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Harbor Laboratory Press
Memory Consolidation
Larry R. Squire1,2,3, Lisa Genzel4, John T. Wixted3, and Richard G. Morris4

1
VA San Diego Healthcare System, San Diego, California 92161
2
Departments of Psychiatry and Neurosciences, University of California, San Diego, La Jolla, California 92093
3
Department of Psychology, University of California, San Diego, La Jolla, California 92093
4
Centre for Cognitive and Neural Systems, The University of Edinburgh, Edinburgh EH8 9JZ, United Kingdom
Correspondence: lsquire@ucsd.edu
Conscious memory for a new experience is initially dependent on information stored in both
the hippocampus and neocortex. Systems consolidation is the process by which the hippo-
campus guides the reorganization of the information stored in the neocortex such that it
eventually becomes independent of the hippocampus. Early evidence for systems consoli-
dation was provided by studies of retrograde amnesia, which found that damage to the
hippocampus-impaired memories formed in the recent past, but typically spared memories
formed in the more remote past. Systems consolidation has been found to occur for both
episodic and semantic memories and for both spatial and nonspatial memories, although
empirical inconsistencies and theoretical disagreements remain about these issues. Recent
work has begun to characterize the neural mechanisms that underlie the dialogue between
the hippocampus and neocortex (e.g., neural replay, which occurs during sharp wave
ripple activity). New work has also identified variables, such as the amount of preexisting
knowledge, that affect the rate of consolidation. The increasing use of molecular genetic tools
(e.g., optogenetics) can be expected to further improve understanding of the neural mech-
anisms underlying consolidation.
emory consolidation refers to the process Ribot (1881). The key observation was that re-
M by which a temporary, labile memory is
transformed into a more stable, long-lasting
cent memories are more vulnerable to injury or
disease than remote memories, and the signifi-
form. Memory consolidation was first proposed cance of this finding for consolidation was im-
in 1900 (Muller and Pilzecker 1900; Lechner mediately appreciated.
et al. 1999) to account for the phenomenon of
retroactive interference in humans, that is, the In normal memory a process of organization is
finding that learned material remains vulnera- continually going ona physical process of or-
ganization and a psychological process of repe-
ble to interference for a period of time after
tition and association. In order that ideas may
learning. Support for consolidation was already become a part of permanent memory, time must
available in the facts of retrograde amnesia, es- elapse for these processes of organization to be
pecially as outlined in the earlier writings of completed. (Burnham 1903, p. 132)
Editors: Eric R. Kandel, Yadin Dudai, and Mark R. Mayford

Additional Perspectives on Learning and Memory available at www.cshperspectives.org
Copyright # 2015 Cold Spring Harbor Laboratory Press; all rights reserved; doi: 10.1101/cshperspect.a021766
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L.R. Squire et al.
It is useful to note that the term consolidation hippocampal system. This information directs
has different contemporary usages that derive the training of a slow learning neocortex,
from the same historical sources. For example, whereby the hippocampus gradually guides
the term is commonly used to describe events at the development of connections between the
the synaptic/cellular level (e.g., protein synthe- multiple cortical regions that are active at the
sis), which stabilize synaptic plasticity within time of learning and that represent the memory.
hours after learning. In contrast, systems con- Training of the neocortex by the hippocampus
solidation, which is the primary focus of this (termed interleaved training) allows new in-
review, refers to gradual reorganization of the formation to be assimilated into neocortical
brain systems that support memory, a process networks with a minimum of interference. In
that occurs within long-term memory itself simulations (McClelland et al. 1995), rapid
(Squire and Alvarez 1995; Dudai and Morris learning of new information, which was incon-
2000; Dudai 2012). sistent with prior knowledge, was shown to
Systems consolidation is typically, and accu- cause interference and disrupt previously estab-
rately, described as the process by which mem- lished representations (catastrophic interfer-
ories, initially dependent on the hippocampus, ence). The gradual incorporation of informa-
are reorganized as time passes. By this process, tion into the neocortex during consolidation
the hippocampus gradually becomes less im- avoids this problem. In a recent revision of this
portant for storage and retrieval, and a more framework (McClelland 2013), neocortical
permanent memory develops in distributed re- learning is characterized, not so much as fast
gions of the neocortex. The idea is not that or slow, but as dependent on prior knowledge.
memory is literally transferred from the hippo- If the information to be learned is consistent
campus to the neocortex, for information is en- with prior knowledge, neocortical learning can
coded in the neocortex as well as in hippocam- be more rapid.
pus at the time of learning. The idea is that This review considers several types of evi-
gradual changes in the neocortex, beginning at dence that illuminate the nature of the consol-
the time of learning, establish stable long-term idation process: studies of retrograde amnesia in
memory by increasing the complexity, distribu- memory-impaired patients, studies of healthy
tion, and connectivity among multiple cortical volunteers with neuroimaging, studies of sleep
regions. Recent findings have enriched this per- and memory, studies of experimental animals,
spective by emphasizing the dynamic nature of both with lesions or other interventions, and
long-term memory (Dudai and Morris 2013). studies that track neural activity as time passes
Memory is reconstructive and vulnerable to after learning.
error, as in false remembering (Schacter and
Dodson 2001). Also, under some conditions,
STUDIES OF RETROGRADE AMNESIA
long-term memory can transiently return to a
IN MEMORY-IMPAIRED PATIENTS
labile state (and then gradually stabilize), a phe-
nomenon termed reconsolidation (Nader et al. One useful source of information about mem-
2000; Sara 2000; Alberini 2005). In addition, the ory consolidation comes from studies in mem-
rate of consolidation can be influenced by the ory-impaired patients of memory for past news
amount of prior knowledge that is available events or other public facts. In an early study
about the material to be learned (Tse et al. of memory for television programs that had
2007; van Kesteren et al. 2012). broadcast for only a single season, patients re-
Neurocomputational models of consolida- ceiving electroconvulsive therapy for depressive
tion (McClelland et al. 1995; McClelland 2013) illness showed temporally limited retrograde
describe how the acquisition of new knowledge amnesia extending back 1 3 years (Squire
might proceed and suggest a purpose for con- et al. 1975). This phenomenon was slow to be
solidation. As originally described, elements of related to neuroanatomy because of the need to
information are first stored in a fast-learning test patients with well-characterized lesions who
2 Cite this article as Cold Spring Harb Perspect Biol 2015;7:a021766

developed a memory impairment at a known from studies of autobiographical memory are

time. In one of the first studies to meet these mixed. In several studies, patients with restrict-
requirements, six memory-impaired patients ed hippocampal lesions, or larger medial tem-
with bilateral damage limited to the hippocam- poral lobe lesions, successfully recalled detailed
pus were given a test of 250 news events cover- memories from early life (Eslinger 1998; Bayley
ing 50 years (Manns et al. 2003). The patients et al. 2003; Buchanan et al. 2005; Kirwan et al.
showed a similar graded memory loss extending 2008; Kopelman and Bright 2012). Squire and
just a few years into the premorbid period (for Bayley (2007) offer additional discussion of sin-
two additional patients, see Kapur and Brooks gle-case reports. Whether assessed by counting
1999). Similar results have been obtained in the details in tape-recorded narratives, rating
neuroimaging studies of hippocampal activity, the quality of narratives, or scoring responses
for example, when volunteers recalled past news to a few standardized questions (on a 0 9
events that had occurred 1 30 years ago (Smith scale), patients performed like controls (Fig.
and Squire 2009). These results suggest a con- 1). Recall of episodes from the recent past was
solidation process whereby the human hippo- impaired (see also Thaiss and Petrides 2008).
campus can be needed to support memory for Yet, other patients produced fewer details about
factual information (semantic memory) for as past events, even events from early life (Rosen-
long as a few years after learning, but is not baum et al. 2005; Steinvorth et al. 2005; Race
needed after that time. et al. 2011).
Patients with damage that not only includes Why are the findings mixed? A lingering and
the hippocampus but larger regions of the me- challenging issue concerns the locus and extent
dial temporal (and sometimes lateral temporal) of brain damage and the possibility that damage
lobes as well can have severe retrograde memory outside the medial temporal lobe contributes to
loss covering decades (Bayley et al. 2006; Bright impaired performance. Lesions that extend lat-
et al. 2006). Nevertheless, patients with medial eral to the medial temporal lobe, for example,
temporal lobe lesions can have considerable
sparing of premorbid memory (e.g., recogni-
tion of famous faces: patient H.M. in Marslen- 9
Wilson and Teuber 1975; spatial knowledge of
Score (maximum = 9)
the childhood environment: patient E.P. in Teng

and Squire 1999). These findings show that the 6
brain regions damaged in such patients, for ex-
ample, the entorhinal, perirhinal, and parahip-
3
pocampal cortices, although important for new
learning, are not similarly important for recol-
lecting the past. The implication is that infor- 0
mation initially requires the integrity of medial CON H MTL MTL+
temporal lobe structures, but is reorganized as (n = 13) (n = 6) (n = 2) (n = 3)
time passes so as to depend much less (or not at Figure 1. Performance on the remote memory (child-
all) on these same structures. hood) portion of the autobiographical memory in-
Another useful source of evidence about terview (Kopelman et al. 1989; three questions; max-
memory consolidation comes from studies of imum score 9) by controls (CON), patients with
autobiographical memory for past events (epi- circumscribed hippocampal (H) lesions, patients
sodic memory). The study of autobiographical with large medial temporal lobe (MTL) lesions, and
memory presents unique challenges because it patients with medial temporal lobe lesions plus ad-
ditional damage in the neocortex (MTL). Brackets
depends on the analysis of spoken narratives show standard error of the mean. Patients with dam-
that are often difficult to corroborate and on age limited to the MTL have the capacity to recall
elaborate scoring methods that can be difficult remote events, but this capacity is diminished when
to duplicate across laboratories. The findings the damage extends into the neocortex.
Cite this article as Cold Spring Harb Perspect Biol 2015;7:a021766 3

L.R. Squire et al.
could impair remote memory by damaging re- own past). In the latter case, the experience is
gions thought to be repositories of long-term knowing, as when one is simply convinced that
memory. In one of the studies reporting an something is true without appreciating when or
extensive deficit in autobiographical memory where the knowledge was acquired.
(Rosenbaum et al. 2005), all four patients had The method then involves asking people
significant damage to the posterior temporal when they recall a past event whether they re-
cortex. Although the deficit was attributed to member the occurrence of the event, or wheth-
hippocampal damage, the data show that the er they simply know in some other way that
best predictor of retrograde memory perfor- it occurred. The so-called remember know
mance was the volume of the posterior tempo- procedure has been used extensively in studies
ral cortex and the cingulate cortex. The findings of learning and memory and has also been used
seem as consistent with the idea that an extend- to assess the quality of retrieved memories from
ed network of regions supports remote auto- the past. This procedure is well suited to address
biographical recollection (Svoboda et al. 2006) the question of interest. When memory-im-
as with the idea that the medial temporal lobe paired patients with restricted medial temporal
itself is especially critical. In another study of lobe lesions recollect an event from the remote
eight patients (Race et al. 2011), quantitative past, do they report that they remember or
magnetic resonance imaging (MRI) data were that they simply know about the event? It
available for only four and, of these, two had took a long time to test this question experi-
damage to lateral temporal cortex. mentally. In the first formal test, three patients
The fate of past autobiographical memories with hippocampal lesions and two with large
has special significance for ideas about consol- medial temporal lobe lesions recalled events
idation. Multiple-trace theory (Moscovitch from their early life and, then, were asked to
et al. 2006), later elaborated as the transfor- decide whether they remembered the incident
mation hypothesis (Winocur and Moscovitch or simply knew that it had happened (Bayley
2011), holds that memories retaining contextu- et al. 2005). The patients produced as many
al details (such as episodic memories) remain details as controls and also rated most of their
dependent on the hippocampus so long as they memories as remember (87.1% vs. 80.3% for
persist. The consolidation of memory into the controls). Thus, these patients reported that
neocortex is thought to involve a loss of time they were remembering and retrieving from
and place, contextual information, and a tran- episodic memory. The results suggest that epi-
sition to more gist-based, fact-like semantic sodic retrieval from the remote past is possible
memory. By this account, detailed context in- after medial temporal lobe damage and that
formation about past autobiographical events such retrieval is independent of the medial tem-
does not consolidate into the neocortex. Note poral lobe.
that, if the hippocampus supports the capacity There are patients who cannot remember
for episodic recollection during the full lifetime the past at all, but these are not patients with
of a memory, then hippocampal damage should damage limited to the hippocampus. These are
not only reduce the number of details that can patients with significant damage outside the
be produced (as has sometimes been reported), medial temporal lobe whose narratives are not
but should also result in fact-based narratives just short on detail, but also lack any episodic
that reflect semantic knowledge and lack epi- content. Their knowledge of the past seems im-
sodic (time and place) information. personal like their other knowledge of the world
Tulving (1985) introduced a method that ( patient S.S. in Cermak and OConnor 1983;
can be used to test this idea. He argued that it patient K.C. in Rosenbaum et al. 2005; patient
is possible to recover information about past G.T. in Bayley et al. 2005). They know a few facts
events from either episodic or semantic memo- about their own past, but cannot recall a single
ry. In the former case, the phenomenal experi- incident or event. For example, patient K.C. is
ence is remembering (becoming aware of ones described as follows:

The most striking fact about K.C.s amnesia is recent memories compared with remote mem-
that he cannot recollect a single personal hap- ories (Haist et al. 2001; Douville et al. 2005;
pening or event from his life. He does not re- Smith and Squire 2009), but other studies
member any incidents from all the years preced-
have found no difference (e.g., Maguire et al.
ing his accident, nor can he remember any of the
normally highly memorable things that have 2001; Maguire and Frith 2003; Bernard et al.
happened to him. (Tulving et al. 1988, p. 9) 2004). The latter results (like all null results)
are difficult to interpret and may reflect a failure
If episodic memory depends on the hippocam-
to detect a true difference. If so, the available
pus for as long as memory persists, then patients
results may not be as contradictory as they ap-
with restricted hippocampal lesions should be
pear. More work is needed to settle this issue.
as empty of a personal past as patient K.C. Yet, a
With respect to episodic (autobiographical)
condition so severe has not, to our knowledge,
memories, several approaches have been used,
been described for patients with restricted
and the literature is similarly mixed. In one typ-
hippocampal lesions. The available evidence
ical design, a prescan interview is conducted to
suggests that autobiographical memories con-
elicit autobiographical memories from the re-
solidate and ultimately depend on a distributed
cent and remote past, and these memories are
network of cortical regions.
then queried during scanning (e.g., Niki and
Luo 2002; Piefke et al. 2003; Bonnici et al.
2012, 2013; Soderlund et al. 2012). Studies us-
NEUROIMAGING STUDIES OF NORMAL
ing this design sometimes found greater medial
MEMORY
temporal lobe activity in association with recent
Consolidation has also been explored in healthy recollections compared with remote recollec-
volunteers using neuroimaging methods like tions (i.e., evidence of a temporal gradient),
positron emission tomography (PET) or func- but sometimes there was no evidence for a tem-
tional magnetic resonance imaging (fMRI). poral gradient. However, a recognized limita-
Neuroimaging studies can establish whether or tion of the prescan interview is, that later in
not a particular structure (e.g., the hippocam- the scanner, participants may retrieve what
pus, medial prefrontal cortex, or a network of they had just recollected about their recent
structures) is active when recent and remote and remote memories. If so, all the memories
memories are retrieved, but this method does are effectively recent, a circumstance that would
not indicate whether a structure is necessary for work against finding a temporal gradient (Ca-
retrieval. Thus, a temporal gradient of hippo- beza and St Jacques 2007).
campal activation (e.g., greater activation for An alternative design involves cueing sub-
recent than for remote memories) might reflect jects in the scanner for recent and remote auto-
a decreasing dependence on the hippocampus biographical memories without a prescan in-
as memories age, but such a result might also terview (e.g., Gilboa et al. 2004; Rekkas and
reflect differences in the extent to which mem- Constable 2005; Viard et al. 2010). In one study
ories of different ages are relearned and re- (Rekkas and Constable 2005), volunteers took a
encoded as they are recollected. Considerations prescan tour of a campus (to create recent mem-
such as these point to the complexities of inter- ories) and then, in the scanner, recalled either
preting neuroimaging data and may help to ex- recent events from the campus tour or remote
plain why the relevant neuroimaging literature events that had occurred during elementary
is decidedly mixed. school years. A temporal gradient of hippocam-
In neuroimaging studies, participants are pal activity was observed, but the level of activ-
often tested for their semantic knowledge of ity was higher for remote memories than for
public events that occurred at various times in recent memories (a result not anticipated by any
the recent and remote past. With this approach, account of memory consolidation). In fMRI
some studies have found greater activity in the studies, it is often difficult to know whether
medial temporal lobe during the recollection of measured activity reflects reencoding or retriev-

L.R. Squire et al.
al (Stark and Okado 2003). One possibility is less durable recent memories. One elegant pro-
that interesting and personally significant mem- spective memory study addressed this issue (Ya-
ories from the remote past might have stimulat- mashita et al. 2009). Activity in the hippocam-
ed greater reencoding activity in the hippocampus and temporal neocortex was monitored as
pus than less interesting, and less significant, participants recalled two sets of paired-associate
memories from the recent past. figures (fractal images), which they had mem-
A different approach is to use a prospective orized at two different times. One set had been
design that affords experimental control over studied 8 weeks before testing (remote memo-
the memories from different time periods. In ries), and the other had been studied just before
this design, participants learn similar materials testing (recent memories). Overall memory ac-
at multiple different time points before scan- curacy at the time of the test was equated for
ning. A number of recent neuroimaging studies these two conditions by providing more study
have used this approach (Takashima et al. 2006, time for the items studied 8 weeks earlier. The
2009; Yamashita et al. 2009; Furman et al. 2012; results were that a region in the right hippocam-
Harand et al. 2012). For example, in one study pus was more active during retrieval of new
(Takashima et al. 2009), participants memo- memories than old memories, whereas in the
rized two sets of face-location associations; left temporal neocortex, the opposite pattern
one was studied 24 h before testing (remote was observed. These results are consistent with
memories) and the other studied 15 min before a decreasing role of the hippocampus and an
testing (recent memories). Activity in the hip- increasing role of the neocortex as memories
pocampus decreased (and activity in the neo- age across a period of 50 days.
cortex increased) as a function of time after Imaging studies have also been used to ex-
learning. Concomitantly, functional connectiv- plore how and under what conditions con-
ity between the hippocampus and cortical areas solidation occursa process that presumably
decreased over time, whereas connectivity with- involves some relatively long-lasting communi-
in the cortical areas increased. This temporal cation between the hippocampus and the
gradient is shorter than what is typically ob- neocortex. One proposal for how this could
served in lesion studies, but the findings are be accomplished is through the phenomenon
nevertheless in agreement with the idea that of neural replay, which refers to the spontane-
the hippocampus becomes less important for ous recurrence of hippocampal activity that
memory as time passes. We shall consider the occurred originally during learning. Neural re-
speed of consolidation in more detail in a later play has most often been observed in rats during
section on animal studies. non rapid eye movement [NREM]) slow-
Furman et al. (2012), also using a prospec- wave sleep (Wilson and McNaughton 1994),
tive design, tested memory of documentary film but something akin to neural replay seems to
clips. Hippocampal activity declined as time occur in humans as well. For example, a study
passed over a period of months when memory of regional cerebral blood flow found that hip-
was tested by recognition (an indication of pocampal areas that were active during route
memory consolidation), but it remained stable learning in a virtual environment (a hippocam-
across time when memory was tested by recall. pus-dependent, spatial learning task) were ac-
A complementary increase in activity in cortical tive again during subsequent slow-wave sleep
areas as a function of time was not observed; (Peigneux et al. 2004). Moreover, the degree of
instead, cortical activity decreased as well. activation during slow-wave sleep correlated
A concern that could be raised about pro- with performance on the task the next day. In a
spective studies is that, by the time memory is conceptually related study (Rasch et al. 2007),
tested in the scanner, many older memories will cueing recently formed odor-card associations
have been forgotten. As a result, the surviving by odor reexposure during slow-wave sleep, but
remote memories are relatively durable and are not during rapid eye movement (REM) sleep,
being compared with a mixture of durable and increased hippocampal activity (as measured

by fMRI), and resulted in less forgetting after ated gradual processes that developed within
sleep. In both studies, hippocampal reactiva- long-term memory. These findings are consis-
tion, which presumably initiated hippocam- tent with the idea that the encoding of a mem-
pal neocortical dialogue, occurred within ory can be followed by replay-like activity dur-
hours of the learning episode. ing subsequent offline periods. The extended
Other studies have found that the replay-like hippocampal cortical communication result-
activity observed during NREM sleep can also ing from replay is thought to lead gradually to
occur during quiet wakefulness, suggesting that a memory that is represented in the neocortex
consolidation-related processes may proceed and independent of the hippocampus.
whenever the hippocampus is not otherwise
engaged in encoding activity (Karlsson and ANIMAL STUDIES OF MEMORY
Frank 2009; Mednick et al. 2011). For example, CONSOLIDATION
following paired-associates learning (objects or
Animal research on memory consolidation
scenes paired with faces), functional connectiv-
has the same starting point as human work:
ity between the hippocampus and a portion of
establishing whether and how memory stabiliz-
the lateral occipital complex increased during a
es with the passage of time. It differs in allowing
postlearning rest period (Tambini et al. 2010).
for invasive experiments using interventions,
Moreover, the strength of this effect predicted
such as lesions, physiological monitoring and
subsequent memory performance. The specific
recording, and molecular techniques. Key em-
patterns of activity associated with encoding
pirical issues include (1) Are temporal gradi-
experiences can also recur during subsequent
ents of retrograde amnesia reliably observed af-
offline rest periods. In one study (Tambini and
ter comparable experimental interventions?
Davachi 2013), hippocampal activity patterns
(2) Is there evidence of time-dependent changes
persisted into postencoding rest periods, and
in physiological function that relate to or
the persistence of some of these patterns corre-
mediate aspects of memory consolidation? (3)
lated with later memory performance for the
Can contemporary molecular-genetic tech-
material presented during the study. In related
niques be used to shed new light on the systems
work, an object-scene paired-associates learn-
issues concerning hippocampal neocortical
ing task was followed by a 2-min delay, followed
dialogue?
by a cued-recall test (Staresina et al. 2013). Suc-
cessful recall of individual study events was
predicted by the degree to which those events Are Temporal Gradients of Retrograde
elicited similar patterns of activation in the en- Amnesia Reliably Observed in Animals?
torhinal cortex during the encoding and delay Beginning more than 20 years ago, studies in
periods. Inasmuch as these studies have in- nonhuman primates, rodents, and other species
volved activity occurring rather soon after learn- confirmed the existence of a temporal gradient
ing, it will be useful to evaluate the possible role of amnesia in animals. Thus, monkeys learned
of rehearsal, either intentional or spontaneous. multiple object discrimination tasks at five dif-
If neural replay is related to memory con- ferent intervals before surgery (Fig. 2A). After
solidation, it should be possible to find evidence lesions of the hippocampal formation, they
of replay at longer time intervals after learning remembered better the problems learned 12
(i.e., across the portion of long-term memory weeks before the lesion than problems learned
during which consolidation is thought to oc- just before the lesion (Zola-Morgan and Squire
cur). In a study of trace eyeblink conditioning 1990). A study of the social transmission of food
in rats, activity in the medial prefrontal cortex, preference task in rats yielded a similar but
selective for the acquired association, developed shorter temporal gradient (Winocur 1990). In
over a period of several weeks and in the absence context fear conditioning, rats given hippo-
of continued training (Takehara-Nishiuchi and campal lesions 28 days after conditioning still
McNaughton 2008). In this case, training initi- displayed fear of the chamber in which condi-

L.R. Squire et al.
A Object discrimination (monkey) B Fear conditioning (rat)

Control MTL lesion Control HPC CNQX
90
70 70
Time spent freezing (s)

Percent correct (%)
80
60 60
70
50 50
60 40 40
Weeks
50 30 30
2 4 8 12 16 1d 28 d Discriminators Generalizers
14 d
C 2-Deoxyglucose (mouse) D SWR disruption (rat)
Control Stimulated control SWR disruption
5-day retention 25-day retention
1.0
aCC
FC
Performance index
Frontal
level
0.8
Relative metabolic
5
activity
4 dHPC pCC PC
3
2 0.6
1
HPC
level 0.4
CA1 Days
CA3 DG
2 4 6 8 10 12 14
E Fear conditioning (mouse) F Fear conditioning (mouse)

RSC optogenetics, HPC pharmacolgy
Control HPC Control HPC TTX + CNQX
100 30
Time spent freezing (%)
Time spent freezing (%)
80 25
20
60
15
40
10
20 5
0 0
1 d 28 d 1 d 28 d 1 d 28 d Prelight 24 h 24 h box
Brief Drug Prolonged Light in RSC
optogenetic inhibition optogenetic
inhibition inhibition
Figure 2. Animal studies revealing temporal gradients and other characteristics of cortical memory measured in
a variety of different tasks. (A) Object discrimination learning in monkeys shows a temporal gradient over a
period of 12 weeks (based on Zola-Morgan and Squire 1990). (B) Context fear conditioning sometimes shows a
temporal gradient, but does not always do so. In a study in which a temporal gradient was observed in animals
tested during pharmacological inhibition of the hippocampus (left panel), animals that successfully discrim-
inated two testing contexts show a loss of memory with hippocampal inhibition, whereas animals that gener-
alized do not (right panel based on Figs. 2 and 5 of Wiltgen et al. 2010). (C) Glucose uptake measured using
radiolabeled 2-deoxyglucose shows a time-dependent increase in the cortex 25 days after radial-maze learning
in mice (based on Bontempi et al. 1999). (Legend continues on following page.)

tioning had occurred (indexed as freezing), Early studies in the water maze also did not
whereas those trained only 1 day before the le- find a temporal gradient (Bolhuis 1994; Suth-
sion did not (Kim and Fanselow 1992). Simi- erland et al. 2001). Our two groups investigated
larly, in a within-subjects procedure, rats froze this in detail. Varying the task to a dry-land
in the context in which fear conditioning had version, called the oasis maze, revealed no
occurred 50 days before a hippocampal lesion, sparing of remote memory after radio frequency
but not in a different context in which fear con- lesions of the hippocampus (Clark et al, 2005a).
ditioning had occurred just before the lesion Extended training of the water maze task before
(Anagnostaras et al. 1999). the lesion, in an effort to minimize floor effects,
These studies made two important points. also did not reveal a gradient (Clark et al.
First, their prospective designs enabled behav- 2005b). One possibility was that this impair-
ioral training to be appropriately timed in rela- ment in remote memory was a retrieval deficit
tion to lesions that could be both complete and rather than a true loss of consolidated memory.
limited to a structure of interest. Second, the To address this, a reminder procedure was used
findings indicated that it was not simply that a in two water maze studies involving neurotoxic
lesion after training caused a deficit in memory. lesions (de Hoz et al. 2004; Martin et al. 2005).
The key finding was that a group with a long The Atlantis platform procedure provided the
time interval between training and surgery per- reminder. The platform is near the bottom of
formed paradoxically better than a group with a the water maze during a probe trial, but be-
shorter training surgery interval. Discussions comes available for escape after 60 sec. In this
of retrograde amnesia have emphasized the way, a probe test can be performed and the an-
importance of this feature of the data (Squire imal is reminded of the correct location. Per-
1992). Indeed, the finding that remote memory formance in a second probe test 1 h later was
can be better than recent memory after a lesion significantly better, indicating that reminding
is usually considered to be the gold standard for can work. However, this effect occurred only
showing memory consolidation. in partially lesioned rats that had been trained
However, not all studies of retrograde am- shortly before the lesion. Furthermore, success-
nesia in animals have yielded a gradient, for ful reminding of memory was not observed in
example, in context fear conditioning. Thus, remote memory groups trained long before the
one group has repeatedly failed to find a tem- lesion. Thus, a temporal gradient can appear in
poral gradient (Lehmann et al. 2007; Suther- the water maze once access to memory is im-
land et al. 2008; Sparks et al. 2011). Another proved but in the direction opposite to that pre-
group found no temporal gradient despite sys- dicted by standard consolidation theory.
tematic manipulation of potentially relevant However, as navigation through space in-
parameters: lesion method, lesion size, single volves the hippocampal formation in rodents
trial training, and massed and spaced multitrial (OKeefe and Nadel 1978; Moser et al. 2008),
training (Broadbent and Clark 2013). the failure to see intact memory could be be-
Figure 2. (Continued) (D) Detection and shutdown of hippocampal sharp-wave ripples (SWR), a candidate
mediator of consolidation, slows learning of a spatial radial-arm maze task (based on Girardeau et al. 2009). (E)
Comparison of short and prolonged optogenetic (halorhodopsin)-induced inhibition of the hippocampus.
There is an unexpected effect of brief hippocampal inhibition after 28 days in a training paradigm that shows a
temporal gradient with more prolonged inhibition (based on Goshen et al. 2011). (F) Optogenetic activation of
neurons in the retrosplenial cortex (RSC) labeled with channelrhodopsin via c-fos activation during context fear
conditioning is sufficient to elicit a freezing response, bypassing the need for hippocampal binding during the
early stage of systems consolidation. Even when the hippocampus (HPC) was inactivated by tetrodotoxin (TTX)
and 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), direct optogenetic activation of RSC elicited greater freez-
ing 24 h after conditioning (middle) than during preconditioning (left). In the absence of optogenetic activation
(right), hippocampal activity was essential to reactivate memory so soon after conditioning (based on Fig. 4E of
Cowensage et al. 2014). MTL, medial temporal lobe.

L.R. Squire et al.
cause of a secondary disruption of the expres- delay condition before the onset of hippocam-
sion of memory, even for a memory that had pal inhibition (which might then show spatial
been consolidated in the cortex. It may be, for memory to be intact), it confirms the idea that
this reason, that the reminding effect was ob- water maze learning may involve posttrain-
served in animals with partial neurotoxic le- ing consolidation just as the standard model
sions with intact fibers of passage. If so, reduc- predicts. However, it is unclear whether the
ing the navigational demands by arranging for pharmacological intervention affects only the
swimming and escape within a circular corri- dialogue between the hippocampus and neocor-
dor or annulus might reveal intact memory tex for stabilization of cortical traces (Alvarez
in animals with larger lesions. However, such and Squire 1994), or might also affect memory
a finding was also not observed (Clark et al. traces within the hippocampus itself (Nadel and
2007). Thus, something about allocentric spa- Moscovitch 1997). A further difficulty is that a
tial memory tasks, at least in the water maze, study using continuous posttraining infusions
appears to be different from the tasks discussed of either lidocaine or CNQX for 7 days did not
earlier, possibly including some long-term stor- replicate the Riedel et al. (1999) findings (Broad-
age of spatial information in the hippocampus. bent et al. 2010). However, a later study using
This difference has recently been driven home postlearning transection of the temporoam-
by a study using a within-subjects design. In the monic path from the entorhinal cortex to area
same experimental subjects, a temporal gradi- CA1 of the hippocampus did reveal poor mem-
ent was found for context fear conditioning but ory tested 28 days later (Remondes and Schu-
not for spatial memory (Winocur et al. 2013). man 2004), which was interpreted as interrupt-
Why the gradient is reliably seen in some studies ing hippocampal neocortical dialogue. That
of context fear conditioning but not in others, is, after learning, ongoing cortical input con-
nor in the water maze, is an issue of current veyed by the temporoammonic path is required
interest (Winocur et al. 2013). to consolidate long-term spatial memory. Fol-
It has been shown that the hippocampus low-up studies need to be conducted that look
has to be active at the time of retrieval for the not only at the impact of sustained and revers-
expression of both recent and remote memory ible inactivation of the hippocampus, but also
in rodents (Liang et al. 1994; Broadbent et al. at relevant structures of the neocortex (retro-
2006), and this fact points to the need for a splenial, anterior cingulate, medial prefrontal
different approach. One would like to inactivate cortex) that might be engaged in systems con-
the hippocampus reversibly during the putative solidation.
memory consolidation process, but allow it to For the present, it is clear that after appro-
work normally during learning and, later, at re- priately timed lesions, a temporal gradient fa-
call. One relevant study used a chronic revers- voring better remote memory is seen too often
ible blockade of GluR1-5 receptors in the dorsal to discount, including in a spatial paired-asso-
hippocampus (for 7 days, beginning 1 or 5 days ciate task to be discussed below (Tse et al. 2007),
after learning), with blockade confirmed meta- but it is unclear why it is not always observed
bolically using 2-deoxyglucose (2-DG). Memo- with either permanent lesions or temporary in-
ry retention was tested 16 days after training activation. The next section identifies some rel-
with the hippocampus, once again, working evant factors.
normally (Riedel et al. 1999). A deficit in the
consolidation of memory was observed whether
Interpreting Behavioral Measures
the inhibition was begun 1 day after training or
and Cognitive Factors
after a delay of 5 days. These findings suggest
that turning off the hippocampus for 7 days Human studies are characterized by distinct
after learning, despite normal function during ways of measuring memoryfrom simple mea-
encoding and retrieval, does cause retrograde sures of percent correct to more subjective mea-
amnesia. Although this study lacked a long- sures, such as the remember know procedure.

It is unclear how to apply such subtle qualitative after training, the animals showed good mem-
distinctions to animals who cannot verbally re- ory. Thus, a rapid temporal gradient was ob-
port a specific event. In a typical task, it is simply served (unlike in the water maze), reflecting
the apparent strength of a memory that is being the apparent assimilation of new information
tested. Recent animal research has endeavored into the previously trained neocortical schema.
to determine whether different temporal gradi- These results raise the question: What is dif-
ents of retrograde amnesia are associated with ferent about context fear conditioning, the wa-
different training protocols and/or whether ter maze, and the event arena? Temporal gradi-
representations in memory change qualitatively ents are seen in the first and third of these, but
with the passage of time. What is emerging is not usually in the second. Spatial navigation
evidence that features of a test protocol can mat- is important in the water maze, but not in con-
ter and that the temporal gradient of retrograde text fear conditioning, and not so important
amnesia is not a fixed entity. in the event arena because the animal can decide
One important variable is whether the in- whether or not to dig for food at each sand well
formation being learned is completely novel or after it gets to it. Another difference between
can be related to previously acquired knowl- these three tasks, to which Tse et al. (2007)
edge. How easily new information can be assim- drew particular attention, is that in studies to
ilated into a neocortical knowledge structure, date, animals entering context fear conditioning
such as a schema, may depend on the extent and water maze experiments are experimental-
to which subjects have an available framework ly nave. That is, they have not been trained on
of prior knowledge relevant to the new infor- other tasks, nor do they have a history of prior
mation being learned (Bransford 1979; McClel- learning like adult humans. The implicit sup-
land 2013; Ghosh and Gilboa 2014). Rapid as- position has been that this exceptional degree of
similation of information into a schema should control is a desirable feature of animal proto-
speed up the time course of systems consolida- cols, but this may be incorrect. The results from
tion. This idea was investigated in rats by first Tse et al. (2007) raise the possibility that the
training them to learn multiple paired associ- temporal parameters of consolidation are not
ates. The associations involved the flavor/odor a biological given (such as the interaction of
of a food reward buried in a sand well and the fast [hippocampal] and slow [cortical] learning
spatial location in an event arena where the systems discussed by McClelland et al. 1995),
food could be found (Tse et al. 2007). The use but can be influenced by cognitive factors, that
of spatial location as one member of a paired is, the time course of consolidation is not fixed,
associate enabled the animals to build a map or and that this is the case is an important topic
schema indicating what food was where. of current study (Tse et al. 2007). The paired-
Learning was slow, 6 weeks, but the animals associate protocol may produce a relatively
could eventually use the taste or smell of the short temporal gradient of retrograde amnesia
food to direct their digging at the location where because the animals do not remember the in-
the corresponding food could be found. The dividual events associated with a paired-associ-
initial learning of paired associates was im- ate learning trial, but can nevertheless modify a
paired by neurotoxic hippocampal lesions given preexisting semantic memory in the cortex (Fig.
before training, indicating that this learning 3B). An additional justification for this second
is hippocampus dependent. Critically, when point is that new computational modeling in-
normal animals were trained and acquired a dicates that past experience may make the ex-
schema, and lesions were made at different traction of statistical regularities easier and fast-
times after the introduction of new paired asso- er (McClelland 2013).
ciates, a temporal gradient of retrograde amne- It is possible that this same idea may illumi-
sia was observed. Specifically, when lesions were nate context fear conditioning studies in some
made only 3 h after training, later memory was circumstances. For example, following up earli-
poor. However, when lesions were made 2 days er work (Riccio et al. 1984), new studies of fear

L.R. Squire et al.
A Standard systems consolidation
Behavior Controls Network

HPC lesion dynamics
Cortical modules Cortical modules
Memory score
Recent Remote Hippocampus Hippocampus

(hours) (weeks) (hours) (weeks)
B Systems consolidation with schema

Cortical modules mPFC Cortical modules mPFC
Memory score
Recent Remote Hippocampus Hippocampus

(3 h) (48 h) (3 h) (48 h)
Figure 3. Hypothetical models of hippocampal neocortical interactions during memory consolidation. (A)
The standard model supposes that information is stored simultaneously in the hippocampus and in multiple
cortical modules during learning and that, after learning, the hippocampal formation guides a process by which
cortical modules are gradually bound together over time. This process is considered to be slow, occurring across
weeks, months, or even longer (based on Frankland and Bontempi 2005). (B) In situations in which prior
knowledge is available and, thus, cortical modules are already connected at the start of learning, a similar
hippocampal neocortical-binding process takes place. However, this process may involve the assimilation of
new information into an existing schema rather than the slower process of creating intercortical connectivity
(based on van Kesteren et al. 2012). HPC, hippocampus; mPFC, medial prefrontal cortex.
conditioning have shown that the ability to dis- gradually extracts statistical regularities while
criminate between the training context (con- permitting details to be lost.
text A) and a novel context (context B) dimin- A study relevant to these issues assessed fear
ishes over the course of a month (Wiltgen and conditioning 14 days after training. A signifi-
Silva 2007; Wiltgen et al. 2010). Importantly, cant negative correlation was found between
these studies revealed a temporal gradient of an individual animals discrimination ability
retrograde amnesia when mice were tested in (trained vs. novel context) and the extent to
the training context (context A) 1 or 28 days which the animal showed freezing in the novel
after training (hippocampal inactivation im- context (Wiltgen et al. 2010). There was no cor-
paired performance after 1 day, but not after relation between discrimination ability and the
28 days). What is the relationship between the extent of freezing in the trained context. In
loss of discriminability between contexts A and addition, pharmacological inactivation of the
B across 28 days and the evidence for consoli- hippocampus after 14 days impaired memory
dation over the same time period? One possi- for the training context in animals that dis-
bility is that consolidation occurs against a criminated between contexts, but not in ani-
background of normal forgetting. Alternatively, mals that failed to discriminate (Fig. 2B). One
the decline in discriminability might mean that interpretation of this result is that, if a de-
consolidation is a time-dependent process that tailed contextual (episodic-like) memory is

available, whether immediately or long after either 1 day or 30 days after training, they could
training, the hippocampus is engaged and re- remember this new location better if it conflict-
quired. Moreover, if only a semantic or gist ed with the distribution of locations learned
memory is available, which does not discrimi- 30 days earlier than if it conflicted with the dis-
nate between contexts, memory can be support- tribution of locations learned only 1 day earlier.
ed by the cortex alone. The nature of this stabilization of pattern
An alternative way to understand these re- memory or gist memory over time remains un-
sults is that they may reflect group differences in clear. The investigators propose that the finding
the rate of consolidation. Mice were separated is unlikely to be caused by the degradation of
into two groups based on their ability to dis- memories over time or to memory strength be-
criminate context A from context B. According- ing simply a function of relative recency. In-
ly, the two groups could have differed from each stead, like Wiltgen et al. (2010), they favor the
other in many other ways as well (notwithstand- view that consolidation entails an active process
ing the finding that performance in context A of extracting the gist or pattern from what was
was similar for the two groups). Indeed, the learned, although forgetting individual instanc-
amount of gist or detailed memory that was es (including the most recent instance). Where-
available may not be relevant. The high-dis- as this perspective does provide an accurate de-
crimination group might take longer to consol- scription of the data, it is unclear whether a
idate than the low-discrimination group and, qualitative process/mechanism of gist extrac-
even after that point is reached, the animals in tion is, in practice, actually required. Successive
the high-discrimination group might still be training days to platforms in distinct locations
able to discriminate between contexts. This re- will create multiple rapidly declining memory
sult would imply that even memory for detail traces whose residual strength over time may
can consolidate. This analysis predicts that if a not decline to zero. Instead, these traces could
much longer period of posttraining consolida- gradually summate to result in particular areas
tion were allowed, enabling the high-discrimi- of the water maze having different associative
nating group to fully consolidate, hippocampal strengths. This summation process could occur
inactivation would have no effect despite suc- during posttraining consolidation and result in
cessful context discrimination. the time-dependent appearance of an apparent
Another study of how memory changes over gist memory even in the absence of a specific
time involved use of the water maze (Richards pattern extraction process.
et al. 2014). Mice were trained on a delayed Taken together, the studies summarized in
matching-to-place protocol in which the escape this section indicate that temporal gradients of
platform moved location each day. On each day, retrograde amnesia can be observed, but there
there was a rapid decline in escape latency as each is presently uncertainty about both the time
new location was learned. In one version of this course of the gradients and the factors that me-
task, the platform was located in various places diate them. The possibility that there are qual-
in the north quadrant of the pool twice as often itative changes in the character of memory dur-
as in various places in the east quadrant. When ing consolidation is currently an active area of
tested 1 day after completing 8 days of training, research.
mice searched primarily in the most recently
trained location. However, when tested after
30 days, mice tended to search twice as often MONITORING METABOLIC, IMMEDIATE
EARLY GENE, AND NEUROPHYSIOLOGICAL
in the north quadrant as in the east quadrant.
SIGNATURES OF CONSOLIDATION AT
That is, after 30 days, search was driven less by
VARIOUS TIMES AFTER TRAINING
any single days training, or even by the last days
training, but rather by the cumulative statistical Monitoring physiological changes over time of-
distribution of training experience across days. fers a different window on consolidation pro-
When mice had to learn a new escape location cesses. One strategy has been to look at region-

L.R. Squire et al.
specific alterations of 2-DG uptake or immedi- that neocortical tags are set early at the time of
ate early gene (IEG) activation in the hippocam- memory encoding and time-dependent changes
pus and neocortex at various times after train- develop across time as dynamic interactions oc-
ing. One study trained mice in an eight-arm cur between the hippocampus and neocortex.
radial-maze task (Olton et al. 1979) in which When animals were tested for their memory
some arms were rewarded and others were never of context fear conditioning at 1 and 30 days
rewarded (Bontempi et al. 1999). Increased 2- after training, correlations in the expression of
DG uptake in the hippocampus was found when the IEG c-fos were observed across brain areas
testing occurred shortly after training. Impor- (Wheeler et al. 2013). Specifically, the absolute
tantly, there was a time-dependent decrease in levels of IEG expression in up to 80 brain areas
hippocampal uptake when testing was delayed revealed a striking change in the correlation
for several weeks, and there was a corresponding matrix between brain areas 1 and 30 days after
increase in 2-DG uptake in the neocortex (Fig. training. These results indicate time-dependent
2C). Follow-up work found similar temporal changes in cortical networks over this time pe-
patterns in the expression levels of IEGs, such riod. This functional connectome is strongly
as c-fos (Frankland et al. 2004; Maviel et al. suggestive of a time-dependent reorganiza-
2004). Direct transfer of information from the tion and stabilization of neocortical networks.
hippocampus to the cortex is not thought to However, given the uncertainty about which
occur in consolidation. However, the process factors influence temporal gradients of be-
of cortical stabilization may require guidance, havioral memory (Broadbent and Clark 2013),
whether the stabilization involves synaptogene- caution is also appropriate in the case of IEG
sis or persistent changes in synaptic strength in measures. That time-dependent changes are
the cortex. One suggestion for this process is the observed in IEG expression is clear. Less clear
idea of a tagging process at neocortical syn- is what these changes correspond to in terms
apses (Lesburgueres et al. 2011). Tagging refers of underlying memory processes. For example,
to a local, posttranslational change in cortical c-fos activation likely reflects increased neural
neurons that occurs in parallel with memory activity at the time of retrieval, but this acti-
encoding. vation does not necessarily measure retrieval
Using a social transmission of food-prefer- itself. Although there was no opportunity for
ence paradigm in which a demonstrator ani- new fear learning during the retrieval tests
mal teaches an observer animal which foods (because reexposure to the training context
are safe to eat, these investigators explored the was not accompanied by additional presenta-
idea that neurons might undergo a tagging tions of the unconditional shock stimulus), it
process in the orbitofrontal cortex at the time is nevertheless possible that retrieval could be
of memory encoding. This process would help associated with new encoding (of the retrieval
to ensure that the gradual, hippocampus-driven test itself, for example). That is, what is proce-
rewiring of cortical networks, which ultimate- durally a retrieval paradigm (Wheeler et al.
ly support long-term memory, is directed ap- 2013) might reflect gene expression associated
propriately. Using a combination of lesions with retrieval-related encoding.
and pharmacological interventions, these stud- IEG expression in the hippocampus and
ies established that tagging was amino-3-(5- cortex has also been measured as animals ex-
methyl-3-oxo-1,2-oxazol-4-yl) propanoic acid press a learned schema in the event arena or
(AMPA)- and N-methyl-D-aspartate receptor are required to assimilate new information
dependent, information-specific, and capable (Tse et al. 2011). In that study, two IEGs, zif-
of modulating remote memory persistence by 268 and Arc, were measured and found to be up-
affecting the temporal dynamics of hippocam- regulated throughout consolidation-relevant
pal cortical interactions. The concept emerg- midline regions of the neocortex at the time of
ing from these studies is in line with standard memory encoding, broadly similar to the areas
consolidation theory. Specifically, the concept is identified in earlier work at long time periods

after learning (Frankland and Bontempi 2005). downscaling is thought to be a more local pro-
The magnitude of the increase for these IEGs cess, which is locally initiated and regulated.
was related to how readily the new information What mechanisms are responsible for mem-
would later be expressed, that is, how easily it ory traces becoming consolidated during sleep?
would be assimilated into the existing and acti- To initiate replay in the hippocampus, a slow
vated knowledge structure if the full period of oscillation starts in the prefrontal cortex, con-
consolidation had been allowed to take place. sisting of an alternation between states of gen-
These findings support the possibility, raised eralized cortical excitation and depolarized
earlier (Lesburgueres et al. 2011), that cortical membrane potentials (UP states) and general-
tagging helps promote the neocortical consoli- ized states of relative neuronal silence (DOWN
dation process. They are also consistent with the states). This oscillation, as seen in intracranial
idea, derived from studies of amygdala-depen- recordings of patients being evaluated for epi-
dent fear conditioning, that neurons are recruit- leptic surgery, travels across the brain to the
ed into a memory trace as a function of neuro- medial temporal lobe (Nir et al. 2011), where
nal excitability (Yiu et al. 2014). it is followed by sharp wave ripples in the hip-
Another and distinct window onto putative pocampus. During sharp wave ripples, 30% of
consolidation mechanisms comes from neuro- hippocampal neurons increase their firing rate,
physiological recordings from relevant neuronal and the replay of sequential firing of neurons
ensembles of the hippocampus and neocortex that encode, for example, previous spatial expe-
during sleep. It has been proposed that con- riences occurs in a temporally compressed form
solidation occurs specifically during NREM (Wilson and McNaughton 1994). Hippocampal
sleep (Jenkins and Dallenbach 1924; Marr replay was first observed in the rat when place
1971; Smith 1996). Two mechanisms have since cells were seen to fire during sleep in the same
been proposed. One is replay, the reactivation sequence as they fired on a linear track when
of patterns of network activity that had oc- the rat was actually running (Wilson and Mc-
curred during previous experience and that Naughton 1994). Since then, many other inter-
are thought to lead to potentiation of relevant esting attributes of sharp wave ripples and re-
synaptic connections in the cortex. Replay starts play have been reported. Replay occurs 7 10
in the hippocampus and propagates to the cor- times faster than the original experience (Eu-
tex, with reprocessing there to extract statistical ston et al. 2007) and seems to be homeostati-
overlap from different encoding episodes (Wil- cally regulated. The increased appearance of
son and McNaughton 1994; Diekelmann and sharp wave ripples after their disruption is
Born 2010; Battaglia et al. 2012; Genzel et al. seen only after a significant learning period (Gi-
2014). The other suggested mechanism for rardeau et al. 2014). Further, the type of neural
consolidation during sleep is downscaling network being activated during replay, that is,
with sleep homeostatically but nonspecifically the specific memory, can be recognized by the
regulating synaptic weights to improve the sig- typical morphology of the ripple (Reichinnek
nal-to-noise ratio of memory traces (Tononi et al. 2010), and longer memories seem to be
and Cirelli 2006, 2014). The combined push replayed across multiple sharp wave ripples
pull action of replay on the one hand (push (Davidson et al. 2009). By recording neuronal
equals potentiating important traces) and firing patterns in the prefrontal cortex at choice
downscaling on the other (pull equals weak- points in a maze and during sleep, it has been
ening irrelevant traces) may together aid the shown that hippocampal replay during sleep
construction and updating of memory networks (but not during the awake state) is directly com-
in the cortex (Diekelmann and Born 2010; municated to the prefrontal cortex. As a result,
Lewis and Durrant 2011; Genzel et al. 2014). there is simultaneous expression in the hippo-
Sleep replay seems to be a widespread phenom- campus and prefrontal cortex of learning-as-
enon requiring participation and cooperation sociated neural firing patterns (Peyrache et al.
among many different brain areas, whereas 2009). Evidence for replay has also been found

L.R. Squire et al.
in other brain areas, including the striatum, or mediate aspects of systems memory consol-
motor cortex, and visual cortex (Euston et al. idation, as now shown with 2-DG, immediate
2007; Ji and Wilson 2007; Aton et al. 2009; Lan- early gene mapping, and electrophysiological
sink et al. 2009; Yang et al. 2014). Additionally, recordings. New technologies, notably optical
if sharp-wave ripples are followed by neocortical recording, offer the opportunity to study these
spindles, secondary larger waves of increased changes dynamically in large numbers of neu-
firing rates can be observed in the cortex (Wier- rons. This approach might require a head-fixed,
zynski et al. 2009). At the same time, by com- virtual-reality paradigm that could be used over
paring unit firing in the cortex and hippocam- the time periods after learning when consolida-
pus during spindles, it was observed in one tion occurs.
study that the cortex became functionally de-
afferented from hippocampal inputs during
sleep spindles (Peyrache et al. 2011). Spindles THE USE OF MOLECULAR GENETIC
TECHNIQUES TO ILLUMINATE
may also play an additional but separate role in
MECHANISMS OF HIPPOCAMPAL
local cortical processing during sleep, which is
NEOCORTICAL DIALOGUE
independent of the hippocampal replay mech-
anism (Andrillon et al. 2011). New approaches are starting to use elegant in-
As discussed earlier, recent studies in hu- ducible and reversible genetic interventions to
mans have tried to increase the probability of examine systems consolidation. The focus here
replay during sleep by cueing recently learned is not on the specific molecular mechanisms
memories via smell or sound associations of consolidation (discussed elsewhere in this
(Rasch et al. 2007; Rudoy et al. 2009). In a relat- collection), but on the use of molecular engi-
ed study in rats, two running tracks were asso- neering approaches to illuminate the dynamics
ciated with distinct sounds. In this case, cueing of systems consolidation. Two studies illustrate
replay during sleep did not increase the absolute the approach.
amount of replay. Instead, cueing biased replay In one study, optogenetic inhibition of the
toward the cued content at the cost of the hippocampus was deployed to examine the in-
noncued content (Bendor and Wilson 2012). terplay of the hippocampus and neocortex,
Interestingly, replay is observed not only emphasizing the opportunity that this tech-
during sleep, but can occur during waking as nique offers for precise temporal intervention
well. Intervention studies have addressed wheth- (Goshen et al. 2011). Halorhodopsin-induced
er there are different functions of replay in sleep inhibition of area CA1 of the hippocampus re-
versus awake states by interrupting sharp wave duced the frequency of cell firing and blocked
ripples with electrical stimulation whenever the acquisition and retrieval of contextual fear
they occur (Fig. 2D). This work has hinted at conditioning. Brief optogenetic inhibition (for
the possibility that replay during sleep is im- 5 min) of hippocampus consistently interfered
portant for consolidation processes, whereas with retrieval (after 28 days, 9 weeks, and 12
awake replay is more associated with spatial weeks). In contrast, more extended pharma-
working memory and navigational planning cological and optogenetic inhibition spared re-
(Girardeau et al. 2009; Ego-Stengel and Wilson mote memory, but impaired recent memory,
2010; Jadhav et al. 2012; Pfeiffer and Foster revealing a temporal gradient (Fig. 2E). Brief
2013). However, both awake and sleep replay inhibition of CA1 resulted in a decreased c-fos
do seem to contribute to later memory perfor- expression at recall in both CA1 and the anterior
mance (Dupret et al. 2010), with awake replay, cingulate cortex (ACC), whereas extended in-
perhaps, serving to initially stabilize memory hibition decreased expression in CA1, but in-
but with sleep replay operating in association creased expression in ACC. These results could
with systems consolidation. mean that prolonged inhibition allows for
To summarize, there are time-dependent compensatory activity to develop and that this
changes in physiological function that relate to compensatory activity supports remote memo-

ry performance. An alternative is that probe bypassed if another (exogeneous) method is

longed inhibition allows nonspecific effects of used to activate the appropriate subset of neo-
the inhibition to wear off and remote memory cortical neurons. Whereas the method of by-
to be successfully expressed. passing the hippocampus is artificial, this is an
The concept of rapid cortical tagging (Les- important proof-of-principle study establishing
burgueres et al. 2011; Tse et al. 2011) suggests that memory traces in the cortex are sufficient
that, even if the hippocampus is normally en- for memory expression.
gaged for a short period for binding disparate
cortical networks during memory encoding CONCLUSIONS
and the early stages of consolidation, a memory
trace of some kind is rapidly formed in the cor- Evidence for memory consolidation has accu-
tex. The cortical trace in this case corresponds mulated in the laboratory and the clinic for
to the episodic memory-like trace that was more than 100 years. Yet, quantitative studies
formed during the initial experience and not of retrograde amnesia began only in the 1970s,
to a gist-memory trace. This trace may ordinar- and the idea that consolidation involves a dia-
ily require co-occurrent activity in the hippo- logue between the hippocampus and neocor-
campus for behavioral expression during the tex is even more recent. Information is stored
initially in both the hippocampus and neo-
consolidation period, but this involvement of
cortex, and the hippocampus then guides a
the hippocampus might be mimicked optoge-
gradual process of reorganization and stabili-
netically. That is, if the role of the hippocampus
zation whereby information in the neocortex
during the consolidation period is to engage
eventually becomes independent of the hippo-
cortical neurons selectively during the stabiliza-
campus. This is the so-called standard model of
tion process, this function of the hippocampus
memory consolidation depicted in Figure 3A.
might be achieved optogenetically by selectively
It is now known that the rate of this process de-
activating those cortical neurons that are in-
pends on the extent to which new information
volved in the memory.
can be related to preexisting knowledge, such as
A relevant step forward has used context fear
networks of connected neurons called sche-
conditioning and tet-TAG mice in which c-fos
mas (Fig. 3B). Consolidation occurs for both
is used to drive the insertion of a channelrho-
facts and events and for both spatial and non-
dopsin-like protein into learning-activated cells
spatial information, although it appears to be
(Cowensage et al. 2014). A subset of neurons in masked in tasks that depend prominently on
the retrosplenial cortex (RSC) was tagged in this spatial navigation (e.g., the water maze in ro-
way during context fear conditioning. Subse- dents), as the integrity of the hippocampal for-
quently, it was possible to activate just this sub- mation is required for memory expression. Mo-
set of RSC cells optogenetically (despite diffuse lecular genetic tools, including optogenetics and
light activation of all cells) because only those metabolic markers, are now being used to ex-
neurons were activated that had been firing at plore further the mechanisms by which consol-
the time of cortical memory encoding and had, idation occurs.
therefore, expressed c-fos. The mice showed el-
evated freezing in response to the light, an ob-
servation made even more secure through the ACKNOWLEDGMENTS
use of a context discrimination procedure (rem- This work is supported by the Medical Research
iniscent of Wiltgens work cited earlier). In- Service of the Department of Veterans Affairs
creased freezing was also observed in response (L.R.S.), The National Institute of Mental
to light activation of the RSC network when Health (NIMH) Grant 24600 (L.R.S.), an Ad-
the hippocampus was simultaneously inactivat- vanced Investigator Grant (Project 268800-
ed with lidocaine (Fig. 2F). Thus, although the NEUROSCHEMA) from the European Re-
hippocampus may ordinarily serve to guide the search Council (R.G.M.), and a postdoctoral
process of neocortical stabilization, its role can fellowship from Society-in-Science (L.G.).

L.R. Squire et al.
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Larry R. Squire, Lisa Genzel, John T. Wixted and Richard G. Morris
Cold Spring Harb Perspect Biol 2015; doi: 10.1101/cshperspect.a021766
Subject Collection Learning and Memory
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Larry R. Squire1,2,3, Lisa Genzel4, John T. Wixted3, and Richard G. Morris4

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developed a memory impairment at a known from studies of autobiographical memory are

the childhood environment: patient E.P. in Teng

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L.R. Squire et al.

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L.R. Squire et al.

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L.R. Squire et al.

A Object discrimination (monkey) B Fear conditioning (rat)

Time spent freezing (s)

E Fear conditioning (mouse) F Fear conditioning (mouse)

Time spent freezing (%)

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L.R. Squire et al.

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L.R. Squire et al.

A Standard systems consolidation

Behavior Controls Network

Recent Remote Hippocampus Hippocampus

B Systems consolidation with schema

Recent Remote Hippocampus Hippocampus

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L.R. Squire et al.

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L.R. Squire et al.

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ry performance. An alternative is that pro- be bypassed if another (exogeneous) method is

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L.R. Squire et al.

REFERENCES training protocol, training-surgery interval, lesion size,

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L.R. Squire et al.

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Cold Spring Harb Perspect Biol 2015; doi: 10.1101/cshperspect.a021766

Subject Collection Learning and Memory

Memory Consolidation The Striatum: Where Skills and Habits Meet

For additional articles in this collection, see http://cshperspectives.cshlp.org/cgi/collection/

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