Sequence Memory in the Hippocampal–Entorhinal Region

Jacob L. S. Bellmund1, Ignacio Polti2, and Christian F. Doeller1,2

Abstract

■ Episodic memories are constructed from sequences of events.
When recalling such a memory, we not only recall individual events,
but we also retrieve information about how the sequence of events
unfolded. Here, we focus on the role of the hippocampal–entorhinal
region in processing and remembering sequences of events, which
are thought to be stored in relational networks. We summarize evi-
dence that temporal relations are a central organizational principle
for memories in the hippocampus. Importantly, we incorporate novel
insights from recent studies about the role of the adjacent entorhinal
cortex in sequence memory. In rodents, the lateral entorhinal

subregion carries temporal information during ongoing behavior.
The human homologue is recruited during memory recall where
its representations reflect the temporal relationships between events
encountered in a sequence. We further introduce the idea that the
hippocampal–entorhinal region might enable temporal scaling of
sequence representations. Flexible changes of sequence progression
speed could underlie the traversal of episodic memories and mental
simulations at different paces. In conclusion, we describe how the
entorhinal cortex and hippocampus contribute to remembering
event sequences—a core component of episodic memory. ■

INTRODUCTION

Episodic memories are classically thought to comprise infor-
mation about specific events as well as about where and when
these events occurred (Tulving, 1972, 1983). Recalling such
an episodic memory is characterized by a vivid feeling of
recollection—famously referred to as “mental time travel”
(Tulving, 1983, 2002). However, episodes do not occur in
isolation but rather in a sequence. Think back to an event
that happened earlier today. For example, you might re-
member meeting your colleague upon arriving at work this
morning: You had just locked your bike and entered the
building before exchanging a few words with her. Then,
you climbed the stairs to the third floor and made your
way to your office. The events that precede and follow an
event are important for defining its temporal context.
Sequence information such as relative times of occurrence
can support memory for when events took place (Friedman,
1993). This can happen in concert with distance information
like the decaying strengths of memory traces or differences
in the accessibility of items that were stored in memory at
different times. Furthermore, location information in the
form of temporal tags or general contextual associations
can be encoded with the event and underlie memory for
when events occurred (Friedman, 1993). Here, we aim to

This article is part of a Special Focus deriving from a symposium
at the 2019 annual meeting of Cognitive Neuroscience Society,
entitled, “Mental Models of Time.”
1Max Planck Institute for Human Cognitive and Brain Sciences,
Leipzig, Germany, 2Kavli Institute for Systems Neuroscience,
Centre for Neural Computation, The Egil and Pauline Braathen
and Fred Kavli Centre for Cortical Microcircuits, Norwegian
University of Science and Technology, Trondheim, Norway

review the role of the hippocampus and entorhinal cortex
in the formation and retrieval of sequence memories.

The hippocampal–entorhinal region, situated in the medial
temporal lobe of the human brain, is thought to be central
for episodic memory. Theoretical accounts suggest that it
forms networks of related experiences, for example, the differ-
ent elements of an event sequence (Eichenbaum, Dudchenko,
Wood, Shapiro, & Tanila, 1999; Eichenbaum & Cohen, 1988).
Different events occurring in temporal proximity can be
linked together in relational networks (Eichenbaum et al.,
1999; Eichenbaum & Cohen, 1988). Associating event details
with contextual information—constituted, for example, by
the time and place at which an event takes place—has been
suggested as a key contribution of the hippocampus to
episodic memory (Diana, Yonelinas, & Ranganath, 2007;
Eichenbaum, Yonelinas, & Ranganath, 2007). Other accounts
have proposed the role of the hippocampus to lie in the gen-
eration of content-free sequences (Buzsáki & Tingley, 2018;
Friston & Buzsáki, 2016). A representation of an event se-
quence might then emerge from associations of these se-
quential states with particular content in neocortical regions
(Friston & Buzsáki, 2016).

How does the brain keep track of how events unfold over
time to allow remembrance of event sequences? In keeping
with its key role in episodic memory and sequence processing
in general, we will center this review on the human hippocam-
pal formation. Specifically, we will focus on recent neuroimag-
ing work investigating the hippocampus and entorhinal
cortex. We further incorporate insights from intracranial re-
cordings in patients as well as theoretical work and findings
from animal models of temporal processing. Where a compre-
hensive description of the different aspects of temporal coding
and memory is beyond the scope of this article, we refer the
reader to insightful reviews.

Journal of Cognitive Neuroscience 32:11, pp. 2056–2070
https://doi.org/10.1162/jocn_a_01592

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We begin by summarizing findings that implicate the hip-
pocampus in the formation and retrieval of sequence mem-
ories. We argue that correlations of activity patterns reflect
sequence information. Subsequently, we will briefly review
recent studies suggesting that sequence representations in
the hippocampal formation include information about the
precise duration of the temporal structure of the sequence.
Next, we shift our focus to the entorhinal cortex as a major
cortical input to the hippocampus. Importantly, we highlight
recent evidence suggesting that the anterior–lateral subre-
gion of the entorhinal cortex is particularly relevant for
temporal processing. We thus emphasize the role of the
entorhinal cortex—in concert with the hippocampus—in
sequence memory. Furthermore, we introduce the idea of
temporal scaling, which has been described for sensory and
motor timing and the corresponding cortical networks.
Specifically, we suggest that the flexible adaptation of se-
quence progression speed, in episodic memory and mental
simulation, is supported by the hippocampal–entorhinal
region. Finally, we present outstanding questions for future
research that emerge from these findings and ideas.

SEQUENCE MEMORY AND
THE HIPPOCAMPUS

The role of the hippocampus in the formation and retrieval
of memories for temporal and sequence information is well
established (for reviews, see, e.g., Ranganath & Hsieh, 2016;
Eichenbaum, 2014). Here, we primarily focus on work in hu-
mans, although the fundamental role of the hippocampus in
sequence memory is also well documented in animals
(Eichenbaum, 2017; Fortin, Agster, & Eichenbaum, 2002;
Kesner, Gilbert, & Barua, 2002). In studies using fMRI, hip-
pocampal activations have been observed when participants
learned stimulus sequences (Ross, Brown, & Stern, 2009;
Kumaran & Maguire, 2006a) or completed serial RT tasks
(Schendan, Searl, Melrose, & Stern, 2003). Likewise, hippo-
campal activity is increased for temporal information that is
later successfully recalled from memory (Tubridy &
Davachi, 2011; Jenkins & Ranganath, 2010). One such study
analyzed activity during the delay period of a serial order
working memory task as a function of later memory for
when individual stimuli were encountered. After the presen-
tation of the stimulus sequence, greater hippocampal activ-
ity related to more accurate subsequent memory for the
temporal position of stimuli (Jenkins & Ranganath, 2010).
Consistently, hippocampal activity during encoding pre-
dicted serial recall for items encountered at event bound-
aries, defined by stimulus category switches, suggesting a
role for the hippocampus in linking different event se-
quences (DuBrow & Davachi, 2016).

These reports of increased hippocampal activity during
the encoding of temporal information that was later remem-
bered are complemented by studies of brain activity during
the retrieval of sequence order. For example, when partic-
ipants recalled the order of scenes from a movie, the hip-
pocampus was more strongly engaged than in a baseline

condition or when participants logically inferred the order
of scene stimuli (Lehn et al., 2009). Likewise, hippocampal in-
volvement in retrieving the order of events during navigation
(Lieberman, Kyle, Schedlbauer, Stokes, & Ekstrom, 2017;
Ekstrom, Copara, Isham, Wang, & Yonelinas, 2011; Ekstrom
& Bookheimer, 2007) or retrieving the next element to com-
plete a learned sequence (Ross et al., 2009) has also been
observed. Collectively, these findings suggest that both suc-
cessful encoding and retrieval of event sequences recruit the
hippocampus.

PATTERN CORRELATIONS REFLECT
SEQUENCE INFORMATION

One way by which the hippocampus could support memory
for temporal relationships is by segregating representations
of events that were originally separated in time. For exam-
ple, the activity of neuronal ensembles in the medial tempo-
ral lobe changes over time, resulting in similar population
signals for nearby points in time and more dissimilar neural
patterns at increased time lags (Folkerts, Rutishauser, &
Howard, 2018; Howard, Viskontas, Shankar, & Fried, 2012).
Slowly drifting signals might arise from decaying traces of
prior experiences or because of changing internal states. In
models of episodic memory, these signals serve as contextual
representations that allow the tagging of individual memo-
ries (Howard, Fotedar, Datey, & Hasselmo, 2005; Howard
& Kahana, 2002). The current state of these contextual rep-
resentations could be incorporated into the mnemonic rep-
resentation of an event occurring at a certain moment,
putatively facilitating memory for how a sequence of events
unfolded over time. Consistent with the notion that changing
neural patterns relate to sequence memory, hippocampal ac-
tivity patterns during the encoding of object sequences were
less similar, when the order of object pairs was remembered
correctly in a later memory test (Jenkins & Ranganath, 2016).
Furthermore, increased correlations of hippocampal multi-
voxel patterns between stimuli were related to remembering
these stimuli as being relatively close in time, compared to
stimuli separated by the same temporal distance that were
judged to be far apart (Ezzyat & Davachi, 2014; Figure 1A).
However, when participants use associative strategies to en-
code stimulus sequences, increased similarity of hippocam-
pal representations has been reported for items whose order
was later discriminated correctly (DuBrow & Davachi, 2014,
2017). This points toward an influence of encoding strategies
on the way hippocampal activity relates to memory for order.
Together, these data and theoretical considerations suggest
that hippocampal activity patterns at encoding support
memory by providing a temporal context representation
allowing the encoding of sequence relationships.

Interestingly, hippocampal activity patterns also carry in-
formation about temporal context and the temporal relations
of events during retrieval. Paralleling behavioral contiguity ef-
fects during the recall of word lists, reinstatement of medial
temporal lobe activity patterns observed during encoding
accompanies the successful recall of information from

Bellmund, Polti, and Doeller

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Figure 1. Sequence memory in the hippocampus and the entorhinal cortex. (A) In an associative learning task, participants saw trial-unique images
of faces or objects paired with scene stimuli defining the context for a sequence of images. In a memory test, they were subsequently asked to
indicate the temporal distances between pairs of images on a 4-point scale. Pattern similarity in the left hippocampus during encoding was higher for
pairs of stimuli subsequently judged to be (very) close together than for those judged to be (very) far apart. Adapted with permission from Ezzyat and
Davachi (2014). (B) Participants navigated a virtual city along a fixed route (blue) to learn where in space, and when during this sequence, they
encountered specific objects (blue circles). Spatial (measured by Euclidean distances and shortest paths) and temporal (measured by walking times)
distances between object pairs were decorrelated using teleporters (pink and purple circles). The similarity of object representations was assessed
before and after learning. Hippocampal representational change correlated with remembered spatial and temporal distances between object pairs.
Adapted from Bellmund et al. (2019) and Deuker et al. (2016), both licensed under CC-BY. (C) While undergoing fMRI scanning, participants
monitored the stimulus order of four-element sequences of scene images. The order of images and the ISIs were varied independently. Hippocampal
pattern similarity was greatest when order and ISI of the test sequence matched the study sequence. Adapted with permission from Thavabalasingam
et al. (2018). (D) After having watched an episode from a TV show, participants saw still frames from the episode and indicated on a timeline when
the presented scene occurred. Activity in the anterior-lateral entorhinal cortex was modulated by the precision of memory recall such that activity was
greater for trials where participants responded most compared to least accurately. This modulation was not observed in the posterior-medial
entorhinal cortex. Adapted with permission from Montchal et al. (2019). (E) In the experiment outlined in B, pattern similarity change, in the
anterior-lateral entorhinal cortex, reflected the temporal relationships of objects from the sequence, which were measured by participants’ walking
times between them. This effect was selective to the anterior-lateral entorhinal cortex. Adapted from Bellmund et al. (2019), licensed under CC-BY.

memory (Folkerts et al., 2018; Yaffe et al., 2014; Howard
et al., 2012; Manning, Polyn, Baltuch, Litt, & Kahana, 2011).
In these studies, neural activity patterns during item recall
correlated with those observed during encoding, not only
of the recalled item but also of those preceding and follow-
ing it during learning (Folkerts et al., 2018; Yaffe et al.,
2014; Howard et al., 2012; Manning et al., 2011).

The analysis of fMRI multivoxel patterns further suggests
that hippocampal activity in response to retrieval cues carries
information about the temporal relationships of memories.
In one study, participants navigated a virtual city along a fixed
route and learned when they encountered certain objects
(Deuker, Bellmund, Navarro Schröder, & Doeller, 2016;
Figure 1B). In a postlearning fMRI scan, they were presented

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Volume 32, Number 11

with images of these objects in random order. Pattern simi-
larity in the anterior hippocampus correlated negatively with
the temporal distances by which participants remembered
the objects to be separated. Relative to a prelearning baseline
scan, the representations of pairs of objects that were re-
membered as being close in time became more similar,
whereas objects separated by large temporal distances be-
came more dissimilar (Deuker et al., 2016). Consistent re-
sults were observed in a study in which participants judged
temporal relations of location triads, visited in a delivery task
(Kyle, Smuda, Hassan, & Ekstrom, 2015). Furthermore, the
relationship between multivoxel pattern similarity in the an-
terior hippocampus and the temporal distances of events
was also demonstrated in a study in which participants
viewed photographs of real-life events, which were taken
with life-logging devices over the course of a month. This
provides encouraging evidence suggesting that the anterior
hippocampus represents temporal relations also between
naturalistic events encountered outside the controlled set-
ting of laboratory studies (Nielson, Smith, Sreekumar,
Dennis, & Sederberg, 2015). Furthermore, hippocampal ac-
tivity patterns have been shown to reflect conjunctions of
item information and sequence position (Hsieh, Gruber,
Jenkins, & Ranganath, 2014). Collectively, these studies sug-
gest that hippocampal activity patterns during retrieval carry
information about the relative sequence position at which
different events were encountered.

One possibility for how such effects could arise is that
related events are reactivated when recalling a memory.
In line with this, during recency judgments, lower classifier
evidence for the visual category of two items has been
reported, if these items were separated by items from a dif-
ferent compared to the same category in the encoding
sequence (DuBrow & Davachi, 2014). Classifier evidence
was correlated with multivoxel pattern similarity during
retrieval and encoding of intervening items from the same
category. Together with behavioral priming effects, this has
been interpreted as reinstatement of associative links be-
tween items during memory recall of temporal relations
(DuBrow & Davachi, 2014). Associative retrieval of related
memories might explain why hippocampal representations
at retrieval reflect temporal relationships.

Despite our lives progressing continuously, we typically
remember segregated episodes from our experience. The
Event Horizon Model describes how ongoing experience is
segmented into sequences of discrete events (Radvansky &
Zacks, 2014). Currently active event models influence mne-
monic processing and are stored in long-term memory
when event boundaries are encountered (Zacks, 2020;
Radvansky & Zacks, 2014). Brain areas at different levels
of the cortical hierarchy process event boundaries at varying
timescales (Baldassano et al., 2017). Evidence suggests that
event boundaries exert a strong influence on sequence
memory, including memory for the order of events, as well
as estimates of temporal distances and duration (Bangert,
Kurby, Hughes, & Carrasco, 2019; Faber & Gennari, 2015,
2017; Ezzyat & Davachi, 2014; for a review, see Clewett,

DuBrow, & Davachi, 2019). In a study where participants
watched a movie consisting of two interleaved narratives,
reflecting alternative storylines involving the same characters
and locations, hippocampal representations differentiated
the two event sequences. Specifically, hippocampal multi-
voxel patterns diverged gradually as the narratives unfolded
(Milivojevic, Varadinov, Grabovetsky, Collin, & Doeller,
2016). Notably, regions of the default network can integrate
narrative information on timescales of around 30 sec, even
when the hippocampus is severely damaged (Zuo et al.,
2020). However, successful memory encoding and retrieval
of event sequences might require interactions with the hip-
pocampus. Consistent with the notion that the hippocampus
supports the grouping of related events from a sequence,
data from statistical learning paradigms demonstrate that
multivoxel pattern representations of events likely to occur
close in time become more similar after repeated expo-
sure (Schapiro, Turk-Browne, Norman, & Botvinick,
2016; Schapiro, Kustner, & Turk-Browne, 2012). Activity
profiles of the dentate gyrus are sensitive to repetitions
of the same spatio-temporal sequence, in line with a role
of the hippocampus in discriminating different sequences
(Azab, Stark, & Stark, 2014). Together, these data impli-
cate the hippocampus in both relating elements of a
sequence to each other and distinguishing different
sequences separated by event boundaries.

INCORPORATING DURATION IN
HIPPOCAMPAL SEQUENCE PROCESSING

The above findings establish a central role for the hippocam-
pus in tracking sequences of events for episodic memory.
However, the fidelity with which event sequences are repre-
sented in the hippocampus is less clear. Behavioral work
suggests that the durations of sequence elements can be
accurately remembered for events that can be recollected
(Brunec, Ozubko, Barense, & Moscovitch, 2017). Under
most circumstances, events separated by a longer temporal
interval are also separated by a larger number of intervening
events. This makes it difficult to study whether and how in-
formation about the relative duration of events or the pre-
cise intervals separating sequence elements influences
hippocampal sequence processing. Nevertheless, recent
evidence suggests that the hippocampus processes time
intervals and that it potentially incorporates duration infor-
mation in sequence representations.

The discovery of sequentially active cells in rodents is cen-
tral to the notion that the hippocampus forms precise repre-
sentations of intervals. These cells were described in animals
running in place throughout the delay periods of working
memory tasks (MacDonald, Lepage, Eden, & Eichenbaum,
2011; Pastalkova, Itskov, Amarasingham, & Buzsáki, 2008).
Over the course of the delay, these cells fire in a fixed se-
quence. In different repetitions of the interval, the same cells
become active at approximately the same points in time,
with respect to the beginning of the delay. Hence, these cells
are often referred to as time cells (Eichenbaum, 2014;

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MacDonald et al., 2011). Building on the fine-grained infor-
mation these cell assemblies carry about elapsed time, time
cells have been suggested as a potential mechanism to
incorporate temporal information in episodic memory (for
review, see Eichenbaum, 2014, 2017). Currently, this is a dif-
ficult idea to test as conscious recollection of past experi-
ences is extremely difficult, if not impossible, to assess in
animals. Theoretical accounts have linked properties of time
cells to a scale-invariant compression of memory for time,
which could allow them to serve as a mechanism for temporal
coding at different timescales (Liu, Tiganj, Hasselmo, &
Howard, 2019; Howard, 2018). Thus, time cells could equip
hippocampal sequence representations with duration
information.

In line with the idea that the hippocampus enables duration
encoding, recent studies of amnesic patients with damage to
the medial temporal lobe suggest that the hippocampus con-
tributes to duration estimates (Palombo et al., 2020; Palombo
& Verfaellie, 2017; Palombo, Keane, & Verfaellie, 2016). In one
such study, patients watched videos and judged their dura-
tions in a forced-choice task. For videos of 4 min or more—
but not for short videos of 90 sec or less—the patients re-
sponded less accurately than matched control participants
(Palombo et al., 2016). Next to this contribution to prospec-
tive duration estimates in the context of long intervals, dam-
age to the medial temporal lobe also impairs duration
estimates in the range of seconds, if events are part of a se-
quence (Palombo et al., 2020). Here, participants watched
pinwheels spin for variable durations. This was followed by
test stimuli moving for the same or a different amount of
time. Amnesic patients performed worse than matched con-
trols. Notably, this effect only emerged for durations that
were part of a sequence of two spins and not for the dura-
tion of individual events (Palombo et al., 2020). Together,
these data suggest hippocampal damage can impair
memory for the duration of event sequences or the in-
dividual elements of a sequence.

Converging evidence from neuroimaging studies further
demonstrates that hippocampal responses to stimulus sequences
are sensitive to duration information (Thavabalasingam, O’Neil,
Tay, Nestor, & Lee, 2019; Thavabalasingam, O’Neil, & Lee,
2018; Barnett, O’Neil, Watson, & Lee, 2014). Specifically, these
studies manipulated the duration of intervals separating
the elements of image sequences. Contrasting hippocampal
activity patterns from a study sequence with the subsequent
test sequence revealed higher pattern similarity when stim-
ulus order and ISIs at test matched. Pattern similarity was
lower if test sequences consisted of the same stimuli in iden-
tical order, but with changed ISIs (Thavabalasingam et al.,
2018; Figure 1C). Follow-up work demonstrated a similar
effect in an adaptation of the paradigm to long-term mem-
ory (Thavabalasingam et al., 2019). Participants studied
four sequences of three images each. The same or differ-
ent stimuli were presented with the same or different ISIs.
During later recall, individual sequences could be decoded
from activity patterns in the anterior hippocampus, whereas
the classification of interval duration and stimulus identity

alone did not exceed chance levels. This suggests that the
anterior hippocampus combines information about stimu-
lus identity and duration (Thavabalasingam et al., 2019).
Together, these studies suggest that the human hippocampus
is sensitive to the duration of intervals separating the individual
elements of sequences (Lee, Thavabalasingam, Alushaj,
Çavdaroğlu, & Ito, 2020).

In summary, the hippocampus is involved in encoding and
retrieving temporal information (Lieberman et al., 2017;
DuBrow & Davachi, 2016; Ekstrom et al., 2011; Tubridy &
Davachi, 2011; Jenkins & Ranganath, 2010; Lehn et al.,
2009; Ross et al., 2009; Ekstrom & Bookheimer, 2007). This
is in line with its well-established role in tracking sequences
and its sensitivity to event boundaries that separate different
sequences of events (Clewett et al., 2019). Hippocampal
activity patterns reflect the temporal relations of different
events (Deuker et al., 2016; Nielson et al., 2015). One inter-
esting question concerns how faithful and precise hippocam-
pal representations of temporal relations are. On the one
hand, biases in pattern similarity for events with identical un-
derlying temporal relationships have been linked to differ-
ences in memory for these relations (Jenkins & Ranganath,
2016; DuBrow & Davachi, 2014; Ezzyat & Davachi, 2014). On
the other hand, recent work emphasizes that the hippocam-
pus is also sensitive to the precise timing between events
within a sequence (Lee et al., 2020; Palombo et al., 2020;
Thavabalasingam et al., 2018, 2019).

ENTORHINAL CORTEX CONTRIBUTIONS TO
SEQUENCE MEMORY

Most cortical inputs are relayed to the hippocampus via the en-
torhinal cortex (for reviews, see, e.g., Witter, Doan, Jacobsen,
Nilssen, & Ohara, 2017; Witter, Kleven, & Flatmoen, 2017; van
Strien, Cappaert, & Witter, 2009). This raises the possibility that
the entorhinal cortex also contributes to sequence memory.
However, its role has long been unclear. An early study ob-
served that the entorhinal cortex is sensitive to violations of
learned stimulus sequences. For example, it responded more
strongly to the latter items of a four-item sequence, when these
violated expectations based on the initial items of the sequence
(Kumaran & Maguire, 2006b). Entorhinal activity also increased
when encountering entirely unknown and novel sequences,
whereas the hippocampus responded more selectively to vio-
lations of sequence expectations, rather than novelty per se
(Kumaran & Maguire, 2006b). In line with overlapping repre-
sentations of successive stimuli from probabilistic sequences,
the entorhinal cortex might extract regularities from repeatedly
encountered sequences (Garvert, Dolan, & Behrens, 2017).

However, how does the entorhinal cortex support the
representation of event sequences for episodic memory?
It is conceivable that the entorhinal cortex provides tempo-
ral information for sequence representations. Consistent
with this, decorrelated activity patterns in the entorhinal cor-
tex during sequence processing have been related to later
memory for temporal intervals (Lositsky et al., 2016).
Over the course of 25 min, participants listened to a science

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fiction story while undergoing fMRI scanning. In a surprise
memory test, they later estimated the time that passed be-
tween pairs of events from the story, which were sepa-
rated by a constant temporal distance. During encoding,
multivoxel patterns changed more strongly for events that
participants remembered to be separated by larger time
intervals. Furthermore, activity patterns in the entorhinal
cortex changed particularly slowly in comparison to other
brain regions (Lositsky et al., 2016). These findings are in
line with contextual representations in the entorhinal cor-
tex that slowly change over time, for example, through
the encounter of different events (Lositsky et al., 2016;
Howard et al., 2005).

Anatomically, the entorhinal cortex is typically subdivided
into two subregions: the lateral and medial entorhinal cortex
in rodents (Witter, Doan, et al., 2017; van Strien et al., 2009). In
humans, these correspond to the anterior-lateral and
posterior-medial portions of the entorhinal cortex (Maass,
Berron, Libby, Ranganath, & Düzel, 2015; Navarro Schröder,
Haak, Zaragoza Jimenez, Beckmann, & Doeller, 2015). Do
the entorhinal subregions differentially contribute to temporal
processing or sequence memory? One recent study suggests
that the rodent lateral entorhinal cortex in particular carries
temporal information during ongoing behavior (Tsao et al.,
2018). Neural activity was recorded from the entorhinal cortex
of navigating rats. For a subset of cells in the lateral entorhinal
cortex, activity patterns were characterized by ramping activity
with firing rates increasing or decreasing with different time
constants (Tsao et al., 2018). Temporal epochs could be de-
coded from population activity at multiple timescales, notably
with greater accuracy in the lateral compared to the medial
entorhinal cortex and hippocampus. Importantly, this tempo-
ral information was suggested to arise through the integration
of experience from ongoing behavior and internal states, rath-
er than from an explicit clocking mechanism (Tsao et al.,
2018). The lateral entorhinal cortex might thus provide an in-
herent code for the temporal progression of experience,
which could potentially subserve the formation of sequence
representations for episodic memory (Sugar & Moser, 2019;
Tsao et al., 2018; Tsao, 2017).

This potential role of the lateral entorhinal cortex in sequence
memory has been investigated in humans. Importantly, recent
neuroimaging studies indeed implicated the anterior-lateral sub-
region of the human entorhinal cortex in sequence memory
(Bellmund, Deuker, & Doeller, 2019; Montchal, Reagh, &
Yassa, 2019), thus offering a novel perspective on the role
of the entorhinal subregions in episodic memory. In one
study, participants were shown snapshots from an episode
of a sitcom and were asked to indicate when, over the course
of the episode, they had seen each scene (Montchal et al.,
2019). The anterior-lateral entorhinal cortex, together with
a network of brain regions including the hippocampus, the
medial pFC, posterior cingulate cortex, and angular gyrus,
was more engaged when more accurately recalling the tem-
poral position of a scene (Figure 1D). Notably, the
posterior-medial entorhinal cortex was not modulated by
memory accuracy (Montchal et al., 2019). These findings

suggest that anterior-lateral entorhinal cortex activity sup-
ports mnemonic precision for when specific events oc-
curred during a sequence.

What contribution does the anterior-lateral entorhinal cor-
tex make to sequence memory? Pattern similarity analyses sug-
gest that it carries information about the temporal
relationships between events of a sequence (Bellmund
et al., 2019). In the experiment, originally described in
Deuker et al. (2016) and briefly outlined above, participants
learned a sequence of events defined by the objects encoun-
tered when navigating a route through a virtual city (Bellmund
et al., 2019). Later, participants saw images of these objects in
random order while undergoing fMRI scanning. Remarkably,
the multivoxel pattern similarity between object pairs reflected
the temporal distance between when the respective objects
were encountered (Figure 1E). Objects encountered at near-
by sequence positions became representationally more sim-
ilar compared to objects at distant sequence positions. This
effect was specific to the anterior-lateral entorhinal cortex
and temporal distances. More specifically, it was neither ob-
served for spatial distances, measured by Euclidean distances
or the lengths of the shortest paths between positions, nor
was it detectable in the posterior-medial subregion.
Importantly, entorhinal pattern similarity was related to the
order in which participants recalled the events during a sub-
sequent and unexpected memory test. Participants, in whom
entorhinal pattern similarity resembled the sequence struc-
ture more closely, tended to recall objects together, which
were originally encountered in temporal proximity.
Furthermore, the timeline of events could be reconstructed
from multivoxel patterns in the anterior-lateral entorhinal
cortex (Bellmund et al., 2019). Together, these findings sug-
gest that anterior-lateral entorhinal cortex forms holistic rep-
resentations of the temporal relations between different
elements in an event sequence.

In sum, the evidence described above allows us to view the
role of the entorhinal cortex in sequence memory from a new
angle. Specifically, these findings suggest the lateral entorhinal
cortex and its human homologue, the anterior-lateral entorhinal
cortex, to be particularly relevant for memory of event se-
quences. Ramping cell activity and population drift in this region
carry precise temporal information. Decaying traces of prior ex-
perience in the entorhinal cortex (Bright et al., 2019; Tsao et al.,
2018) could provide information about how long ago prior
events occurred. Such a mechanism is well suited for episodic
memory because temporal information inherently arises from
experience rather than requiring repeated exposure or training.
Consequently, temporal relations can be incorporated
in mnemonic representations of event sequences. At retrieval,
representations of individual elements might thus reflect tem-
poral interrelations of the events comprising a sequence.

TEMPORAL SCALING OF EPISODIC
MEMORY SEQUENCES

The capacity to represent temporal information embedded
in the environment extends far beyond sequence memory

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in the hippocampal–entorhinal region. Precise timing is
crucial for many behaviors that do not centrally rely on
the medial temporal lobe. For example, dancing tango
requires the execution of a motor sequence consisting of
different steps. Notably, research on sensory and motor
timing has uncovered cellular and network mechanisms
underlying temporal computations in different brain
regions including the basal ganglia and the cerebellum as
well as sensory and motor cortices (Paton & Buonomano,
2018). Once the temporal structure of such a sequence is
well learned, “temporal scaling”—the flexible adaptation of
the speed of a sequence in response to internal or external
demands—becomes possible (Hardy, Goudar, Romero-Sosa,
& Buonomano, 2018; Remington, Egger, Narain, Wang, &
Jazayeri, 2018; Lerner, Honey, Katkov, & Hasson, 2014; Gütig
& Sompolinsky, 2009). Analysis of population activity in
the frontal cortex of macaques, performing a time-interval
reproduction task, demonstrates the scaling effect on the
neural level ( Wang, Narain, Hosseini, & Jazayeri, 2018).
There were two contrasting aspects of the scaling effect.
Although the shape of the trajectories in neural space was
similar for trials with the same target interval, the speed at
which activity evolved along the trajectories depended on
the produced duration (Figure 2A). However, it is unclear
if temporal scaling is observed in episodic memory net-
works in a manner similar to what has been observed in
other cognitive domains (Remington, Narain, Hosseini,
& Jazayeri, 2018; Wang et al., 2018; Mello, Soares, & Paton,
2015; Lerner et al., 2014).

To support flexible temporal scaling, a neural ensemble in
the hippocampal–entorhinal region would need to (1) re-
flect the temporal patterns elicited by externally or internally
generated sequences of stimuli upon recall and (2) tempo-
rally scale the retrieved patterns to flexibly replay the se-
quence at different speeds (Figure 2B). Temporal scaling
of a sequence of events can be advantageous in everyday life
(Boyer, 2008; Schacter, Addis, & Buckner, 2007; Suddendorf
& Corballis, 2007). Consider the way from your office to the
exit of the building. Imagine realizing that you lost your keys
on your way to the office. You might mentally traverse your
memory of arriving at work that day, at a slow pace, to figure
out where you may have dropped the keys, in between
locking your bike and entering your office. Conversely, in
case of a fire emergency, you need to quickly plan an escape
route to leave the building and therefore need to replay the
trajectory at a fast pace.

Temporal compression appears to occur automatically
when event sequences are retrieved from memory. Behavioral
experiments provide evidence that recalled sequences prog-
ress at a faster rate than the original experience. These stud-
ies suggest that recall is particularly compressed when few
contextual changes are recalled, such as turns, or when spa-
tially coherent images of a route can be mentally replayed
(Arnold, Iaria, & Ekstrom, 2016; Bonasia, Blommesteyn, &
Moscovitch, 2016). Conversely, compression is less pronounced
when details of goal-directed actions—during which con-
text is relatively constant—are remembered (Jeunehomme
& D’Argembeau, 2019; Jeunehomme, Folville, Stawarczyk,

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Figure 2. Temporal scaling of a sequence memory. (A, left) Time production task. Macaques rested their hand on a button and focused their gaze on
a square fixation spot. A trial started with a color cue indicating the target interval (red: short, 800 msec; blue: long, 1500 msec). After a random delay,
a white ring appeared around the fixation spot indicating the onset (Set) of the production interval (Tp). The offset of Tp was marked by the animal’s
response (a button press). A juice reward was given for accurate responses. (Right) Neural population activity of frontal cortex during Tp projected
onto the first three principal components (PCs). The evolution of the network state over time forms a path from “Set” to “Response.” The trajectory
of population activity follows a path of similar shape for different Tps belonging to the short (warm colors) or long (cold colors) interval. Note that
the progression speed of the trajectory (diamond shows 700 msec after Tp onset) depends on the length of Tp. Adapted from Wang et al. (2018),
licensed under CC-BY. (B, left) Schematic representation of the proposed temporal scaling of an episodic memory sequence. (Top) Sequence of
events (“A”–“E”) progressing over the course of 60 sec (color gradient). (Bottom) The same sequence of events can be compressed in time (45 sec),
allowing an agent to mentally traverse it at a faster speed. The triangles represent 30 sec from the sequence onset. (Right) State-space representation
of a population trajectory during the mental traversal of the sequence of events depicted in the left panel. The low-dimensional population trajectory
is projected onto three dimensions for visualization purposes. “A” and “E” represent the onset and offset of the event sequence, respectively. The
color gradient reflects the sequence progression over time. In an episodic memory network subserving temporal scaling, the traversal of a mental
sequence of events at different paces would be reflected in state space by trajectories with an identical shape but differing speeds. The triangles
represent 30 sec from sequence onset for the original episode (pink) and for the compressed version of it (magenta).

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Volume 32, Number 11

Van der Linden, & D’Argembeau, 2018). Indeed, the temporal
compression of episodic recall is reduced when experience
is segmented into more fine-grained events (Jeunehomme
& D’Argembeau, 2020). These findings are in line with the
role of contextual boundaries in delineating event sequences
(Bangert et al., 2019; Clewett et al., 2019; Faber & Gennari,
2015, 2017). Moreover, neuroimaging studies show varia-
tions in the amount of temporal compression between par-
ticipants (Chen et al., 2017), and there is evidence suggesting
that the variable duration of memory reactivation is because
of participants skipping sequence elements (Michelmann,
Staresina, Bowman, & Hanslmayr, 2019). In contrast, dura-
tion estimates for recalling a life-threatening situation are
expanded (Stetson, Fiesta, & Eagleman, 2007).

Clues about a potential role of the hippocampus in the scal-
ing of neural activity sequences for episodic memory are pro-
vided by studies of spatial coding. A sequence of place cells in
the hippocampus will become active as an animal traverses its
environment. Notably, comparable hippocampal sequences
have been observed in various situations and experiments
in rodents. Such studies have shown that time-varying activity
of cell assemblies in the hippocampal–entorhinal region can
be driven by either endogenous (self-organized patterning) or
exogenous (environmental and/or self-motion cues) mecha-
nisms (Buzsáki & Tingley, 2018; Tsao et al., 2018; Aronov,
Nevers, & Tank, 2017; Friston & Buzsáki, 2016; Kay et al.,
2016; Kraus et al., 2015; Modi, Dhawale, & Bhalla, 2014;
Kraus, Robinson, White, Eichenbaum, & Hasselmo, 2013;
MacDonald et al., 2011; Pastalkova et al., 2008). The sequential
firing of cells during a trajectory through space has been related
to interval timing (Issa, Tocker, Hasselmo, Heys, & Dombeck,
2020) as well as to the representation of a sequence of events
(Friston & Buzsáki, 2016; Buzsáki, Peyrache, & Kubie, 2014;
Buzsáki & Moser, 2013; Hasselmo, 2009; Byrne, Becker, &
Burgess, 2007). In line with the latter, studies using fMRI
demonstrate that hexadirectional activity modulations in
the human entorhinal cortex, elicited during active virtual
navigation (Doeller, Barry, & Burgess, 2010), are also pres-
ent when participants simulate trajectories through space
during imagined navigation (Bellmund, Deuker, Navarro
Schröder, & Doeller, 2016; Horner, Bisby, Zotow, Bush,
& Burgess, 2016). Hippocampal activity sequences might
underlie memory for episodes unfolding in time.

To speed up or slow down the progress through an episodic
memory sequence, a neural network needs to first learn the
sequence and then reproduce its temporal structure. Rodent
studies demonstrate that learned sequences of traveled paths,
represented by an evolving assembly of hippocampal neu-
rons, can be reactivated spontaneously during wakeful rest
or sleep (Karlsson & Frank, 2009; Nádasdy, Hirase, Czurkó,
Csicsvari, & Buzsáki, 1999; Wilson & McNaughton, 1994).
An important feature of this replay of past experiences is
the temporal compression of the reactivated activity patterns.
In rodents, the average speed of a replayed hippocampal se-
quence at wakeful rest tends to be ∼20 times faster than the
experienced one, ranging between 100 and 300 msec
(Ólafsdóttir, Bush, & Barry, 2018; Pfeiffer & Foster, 2015;

Davidson, Kloosterman, & Wilson, 2009; Diba & Buzsáki,
2007; Lee & Wilson, 2002). Notably, neural correlates of the
replay of learned sequences have been observed in humans
(Wimmer, Liu, Vehar, Behrens, & Dolan, 2020; Liu, Dolan,
Kurth-Nelson, & Behrens, 2019; Michelmann et al., 2019;
Kurth-Nelson, Economides, Dolan, & Dayan, 2016). Recent
studies suggest these decoded sequential patterns, which
reflect previous nonspatial experiences, may originate from
hippocampal activity (Liu, Dolan, et al., 2019; Schuck &
Niv, 2019).

The aforementioned evidence supports the idea that cell
assemblies in the hippocampus can reproduce temporally
structured activity patterns at faster speeds. However, they
do not fully demonstrate that evolving neural ensembles in
the hippocampal–entorhinal region are temporally scalable
because it is unclear whether their speed can be flexibly
adapted. During sensorimotor tasks, cell assembly sequences
in the striatum of rats (Gouvêa et al., 2015), or the frontal cor-
tex of monkeys (Remington, Narain, et al., 2018; Wang et al.,
2018), are able to adapt their rate of change in response to
external or internal demands. A similar observation has been
reported in the medial entorhinal cortex of mice performing
an instrumental timing task. Specifically, the animals’ re-
sponse timing correlated with the sequence progression
speed of a population of neurons in the medial entorhinal
cortex (Heys & Dombeck, 2018). Despite a growing amount
of studies on human spontaneous replay (Liu, Dolan, et al.,
2019; Michelmann et al., 2019; Schuck & Niv, 2019; Kurth-
Nelson et al., 2016), systematic variations in the speed of neu-
ral activity sequences during replay and memory recall have,
to the best of our knowledge, not been studied. Hence, it re-
mains to be tested whether it is possible to alter the speed of
progression through hippocampal activity sequences in re-
sponse to internal or external demands. Investigating the cor-
respondence between episodic memory retrieval and
spontaneous replay could help researchers determine how
memories are both voluntarily and implicitly temporally
scaled.

How could the rate of change of an episodic memory se-
quence be controlled? One possibility is that, in the same way
as running velocity adjusts the transition time between hippo-
campal place cell ensembles within the theta cycle (Maurer,
Burke, Lipa, Skaggs, & Barnes, 2012), an internally generated
signal could adjust the rate of change of this evolving neural
population state (Buzsáki, 2019; Buzsáki & Tingley, 2018).
Evidence consistent with this idea comes from studies show-
ing that changes in internal states such as attention (Polti,
Martin, & van Wassenhove, 2018), emotions (Droit-Volet,
2013), or even body temperature (Hancock, 1993) influence
duration estimates. Interestingly, recent work on a time-cell
model has demonstrated how the temporal scale of a se-
quence can be modified, resulting in sequences progressing
at different speeds (Liu, Tiganj, et al., 2019). Similar temporal
rescaling was observed in a subset of time cells after changes
of the delay duration, although most cells unpredictably
changed their activity profile in response to this alteration
(MacDonald et al., 2011). Notably, temporal scaling of

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sequence memories might be reflected in changes of the
speed at which mnemonic trajectories are traversed
(Buzsáki et al., 2014; Buzsáki & Moser, 2013; Hasselmo,
2009; Byrne et al., 2007).

Taken together, the available experimental evidence sug-
gests that the temporal scaling of episodic memory se-
quences can be supported by the population activity of
neurons in the hippocampal–entorhinal region. Future re-
search could build on this new perspective and aim to un-
derstand the mechanisms that drive the flexible dynamics of
this mnemonic network. Furthermore, it would help to
elucidate how humans are able to voluntarily stretch or
compress episodic memories and which role the hippo-
campus and entorhinal cortex play in the temporal scaling
of event sequences.

OUTSTANDING QUESTIONS

In this review, we have summarized the established role of
the hippocampus in temporal processing and incorporated
recent evidence demonstrating contributions of the ento-
rhinal cortex to sequence memory. In the following, we out-
line some questions that emerge from this new perspective
on the medial temporal lobe memory system. The first
question concerns the way the hippocampus and entorhi-
nal cortex interact when processing sequences of events.
Theoretical work has, for instance, demonstrated that time
cells in the hippocampus might arise from entorhinal time
ramping cells or decaying traces of prior experience (Liu,
Tiganj, et al., 2019; Rolls & Mills, 2019; Howard et al., 2014;
Shankar & Howard, 2012), yielding testable predictions for
future studies. With respect to human memory, elucidat-
ing commonalities and differences between hippocampal
and entorhinal representations poses an intriguing ques-
tion along with the challenge of understanding how they
emerge during learning.

Although we focused mostly on the lateral entorhinal cor-
tex, prior work has also reported temporal coding in the me-
dial entorhinal cortex. For example, grid cells are sensitive to
elapsed time as well as distance while running in place
(Kraus et al., 2015). Furthermore, cell populations sensitive
to specific time points of a delay, during which the animal
was immobile, have also been described in the medial ento-
rhinal cortex (Heys & Dombeck, 2018). Whether and how
the medial entorhinal cortex contributes to human memory
of temporal relations remains to be understood. With re-
spect to the interplay between the hippocampus and medial
entorhinal cortex, there is conflicting evidence concerning
the relevance of the medial entorhinal cortex for hippocam-
pal time cells. Whereas one study reported destabilized time
cell sequences after transient optogenetic inactivation of the
medial entorhinal cortex (Robinson et al., 2017), more re-
cent work observed no effects of medial entorhinal cortex
lesions on time cells (Sabariego et al., 2019). A better under-
standing of the influence of the medial entorhinal cortex on
temporal codes in the hippocampus, in animal models,

could help to generate more precise predictions to dissect
their potential interplay in human sequence memory.

We have discussed evidence that the hippocampus sup-
ports the representation of temporal relations, particularly
its anterior portion. However, a better understanding is
needed of the role different hippocampal subfields might
play beyond functional segregation along its long axis.
Studies in rodents have uncovered changes in the activity
patterns of cells in CA1 and CA2, which might provide tem-
poral context information for memory (Mau et al., 2018;
Mankin, Diehl, Sparks, Leutgeb, & Leutgeb, 2015; Mankin
et al., 2012; Manns, Howard, & Eichenbaum, 2007). In con-
trast, CA3 activity patterns are comparatively stable over
time (Mankin et al., 2012, 2015). Recent evidence in humans
suggests an overlapping representation of items from the
same episode in CA1, whereas CA3 differentiated these
items (Dimsdale-Zucker, Ritchey, Ekstrom, Yonelinas, &
Ranganath, 2018). Given ongoing improvements of high-
resolution neuroimaging techniques, it will be interesting
to further disentangle the roles of the different hippocampal
subfields in human sequence memory.

Recent theoretical work has taken different perspectives
on domain-general coding principles of the entorhinal cor-
tex (Mok & Love, 2019; Behrens et al., 2018; Bellmund,
Gärdenfors, Moser, & Doeller, 2018; Buzsáki & Tingley,
2018; Stachenfeld, Botvinick, & Gershman, 2017). In the
medial entorhinal cortex, grid cells are thought to provide
a distance function for cognitive spaces (Bellmund et al.,
2018) and might extract structural information from transi-
tion statistics (Behrens et al., 2018). As alluded to above, this
raises the question of how medial versus lateral entorhinal
cortices are differentially involved in sequence memory.
The lateral entorhinal cortex has been implicated in object
processing (Knierim, Neunuebel, & Deshmukh, 2014; Tsao,
Moser, & Moser, 2013; Deshmukh & Knierim, 2011), a func-
tion mirrored in some proposals (Behrens et al., 2018).
Possibly, traces of prior events in the entorhinal cortex
(Bright et al., 2019; Tsao et al., 2018) allow it to contribute
information not only about item identities but also about
temporal relationships between different sequence ele-
ments to memory. This might explain the involvement of
the anterior-lateral entorhinal cortex in recent studies of ep-
isodic memory (Bellmund et al., 2019; Montchal et al.,
2019). The medial entorhinal cortex has been suggested
to play a central role in extracting structural information
(Behrens et al., 2018). For example, the sequences of events
unfolding on your way to work might share a similar struc-
ture across days. Notably, prior work has emphasized the
role of a posterior-medial memory network in representing
shared sequence structure (Cohn-Sheehy & Ranganath,
2017; Hsieh & Ranganath, 2015). Future research should
aim to elucidate how different sequences, which might
share a similar structure, are represented in the hippocam-
pus and entorhinal cortex.

We have highlighted contributions of the hippocampus
and the adjacent entorhinal cortex to sequence memory.
Notably, the hippocampal–entorhinal system supports

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episodic memory in close connection with cortical net-
works, which can integrate episodic information from the
past 30 sec even when the hippocampus is damaged (Zuo
et al., 2020). How temporal integration processes in cortical
areas interact with the hippocampal–entorhinal region to
create sequence memories remains to be understood.

Conclusion

In this review, we have focused on memory for event se-
quences. We have summarized influential findings demon-
strating a role of the hippocampus in both the encoding
and retrieval of sequence information. We have incorpo-
rated novel evidence implicating the entorhinal cortex in
sequence memory to take a new perspective on the
hippocampal–entorhinal memory system. Population sig-
nals well suited to provide temporal information for episodic
memory have been discovered in the rodent lateral entorhi-
nal cortex, and consistent with that, studies in humans have
demonstrated the involvement of its homologue region in
memory recall. Furthermore, we have discussed the idea of
temporal scaling in the context of event sequences and de-
scribed how flexibly adapting the speed of sequence progres-
sion could benefit episodic memory and mental simulation.

Acknowledgments

The authors thank Raphael Kaplan and Jørgen Sugar for helpful
comments on a previous version of this article and Iván Andrés
Davidovich for insightful discussions. C. F. D.’s research was
supported by the Max Planck Society, the Kavli Foundation, the
European Research Council (ERC-CoG GEOCOG 724836),
the Centre of Excellence scheme of the Research Council of
Norway–Centre for Neural Computation (223262/F50), the Egil
and Pauline Braathen and Fred Kavli Centre for Cortical
Microcircuits, and the National Infrastructure scheme of the
Research Council of Norway–NORBRAIN (197467/ F50). I. P.
conceived the idea of temporal scaling in episodic memory and
drafted the corresponding section of the manuscript. J. B. drafted
the sections on sequence memory in the hippocampus and ento-
rhinal cortex as well as the abstract, introduction, outstanding
questions and conclusion. C. D. supervised the project. All authors
provided critical feedback and contributed to the final manuscript.

Reprint requests should be sent to Jacob L. S. Bellmund,
Department of Psychology, Max Planck Institute for Human
Cognitive and Brain Sciences, Stephanstraße 1a, 04103
Leipzig, Germany, or via e-mail: bellmund@cbs.mpg.de or
Ignacio Polti, Kavli Institute for Systems Neuroscience, Centre
for Neural Computation, The Egil and Pauline Braathen and
Fred Kavli Centre for Cortical Microcircuits, Norwegian
University of Science and Technology, Olav Kyrres Gate 9,
7030 Trondheim, Norway, or via e-mail: ignacio.polti@ntnu.no.

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Journal of Cognitive Neuroscience

Volume 32, Number 11 Sequence Memory in the Hippocampal–Entorhinal Region image

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