 97

Griessenberger H, Hoedlmoser K, Heib DP, Lechinger J, Klimesch W, Schabus M. 2012. Consolidation of

www.annualreviews.org • Sleep and Episodic Memory 99

100 Inostroza · Born

Steriade M. 2006. Grouping of brain rhythms in corticothalamic systems. Neuroscience 137(4):1087–106

www.annualreviews.org • Sleep and Episodic Memory 101

102 Inostroza · Born

Volume 36, 2013

Active Properties of Neocortical Pyramidal Neuron Dendrites

Developmental Mechanisms of Topographic Map Formation

Jianhua Cang and David A. Feldheim p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p51

Cortical Control of Arm Movements: A Dynamical

Rafael Yuste p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 429

Prefrontal Contributions to Visual Selective Attention

Cumulative Index of Contributing Authors, Volumes 27–36 p p p p p p p p p p p p p p p p p p p p p p p p p p p 569

An online log of corrections to Annual Review of Neuroscience articles may be found at

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