Place Cells, Grid Cells, and Memory
May-Britt Moser, David C. Rowland, and Edvard I. Moser
Centre for Neural Computation, Kavli Institute for Systems Neuroscience, Norwegian University of Science
and Technology, 7489 Trondheim, Norway
The hippocampal system is critical for storage and retrieval of declarative memories, includ-
ing memories for locations and events that take place at those locations. Spatial memories
place high demands on capacity. Memories must be distinct to be recalled without interfer-
ence and encoding must be fast. Recent studies have indicated that hippocampal networks
allow for fast storage of large quantities of uncorrelated spatial information. The aim of the
this article is to reviewand discuss some of this work, taking as a starting point the discovery
of multiple functionally specialized cell types of the hippocampal– entorhinal circuit, such
as place, grid, and border cells. We will show that grid cells provide the hippocampus with a
metric, as well as a putative mechanism for decorrelation of representations, that the forma-
tion of environment-speciﬁc place maps depends on mechanisms for long-term plasticity in
the hippocampus, and that long-term spatiotemporal memorystorage may depend on ofﬂine
consolidation processes related to sharp-wave ripple activity in the hippocampus. The mul-
titude of representations generated through interactions between a variety of functionally
specialized cell types in the entorhinal–hippocampal circuit may be at the heart of the
mechanism for declarative memory formation.
The scientiﬁc study of human memory started
with Herman Ebbinghaus, who initiated the
quantitative investigation of associative memo-
ry processes as they take place (Ebbinghaus
1885). Ebbinghaus described the conditions
that inﬂuence memory formation and he deter-
mined several basic principles of encoding and
recall, such as the law of frequency and the effect
of time on forgetting. With Ebbinghaus, higher
mental functions were brought to the laborato-
ry. In parallelwith the human learning tradition
that Ebbinghaus started, a new generation of
experimental psychologists described the laws
of associative learning in animals. With behav-
iorists like Pavlov, Watson, Hull, Skinner, and
Tolman, a rigorous program for identifying the
laws of animal learning was initiated. By the
middle of the 20th century, a language for asso-
ciative learning processes had been developed,
and many of the fundamental relationships be-
tween environment and behavior had been de-
scribed. What was completely missing, though,
was an understanding of the neural activity un-
derlying the formation of the memory. The be-
haviorists had deliberately shied away from
physiological explanations because of the in-
tangible nature of neural activity at that time.
Then the climate began to change. Karl
Lashley had shown that lesions in the cerebral
cortex had predictable effects on behavior in
Editors: Eric R. Kandel, Yadin Dudai, and Mark R. Mayford
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animals (Lashley 1929, 1950), and Donald Hebb
introduced concepts and ideas to account for
complex brain functions at the neural circuit
level, many of which have retained a place in
modern neuroscience (Hebb 1949). Both Lash-
ley and Hebb searched for the engram, but they
found no speciﬁc locus for it. A signiﬁcant turn-
ing point was reached when Scoville and Milner
(1957) reported severe loss of memory in an
epileptic patient, patient H.M., after bilateral
surgical removal of the hippocampal formation
and the surrounding medial temporal lobe ar-
eas. “After operation this young man could no
longer recognize the hospital staff nor ﬁnd his
way to the bathroom, and he seemed to recall
nothing of the day-to-day events of his hospital
life.” (Scoville and Milner 1957). This tragic mis-
fortune inspired decades of research on the func-
tion of the hippocampus in memory. H.M.’s
memory impairment could be reproduced in
memory tasks in animals and studies of H.M.,
as well as laboratory animals, pointed to a crit-
ical role for the hippocampus in declarative
memory—memory, which, in humans, can be
consciously recalled and declared, such as mem-
ories of experiences and facts (Milner et al. 1968;
Mishkin 1978; Cohen and Squire 1980; Squire
1992; Corkin 2002). What was missing from
these early studies, however, was a way to address
the neuronal mechanisms that led information
to be stored as memory.
The aim of this article is to show how studies
of hippocampal neuronal activity during the
past few decades have brought us to a point at
which a mechanistic basis of memory forma-
tion is beginning to surface. An early landmark
in this series of investigations was the discovery
of place cells, cells that ﬁre selectively at one or
few locations in the environment. At ﬁrst, these
cells seemed to be part of the animal’s instanta-
neous representation of location, independent
of memory, but gradually, over the course of
several decades, it has become clear that place
cells express current as well as past and future
locations. In many ways, place cells can be used
as readouts of the memories that are stored in
the hippocampus. More recent work has also
shown that place cells are part of a wider net-
work of spatially modulated neurons, including
grid, border, and head direction cells, each with
distinct roles in the representation of space and
spatial memory. In this article, we shall discuss
potential mechanisms by which these cell types,
particularly place and grid cells, in conjunction
with synaptic plasticity, may form the basis of a
mammalian system for fast high-capacity de-
PLACE CELLS, SYNAPTIC PLASTICITY,
The growing interest in hippocampal function
and memory led John O’Keefe and John Dos-
trovsky (O’Keefe and Dostrovsky 1971) and Jim
Ranck (Ranck 1973) to introduce methods for
recording activity from hippocampal neurons
in awake and freely moving animals. Using min-
iaturized electrodes for extracellular single-cell
recording, they were able to show reliable links
between neural activity and behavior. The most
striking relationship was noted by O’Keefe and
Dostrovsky, who found that hippocampal cells
responded speciﬁcally to the current location of
the animal. They called these cells “place cells”
(Fig. 1). Different place cells were found to have
different ﬁring locations, or place ﬁelds (O’Keefe
1976). Place was mapped nontopographically in
the sense that place ﬁelds of neighboring cells
were no more similar than those of cells that
were far apart (O’Keefe 1976; Wilson and Mc-
Naughton 1993), although the size of the ﬁr-
ing ﬁelds increased from dorsal to ventral hip-
pocampus (Jung et al. 1994; Kjelstrup et al.
2008). The combination of cells that were active
at each location in the environment was unique,
despite the lack of location topography, leading
O’Keefe and Nadel (1978) to suggest that the
hippocampus is the locus of the brain’s internal
map of the spatial environment, a manifestation
of the cognitive map proposed from purely be-
havioral experiments by Edward Tolman several
decades earlier (Tolman 1948).
The discovery of place cells changed the way
many experimental neuroscientists thought
about hippocampal functions. Clinical studies
starting with patient H.M. pointed to a role
for the hippocampus in declarative memory
(Squire 1992), but the fact that hippocampal
M.-B. Moser et al.
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neurons were so strongly modulated by location
suggested that space was primary. Moreover, for
the most part, place cells represented current
space, not as expected if the function of the hip-
pocampus was purely mnemonic. Reconciling
space and memory functions remained a chal-
lenge for several decades after the discovery of
A framework that accounts for both lines of
observation has now emerged. Converging evi-
dence has suggested that hippocampal neurons
respond also to nonspatial features of the envi-
ronment, such as odors (Eichenbaum et al.
1987; Wood et al. 1999; Igarashi et al. 2014),
tactile inputs (Young et al. 1994), and timing
(Hampson et al. 1993). The same cells that re-
spond to nonspatial stimuli ﬁre like place cells
when animals move around in space, suggest-
ing that place cells express the location of the
animal in combination with information about
events that take place or took place there (Leut-
geb et al. 2005b; Moser et al. 2008). The repre-
sentation of space does not exclude a central role
of the hippocampus in declarative memory, as
space is a central element of all episodic and
many semantic memories (Buzsa
´ki and Moser
A role for place cells in hippocampal mem-
ory was apparent already in the earliest studies
of place cells. It was shown in these studies that
ensembles of place cells represent not only the
animal’s current location but also locations that
the animal had visited earlier. In maze tasks,
place cells ﬁred when the animal made errors,
as if the animal was in the locationwherethe cell
ﬁred normally (O’Keefe and Speakman 1987).
In spatial alternation tasks, ﬁring patterns re-
ﬂected locations that the animal came from, as
well as upcoming locations (Frank et al. 2000;
Woods et al. 2000; Ferbinteanu and Shapiro
2003), and during sequential testing in multiple
environments, place-cell activity was found to
carry over from one environment to the next
(Leutgeb et al. 2004, 2005a). Moreover, sequenc-
es of spatial ﬁring during exploration were
shown to be replayed during rest or sleep subse-
quent to the behavioral experience, as if those
patterns were stored in the hippocampal net-
work during exploration and retrieved later in
ofﬂine mode, when the animal was not acquir-
Figure 1. Grid cells and place cells. (Left) A grid cell from the entorhinal cortex of the rat brain. The black trace
shows the trajectory of a foraging rat in part of a 1.5-m-diameter-wide square enclosure. Spike locations of the
grid cell are superimposed in red on the trajectory. Each red dot corresponds to one spike. Blue equilateral
triangles have been drawn on top of the spike distribution to illustrate the regular hexagonal structure ofthe grid
pattern. (Right) Grid cell and place cell. (Top) Trajectory with spike locations, as in the left part. (Bottom) Color-
coded rate map with red showing high activity and blue showing low activity. Grid cells are thought to provide
much, but not all, of the entorhinal spatial input to place cells.
Place Cells, Grid Cells, and Memory
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ing new information (Pavlides and Winson
1989; Wilson and McNaughton 1994; Foster
and Wilson 2006; O’Neill et al. 2006).
The fact that place cells express past experi-
ence raises the question whether ensembles of
place cells are completely formed by experience
or if there is an underlying component that is
hardwired in the circuit. Hill (1978) sought to
address this issue by recording place ﬁelds as
rats entered a novel environment. Of the 12 cells
that he recorded, 10 appeared to have spatial
ﬁring ﬁelds immediately, supporting the idea
that the place-cell map was largely predeter-
mined. Subsequently, studies with larger en-
sembles of cells found that place ﬁelds often
took several minutes of exploration before set-
tling into a stable ﬁring ﬁeld (McNaughton and
Wilson 1993; Frank et al. 2004) and the forma-
tion of new and stable place ﬁelds was depen-
dent on the animal’s behavior and attention to
the spatial features of the environment (Kentros
et al. 2004; Monaco et al. 2014). These results
point to a critical role for experience in forming
the hippocampal map of space. However, the
plasticity can occur extremely rapidly (Leutgeb
et al. 2006) and, just as Hill observed, some
place cells show stable ﬁring ﬁelds immediately
(Frank et al. 2004). Thus, place maps are ex-
pressed, in some form, from the very moment
when animals are put into an environment for
the ﬁrst time, although the map may evolve fur-
ther with experience. The ﬁndings raise the pos-
sibility that a skeletal map of a novel environ-
ment is drawn from a set of preexisting maps,
and then gets modiﬁed to ﬁt the speciﬁcs of
the environment through experience-depen-
dent plasticity (Samsonovich and McNaughton
1997; Dragoi and Tonegawa 2011, 2013).
The role of synaptic plasticity in the forma-
tion of place maps has been tested experi-
mentally. In agreement with the proposed ex-
istence of prewired maps, neither systemic
pharmacological blockade of N-methyl-D-as-
partate (NMDA) receptors, nor subﬁeld-specif-
ic targeted knockouts of such receptors, have
a large effect on the basic ﬁring patterns of
place cells in familiar or novel environments
(McHugh et al. 1996; Kentros et al. 1998), sug-
gesting that place-ﬁeld expression is quite inde-
pendent of at least one major form of long-term
synaptic plasticity. However, cellular mecha-
nisms involved in long-term plasticity are clear-
ly required for the long-term stability of newly
formed maps (Rotenberg et al. 1996; Kentros
et al. 1998). These studies suggest that the
place-cell map of the environment is stored
and stabilized through changes in synaptic
weights, similar to other memory systems (Kan-
del and Schwartz 1982).
NMDA receptors also play a role in more
subtle forms of experience-dependent modiﬁ-
cations of place ﬁelds. One example is the ex-
perience-dependent asymmetric expansion of
place ﬁelds observed following repeated travers-
als of place ﬁelds on a linear track (Mehta et al.
1997, 2000). It was suggested in theoretical
studies in the 1990s that as a rat moves through
locations A, B, and C along a linear track, the
cells coding for location A will repeatedly acti-
vate the cells coding for location B and the cells
coding for location B will, in turn, activate cells
coding for location C. By the logic of Hebbian
plasticity, the connections from A to B and B
to C should become strengthened, with the re-
sult that place ﬁelds of cells A, B, and C are
shifted forward on the track, against the direc-
tion of motion (Abbott and Blum 1996; Blum
and Abbott 1996). Experimental evidence for
such experience-dependent asymmetric expan-
sion was obtained by Mehta and colleagues
(1997, 2000). Subsequently, studies found that
the asymmetric shift depends on NMDA recep-
tor activation (Ekstrom et al. 2001), consistent
with the suggestion that place maps are reﬁned
by experience-dependent long-term synaptic
What are the factors that determine whether
new place maps are stabilized? One of the hall-
marks of episodic memories is that attended
information is more likely to be encoded and
stored long term (Chun and Turk-Browne
2007). It is simply impossible to remember ev-
erything, and as Ebbinghaus’s curve of memory
shows, most memories will fade over time.
However, some particularly meaningful mem-
M.-B. Moser et al.
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ories become permanent. On this background,
Kentros et al. (2004) considered whether atten-
tion to spatial cues could improve the long-term
stability of place ﬁelds. They trained mice to
ﬁnd an unmarked goal location in a cylinder
(similar to the Morris water maze) while re-
cording hippocampal place cells. The mice that
learned the task had more stable place ﬁelds
than mice that were simply running in the same
cylinder with no task requirements. To test
whether the driving force was true selective at-
tention, as opposed to general arousal, Muzzio
et al. (2009) trained mice to attend to odor cues
and ignore spatial cues or vice versa. When the
odors were the relevant cues, the hippocampal
neurons acquired stable odor representations,
but had less stable spatial representations. The
reverse was true when space was relevant. Taken
together with recent evidence suggesting that
place ﬁelds can be induced by attentive scann-
ing (Monaco et al. 2014), the ﬁndings point to
selective attention, and not merely general
arousal, as a major determinant of experience-
dependent stabilization of hippocampal place
What could be the mechanisms for selective
attention in the hippocampus? Recently, Igara-
shi et al. (2014) recorded simultaneously from
the lateral entorhinal cortex and CA1 region of
the rat hippocampus as the animals learned an
odor–place association. As the animals learned
the association, the two structures showed an
increasing degree of synchronous oscillatory ac-
tivity in the 20- to 40-Hz range and a corre-
sponding increase in spiking activity to the re-
warded odors. The development of temporal
coherence between activity in the hippocampus
and entorhinal cortex may allow CA1 cells to
respond to particular entorhinal inputs at the
same time as the cells are closest to ﬁring thresh-
old (Singer 1993). The 20- to 40-Hz oscillation
is substantially lower than the fast (60-100 Hz)
gamma oscillation found in the medial entorhi-
nal cortex (Colgin et al. 2009). The two subdi-
visions of the entorhinal cortex may, therefore,
convey relevant information to the hippo-
campus via distinct frequency channels, each
leading to a different ﬁring pattern in the hip-
Once encoded, the memories must be consoli-
dated. In an early theoretical paper, Buzsa
(1989) proposed that hippocampal memory
formation occurs in two stages. First, there is a
stage in which memory is encoded via weak syn-
aptic potentiation in the CA3 network when the
network is in theta-oscillation mode during ex-
ploratory behavior. Then, there is a memory
consolidation stage, which can take place hours
later during sharp-wave activity, associated with
sleep and resting. In this stage, synapses that were
weakly potentiated during the preceding explo-
ration participate in sharp-wave activity that, in
turn, evokes ripple activity in the CA1 area of the
hippocampus. Ripples occur at a frequency that
is optimal for induction of long-term potentia-
tion (LTP) in efferent synapses of CA1 cells, pos-
sibly including long-distance targets in the cor-
tex. By this mechanism, memory was thought to
be slowly induced in the neocortex, consistent
with a large body of evidence pointing to gradual
recruitment of neocortical memory circuits in
long-term storage of hippocampal memories
(McClelland et al. 1995; Squire and Alvarez
1995; Frankland et al. 2001). Over the years,
considerable evidence has accumulated to point
to a role for sharp waves and ripples in the for-
mation of hippocampus-dependent long-term
memories. Selectively disrupting sharp-wave
ripple activity during posttraining rest periods
impairs learning, providing a causal link be-
tween sharp-wave ripples and consolidation
(Girardeau et al. 2009; Ego-Stengel and Wilson
2010). Moreover,it is now clear that sequences of
ﬁring among place cells are replayed during sub-
sequent sharp-wave ripples in the same or re-
verse order that the cells were active during ex-
perience (Wilson and McNaughton 1994; Foster
and Wilson 2006; Diba and Buzsa
Structured replay is seen across many brain re-
gions (Hoffman and McNaughton 2002), indi-
cating that the sequence information from the
hippocampus may be conferred on downstream
Recent work points to awider role for replay
in which replay may contribute not only to con-
Place Cells, Grid Cells, and Memory
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solidation and recall of memory, but also to
planning of future behavior. Studies in human
subjects show that overlapping hippocampal
networks are activated during episodic recall
and imagination of ﬁctitious experiences (Has-
sabis et al. 2007). In animals, sharp-wave ripples
can activate cells along both past and future
trajectories (Karlsson and Frank 2009; Gupta
et al. 2010; Pfeiffer and Foster 2013). Pfeiffer
and Foster (2013), for example, trained rats to
ﬁnd a rewarded well within a large environment
while sharp-wave ripple-associated replay events
were recorded in the hippocampus. In many of
the events, the sequence of active cells began at
the current location and ended at the goal loca-
tion, followed by the animal taking the path
deﬁned by the place-cell activity. Although the
sequence of activated cells clearly preceded be-
havior, the phenomenon also depended on pre-
vious experience with the environment and the
rules of the task. Thus, the replay can either lead
or follow the behavior once the map of space is
established. In that sense, the replay phenome-
non may support “mental time travel” (Sudden-
dorf and Corballis 2007) through the spatial
map, both forward and backward in time.
Whether the sharp-wave ripple-mediated replay
in rats represents conscious recall is impossible
to know, but observations in humans during
free recall provide a clue (Gelbard-Sagiv et al.
2008; Miller et al. 2013). Miller et al. (2013), for
example, recorded from the medial temporal
lobe of human subjects as they navigated a vir-
tual town (the subjects were awaiting surgery
for epilepsy and had electrodes placed in their
medial temporal lobe to localize the origin of
the seizures, affording Miller et al. the rare op-
portunity to record place cells in humans). After
an initial familiarization period, subjects were
asked to deliver items to one of the stores in the
town and when all the deliveries were complete,
the subjects were asked to recall only the items
they delivered. Remarkably, the place cells re-
sponsive to the area where the item was deliv-
ered became active during recall of the item,
closely mirroring the reactivation of place cells
during replay events in rodents. Although free
recall in humans is not likely to correspond to
sharp-wave ripple events (Watrous et al. 2013),
the time course of reactivation was similar to a
typical sharp-wave ripple event in rodents, and
may therefore reﬂect a qualitatively similar phe-
nomenon. The place cell activity during recall of
events or items likely brings to mind the spatial
context in which the events and items were ex-
perienced, creating a fully reconstructed mem-
ory for what was experienced, along with where
it was experienced.
UPSTREAM OF PLACE CELLS: GRID CELLS
AND OTHER CELL TYPES
To get a better insight into the mechanisms of
memory formation in hippocampal place-cell
circuits, it may pay off to consider how place
cells interact with cells in adjacent brain systems.
The origin of the place-cell signal was long
thought to be intrahippocampal, considering
that early recordings upstream in the entorhinal
cortex showed only weak spatial modulation
(Barnes et al. 1990; Quirk et al. 1992; Frank
et al. 2000). At the turn of the millennium, we
started a series of experiments aimed at localiz-
ing the sources of the place signal. First, we iso-
lated the CA1 region of the hippocampus from
the earlier parts of the hippocampal excitatory
circuit, that is, the dentate gyrus and the CA3
(Brun et al. 2002). Activity was then recorded
from the remaining CA1. Place cells were still
present, suggesting that intrahippocampal cir-
cuits are not necessary for spatial signals to de-
velop. The ﬁndings pointed to direct inputs
from the entorhinal cortex as an alternative
source of incoming spatial information to the
hippocampus. Thus, in a subsequent study, we
recorded directly from the entorhinal cortex,
not in the deep ventral areas where cells had
been recorded in previous studies, but in the
dorsal parts that projected directly to the hip-
pocampal recording locations used by O’Keefe
and others (Fyhn et al. 2004). Electrodes were
placed in the medial part of the entorhinal cor-
tex. We found that many neurons in this area
were as sharply modulated by position as place
cells in the hippocampus. Entorhinal neurons
had multiple ﬁring ﬁelds with clear regions of
silence between the ﬁelds. In a third study, we
expanded the size of the recording environment
M.-B. Moser et al.
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to determine the spatial structure of the many
ﬁring ﬁelds (Hafting et al. 2005). The multiple
ﬁring ﬁelds of individual entorhinal neurons
formed a regularly spaced triangular or hexag-
onal grid pattern, which repeated itself across
the entire available space. We named these cells
“grid cells.” Grid cells were organized in a non-
topographic manner, much like place cells. The
ﬁring ﬁelds of neighboring grid cells were no
more similar than those of grid cells recorded
at different brain locations. However, the scale
of the grid increased from dorsal to ventral me-
dial entorhinal cortex (Fyhn et al. 2004; Hafting
et al. 2005), suggesting that the earliest record-
ings in the entorhinal cortex had missed the grid
pattern because the period of the ﬁring pattern
was too large for repeated ﬁelds to be observed in
conventionally sized recording boxes. The dis-
coveryof grid cells was followed by studies show-
ing that these cells were part of a wider spatial
network comprising other cell types as well,
such as head direction–modulated cells (Sargo-
lini et al. 2006) and cells that ﬁre speciﬁcally along
one or several borders of the local environment
(border cells) (Savelli et al. 2008; Solstad et al.
2008). Head direction cells had previously been
observed in a number of brain systems, from the
dorsal tegmental nucleus in the brain stem to
the pre- and parasubiculum in the parahippo-
campal cortex (Ranck 1985; Taube et al. 1990;
Taube 2007). Border cells were described at the
same time in the subiculum (Barry et al. 2006;
Lever et al. 2009). Thus, by the end of the ﬁrst
decade of the new millennium, it was clear that
place and grid cells were part of a diverse and
entangled network of cell types with distinct
functions in spatial representation.
How place cells are formed from the diver-
sity of cell types remains to be determined. An
obvious possibility is that place cells are gener-
ated by transformation of spatial input from
grid cells. The presence of grid cells in the super-
ﬁcial layers of the entorhinal cortex, the main
cortical input to the hippocampus, led investi-
gators to propose that place ﬁelds form by linear
combination of periodic ﬁring ﬁelds from grid
cells with a common central peak, but different
grid spacing and orientation (O’Keefe and Bur-
gess 2005; Fuhs and Touretzky 2006; McNaugh-
ton et al. 2006; Solstad et al. 2006). The sugges-
tion was that, because the wavelength of the
individual grid patterns is different, the patterns
cancel each other except at the central peak,
which becomes the place ﬁeld of the receiving
cell (Fig. 3).
Experimental observations have suggested
that the mechanisms are more complex, howev-
er. If place cells were generated exclusively from
grid cells, grid and place cells would be expected
to appear simultaneously in developing animals
or with a faster time course for grid cells than
place cells. Recordings from rat pups suggest
that this is not the case (Langston et al. 2010;
Wills et al. 2010). When pups leave the nest for
the ﬁrst time at 2–2.5 weeks of age, sharp and
conﬁned ﬁring ﬁelds are present in a large pro-
portion of the hippocampal pyramidal-cell
population. In contrast, grid cells show only
weakly periodic ﬁelds at that age. Strong peri-
odicity is not expressed until 3–4 weeks of age.
The delayed maturation of the grid cells offers at
least two interpretations. First, weak spatial in-
puts may be sufﬁcient for place-cell formation.
Sharply conﬁned ﬁring ﬁelds may be generated
by local mechanisms in the hippocampal net-
work, such as recurrent inhibition (de Almeida
et al. 2009; Monaco and Abbott 2011), Hebbian
plasticity (Rolls et al. 2006; Savelli and Knierim
2010), or active dendritic properties (Smith et
al. 2013). Alternatively, place cells may be gen-
erated from other classes of spatially modulated
cells, such as border cells, which have adult-like
properties from the very ﬁrst day of exploration
outside the nest (Bjerknes et al. 2014). Retro-
grade labeling studies suggest that border cells
have projections to the hippocampus that may
be equally dense as those from grid cells, al-
though the latter are more abundant (Zhang
et al. 2013). A potential role for border cells in
place-cell formation would be consistent with
early models, suggesting that place cells arise by
linear combination of inputs from cells with
ﬁring ﬁelds deﬁned by their proximity to geo-
metric boundaries (O’Keefe and Burgess 1996;
Hartley et al. 2000). Recordings in the medial
entorhinal cortex have, so far, identiﬁed such
cells only near the boundaries of the environ-
ment (Solstad et al. 2008; Zhang et al. 2013;
Place Cells, Grid Cells, and Memory
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Bjerknes et al. 2014), suggesting that a contri-
bution by these cells may be limited to place
cells with peripheral ﬁring ﬁelds.
The exact function of different entorhinal
cell types in place-cell formation remains to be
determined, but it is not unlikely that individual
place cells receive inputs from both grid and
border cells, possibly with grid cells providing
self-motion-based distance information and
border cells providing position in relation to
geometric boundaries (Bush et al. 2014; Zhang
et al. 2014). The strongest input may originate
from grid cells, which, in the superﬁcial layers of
the medial entorhinal cortex, are several times
more abundant than border cells (Sarg olini et al.
2006; Solstad et al. 2008; Boccara et al. 2010).
Under most circumstances, the two classes of
input are likely to be coherent and redundant.
If one is absent, the other may oftenbe sufﬁcient
to generate localized ﬁring in the hippocampus.
REMAPPING AND MEMORY
One of the events that pointed to place cells as an
expression of declarative memory was the dis-
covery of remapping, or the fact that any place
cell is part of not one, but many independent
representations. In 1987, Bob Muller and John
Kubie found that place cells can alter their ﬁring
patterns in response to minor changes in the
experimental task, such as alterations in the
shape of the recording enclosure (Fig. 3) (Muller
and Kubie 1987; Bostock et al. 1991). Place cells
may begin ﬁring, stop ﬁring, or change their
ﬁring location. The changes are expressedw idely
across the place-cell population, such that a new
map is installed for each occasion. Remapping
could also be induced by changes in motivation-
al state or behavioral context (Markus et al.
1995; Frank et al. 2000; Wood et al. 2000; Moita
et al. 2004).
White WhiteBlack Black
14 Hz 12 Hz 14 Hz
12 Hz 22 Hz
18 Hz 27 Hz
AAB Rat 11554
4 5 6 7 8 9 10 11
Figure 2. Schematic illustration of how periodic grid cells could be transformed to nonperiodic place cells by
linear summation of output from grid cells with overlapping ﬁring ﬁelds, but different spacing and orientation,
and how differential responses among modules of grid cells might give rise to remapping in the hippocampus.
(Left) Map 1, grid cells with different spacing converge to generate place cells in a subset of the hippocampal
place-cell population. Each grid cell belongs to a different grid module. (Right) Map 2, differential realignment
of each of the grid maps induces recruitment of a new subset of place cells. (From images in Solstad et al. 2006
and Fyhn et al. 2007; modiﬁed, with permission, from the authors and Nature Publishing Group #2006 and
M.-B. Moser et al.
8Advanced Online Article. Cite this article as Cold Spring Harb Perspect Biol doi: 10.1101/cshperspect.a021808
for fig 3.
The remapping experiments showed that
place cells participate in multiple spatial maps.
Different maps could be recruited not only in
different environments, but also when animals
are tested under different conditions in the same
location (Markus et al. 1995; Leutgeb et al.
2005b). Maps for different conditions or places
were often completely uncorrelated (global re-
mapping) (Leutgeb et al. 2004; Fyhn et al. 2007),
as if a pattern-separation process takes place
when information enters the hippocampus
from the surrounding cortex (Marr 1971; Mc-
Naughton and Morris 1987; Leutgeb et al. 2004,
2007). The discovery of remapping and the un-
correlated nature of place maps was important
because it showed that place cells participate in
multiple orthogonal representations, as expect-
ed if the hippocampus plays a role in accurate
storage and retrieval of high-capacity declarative
memory. The numberof place maps stored in the
hippocampus is not known, but if place maps are
expressions of individual memories, that num-
ber should be very large. Remapping is, thus, a
necessity if place cells express memories.
Do spatial inputs from medial entorhinal
cortex contribute to remapping in the hippo-
Map #1 Map #2
Figure 3. Remapping in placecells and grid cells. (Top left) John Kubie and Bob Muller in 1983. (Top right) Color-
coded ﬁring rate map for a hippocampal place cell from an early remapping experiment ( purple, high rate;
yellow, low rate). The cell ﬁred at different locations in different versions of the recording cylinder, one with a
black cue card and one with a white cue card. (Bottom left) Realignment of entorhinal grid cells under conditions
that generate global remapping in the hippocampus. The rat was tested in boxes with square orcircular surfaces.
The left panel shows color-coded rate maps for three grid cells (t5c2, t6c1, and t6c3) (color coded as in Fig. 1).
The right panel shows cross-correlation maps for pairs of rate maps (same grid cells as in the left panel; repeated
trials in Aor one trial in Aand one trial in B). The cross-correlation maps are color-coded, with red corre-
sponding to high correlation and blue to low (negative) correlation. Note that the center of the cross-correlation
map is shifted in the same direction and at a similar distancefrom the origin in all three grid cells, suggesting that
all grid cells in an ensemble respond coherently to changes in the environment very much unlike the remapping
that is observed in the hippocampus. (Bottom right) Response to a change in the environment (darkness) in a
simultaneously recorded pair of grid and place cells. (Top left photo courteously provided by John Kubie; top
right image is modiﬁed from data in Bostock et al. 1991; bottom image from Fyhn et al. 2007; reprinted, with
permission, from the authors and Nature Publishing Group #2007.)
Place Cells, Grid Cells, and Memory
Advanced Online Article. Cite this article as Cold Spring Harb Perspect Biol doi: 10.1101/cshperspect.a021808 9
this is the
campus? The ﬁrst clue to the underlying mech-
anism is that remapping is unique to the hip-
pocampus. The orthogonal nature of place-cell
maps is not shared by any of the known spatial
cell types upstream of the hippocampus. In the
hippocampus, and particularly in the CA3 sub-
ﬁeld, different subsets of the place-cell popula-
tion are active in different environments. The
overlap between active subsets in two environ-
ments is not larger than expected by chance
(Leutgeb et al. 2004). The apparent indepen-
dence of the place-cell maps contrasts with the
functional rigidity of the grid-cell population.
Changes in the environment, which lead to
global remapping in the hippocampus, induce
changes in the ﬁring locations of simultane-
ously recorded grid cells, but these changes are
always coherent among numbers of grid cells
(Fyhn et al. 2007). Among grid cells with similar
grid spacing, the ﬁring locations of the grid cells
shift in the xy plane from one environment to
the other, but the distance and direction of grid
displacements are similar across the cell popu-
lation. Similarly, internal coherence is observed
in head direction and border cells. When ani-
mals are moved from one task to another, head
direction cells in the presubiculum and anterior
nuclei of the thalamus rotate coherently such
that the magnitude of the difference in direc-
tional preference among any pair of head direc-
tion cells is retained from one condition to the
next (Taube et al. 1990; Taube and Burton 1995;
Yoganarasimha et al. 2006). A similar spatial
coherence is seen among border cells (Solstad
et al. 2008). Pairs of cells that ﬁre along the same
wall in one environment also ﬁre along the same
wall in another environment; cells that ﬁre along
opposite walls in one box ﬁre along opposite
walls in another box. Changes in orientation
are coherent also across entorhinal cell types;
if border ﬁelds switch to the opposite wall,
this is accompanied by a 180-degree change in
the orientation of head direction cells, as well as
grid cells (Solstad et al. 2008). Taken together,
these observations suggest that remapping is
generated not in the entorhinal cortex, but in
the hippocampus itself.
The ﬁndings do not rule out, however, that
inputs from realigned or reoriented entorhinal
cells give rise to remapping in the hippocampus.
Two classes of explanations were put forward
when we observed that remapping in the hip-
pocampus is accompanied by coherent realign-
ment in the grid-cell population (Fyhn et al.
2007). The ﬁrst class assumed a continuous
map of space in the medial entorhinal cortex.
In this scenario, different portions of a universal
entorhinal map would be activated in different
environments. Different subsets of hippocam-
pal cells would be activated from independent
portions of the entorhinal map and global re-
mapping would be seen in the hippocampus.
The second class of explanation assumes that
grid cells have a modular organization and that
different modules of grid cells respond indepen-
dently to changes in the environment. Place
cells were thought to receive input from several
modules. Differential realignment across mod-
ules would lead to different overlap of incoming
grid signals in hippocampal target cells; the sub-
set of hippocampal cells activated by entorhinal
grid-cell inputs would be entirely dependent on
the difference in realignment between different
Subsequently, experimental studies have
provided evidence for a modular organization
of grid cells, consistent with the second expla-
nation (Stensola et al. 2012). For many years,
the low number of simultaneously recorded
grid cells prevented a clear answer to the ques-
tion of whether grid cells were modular or not,
although early studies pointed in that direction
(Barry et al. 2007). With a more than 10-fold
increase in the number of grid cells from the
same animal, it was possible to show that grid
cells cluster into modules with distinct grid scale
and grid orientation (Stensola et al. 2012). Four
modules could be detected in most animals, but
the number may be larger, considering that only
a part of the medial entorhinal cortex was sam-
pled. It was not only the properties of the grid
pattern that differed between modules, howev-
er; they also responded independently to chang-
es in the environment (Stensola et al. 2012).
When the recording environment was com-
pressed, changing it from a square to a rectan-
gle, grid cells in the module with the smallest
grid spacing maintained their ﬁring locations,
M.-B. Moser et al.
10 Advanced Online Article. Cite this article as Cold Spring Harb Perspect Biol doi: 10.1101/cshperspect.a021808
whereas cells in the larger modules rescaled
completely and consistently, ﬁring at shorter
spatial wavelengths in the compressed direction,
but maintaining wavelengths in the orthogonal
unaltered direction. The apparent indepen-
dence between grid modules contrasts with the
strong coherence observed in earlier recordings
from grid cells (Fyhn et al. 2007). The difference
is likely to reﬂect the fact that the earlier record-
ings were all made from the same location and,
probably, mostly from a single module.
The new data suggest that modules respond
with different degrees of displacement and re-
orientation when animals move from one envi-
ronment to another. Computational simula-
tions have shown that independent realignment
in four or fewer modules is sufﬁcient to generate
complete or global remapping in the hippo-
campus (Monaco and Abbott 2011). Indepen-
dent responses among only a handful of grid
modules may be sufﬁcient to create an enor-
mous diversity of ﬁring patterns in the hippo-
campus because the number of displacements or
phases that each module may take is large. The
mechanism would be similar to that of a com-
bination lock in which 10,000 combinations
may be generated with only four modules of
10 possible values each (Rowland and Moser
2014), or that of an alphabet in which all words
of a language can be generated by combining
only 30 letters or less. The proposed mechanism
is only a hypothesis, however. Whether hippo-
campal remapping actually requires indepen-
dent realignment among grid modules remains
to be determined. It should also be noted that a
possible connection between grid modules and
remapping does not rule out roles for other cell
types, such as border cells, in inducing hippo-
campal remapping, although modular organi-
zation has not yet been observed in any of the
other functional cell populations (Giocomo
et al. 2014).
Finally, we would like to emphasize that, up
to this point, we have mostly discussed the en-
torhinal–hippocampal space circuit as if inter-
actions between cell types were constant over
time. However, the connectivity of this network
is dynamic (Buzsa
´ki and Moser 2013). Whether
entorhinal and hippocampal neurons inﬂuence
each other depends strongly on the state of theta
and gamma oscillations, which, during active
awake behavior, predominates frequency spec-
tra in both regions (Buzsa
´ki et al. 1983; Bragin
et al. 1995; Chrobak and Buzsa
´ki 1998; Csicsvari
et al. 2003; Colgin et al. 2009). Theta oscillations
are generally coherent across most of the ento-
rhinal–hippocampal network, but the coher-
ence of beta and gamma oscillations is more
local and ﬂuctuates at subsecond timescales
(Colgin et al. 2009; Igarashi et al. 2014). Such
ﬂuctuations may enable place cells to interact
with different entorhinal subpopulations at dif-
ferent times. Coincidence of pre- and postsyn-
aptic activity may be a prerequisite not only for
synaptic strengthening of connections between
entorhinal and hippocampal cell pairs (Singer
1993; Bi and Poo 1998), but also for pattern-
completion processes during retrieval of al-
ready-stored information. Whether a place cell
responds to inputs from grid or border cells may
change with time, as may the inﬂuence of dif-
ferent modules of grid cells. Recordings from
CA1 and lateral entorhinal cortex suggest that
place cells also respond dynamically to nonspa-
tial inputs, such as odors, with learned relation-
ships to locations in the environment (Igarashi
et al. 2014). Beta and gamma oscillations may
enable place cells to respond temporarily to in-
formation about the content of locations in the
We have known for almost six decades that cer-
tain types of memory depend on the hippocam-
pus and surrounding areas. The discovery of
place cells showed that space is a critical element
of the information that is stored and expressed
by neurons in the hippocampus; however, it is,
perhaps, with studies of place cells at the ensem-
ble or population level and interventions that
selectively change synaptic plasticity in speciﬁc
brain circuits, that the mechanisms of memory
processing have become accessible. Today, we
know that hippocampal networks can rapidly
store a multitude of uncorrelated representa-
tions, a property that any high-capacity episod-
ic memory network must have. We know that
Place Cells, Grid Cells, and Memory
Advanced Online Article. Cite this article as Cold Spring Harb Perspect Biol doi: 10.1101/cshperspect.a021808 11
place cells are only one element of a wider net-
work for spatial mapping. Place cells coexist
with grid, head direction, and border cells, all
likely to interact with each other to yield a global
representation of the animal’s changing posi-
tion, which may be used to guide the animal
to particular locations in the environment.
With a modular organization of grid cells, the
network may be able to generate not only one
map of the external environment, but thou-
sands or millions. Whether and how these
maps contribute to declarative memory remains
to be determined, but the investigation of the
hippocampal–entorhinal circuit is now at a
stage in which the computational mechanisms
underlying speciﬁc memory processes are fully
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Place Cells, Grid Cells, and Memory
Advanced Online Article. Cite this article as Cold Spring Harb Perspect Biol doi: 10.1101/cshperspect.a021808 15
Place Cells, Grid Cells, and Memory
May-Britt Moser, David C. Rowland, and Edvard I. Moser
TOC Blurb: Hippocampal networks allow for fast storage of large quantities of uncorrelated
spatial information. Functionally specialized cell types (e.g., place cells and grid cells) may
form the basis of this system.