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Layman’s summary
In this literature review I discuss the temporal and spatial properties underlying our memory
processes. Research of spatial processes has been focused on neurons in the rat hippocampus
that fired at particular locations. These cells are now called place cells and together with other
spatially sensitive neurons they are thought to underlie a great deal of our spatial processing.
Recently, cells have been discovered that seem to do the same for our temporal processing,
these cells fired at specific moments in time and were thus called time cells. I discuss the
temporal and spatial processes in the hippocampus and the memory processes they are
thought to underlie. Furthermore, I also discuss the limitations of these time and place cells
and the gaps in the literature. Finally, I emphasize the importance of a network including the
hippocampus and the entorhinal cortex and the need for more research into this network
regarding spatiotemporal processing in our memory system.
In a galaxy not too far away; Space and Time in the
Hippocampal-Entorhinal System
S. van Bijnen1
1
Experimental Psychology, Utrecht University, Utrecht, The Netherlands.
Corresponding author: [email protected]
Abstract
The long tradition of research on hippocampal involvement in spatial memory and spatial
properties of episodic memory has often been focused on spatially sensitive neurons called
place cells. Together with other spatially sensitive neurons they are proposed to function as an
internal representation of the outside world (i.e. a cognitive map). More recently, cells were
discovered that encode for a specific moment time. These ‘time cells’ have been found to
parse temporally defined environments analogous to how place cells parse spatially defined
environments. Similarities between time and place cells have led researchers to propose that
they are not distinct cell types, but rather that cells become sensitive to either spatial or
temporal information based on the context in which learning occurs. Some evidence supports
this notion. However, if time cells, like place cells, are to be an important component of
episodic memory, they should be able to code for multiple time domains. The hippocampalentorhinal system has been proposed to be able to do this using distinct, variable, neuronal
representations. Interestingly, input from grid cells in the entorhinal cortex to CA1 cells in the
hippocampus have also been suggested to combine linearly to create the place fields,
emphasizing the importance of this network. However, the role of the hippocampal-entorhinal
system in the creation and stability of place cells have been questioned. Concluding, evidence
is beginning to support a role for the temporally sensitive neurons in episodic memory,
analogous to the spatial sensitive neurons. However, the importance of the hippocampal-EC
connections for the basic properties of both time and place cells needs further investigation.
Key words: Hippocampus – Episodic memory – Entorhinal cortex – Place cell – Time cell
Introduction
As one of the neurocognitive memory systems, episodic memory is an impressive
neuroevolutionary feat that is supposedly uniquely human. Tulving (2002) defined it as “the
ability to remember personally experienced episodes in a spatial and temporal context”. It is
often referred to as “what”, “where” and “when” memory because episodic memory makes it
possible to re-experience personal events (what) in a spatial (where) and temporal (when)
context. Importantly, episodic memory is a hypothetical memory system, assumed to have
evolved from semantic memory; it is defined by its properties and functions and it shares
many features with other memory systems. According to Tulving (2002) however, core
features of episodic memory are the self, autonoetic awareness and subjectively sensed time.
These features allow us to mentally travel through time; we consciously recollect and reexperience events while being aware of the experiencing self through time. This paper will
focus on the spatial (where) and temporal (when) components and structures of episodic
memory.
The hippocampus has been implicated in a broad range of memory processes,
including but not limited to: spatial memory, spatial properties of episodic memory,
recollection and temporal order of events (Bird & Burgess, 2008; Eichenbaum, Yonelinas,
Ranganath, 2007; Eichenbaum, 2013). However, as Tulving already stated, it is not fruitful to
identify particular memories as being in one memory system or another (Toth & Hunt, 1999,
p. 233 in Tulving, 2002). Therefore, I discuss the neural mechanisms proposed to underlie the
spatial and temporal mechanisms of (episodic) memory. Importantly, they also subserve other
cognitive (memory) processes.
The debate about the neural mechanisms behind spatial properties of episodic memory
has been strongly focused on a specific type of cells, called place cells, in the hippocampus.
Recently, MacDonald and colleagues (2011) discovered cells that encode for specific
moments in time and named them “time cells”. This focused the attention of researchers on
the hippocampus and its proposed role in episodic memory once again. However, knowledge
about the place cells greatly exceeds that of the time cells. First, I will summarize the findings
and conclusions related to place cells and spatial processing. Next, I will move on to time
cells and temporal processes in the hippocampus. Finally, I will discuss the spatio-temporal
context that time and place cells are thought to underlie.
Place cells and spatial processing
In 1971, O’Keefe and Dostrovsky discovered pyramidal cells in CA1 and CA3 region of the
rat hippocampus that increased their firing rate at particular locations. They recorded
extracellular action potentials from the rat hippocampus which showed spatially localized
firing. These cells characteristics make them very likely to function as a marker for certain
locations in an environment and were thus termed “place cells”. Importantly, their firing rate
was independent of the orientation of the rats head as well as which direction the rat was
heading (O’Keefe & Dostrovsky, 1971). Numerous studies have been performed since, vastly
increasing the knowledge of place cells as well as documenting these cells in monkeys and
humans (Ono, Nakamura, Fukuda & Tamura, 1991; Ekstrom et al., 2003). Originally it was
related to spatial cognition, however, the underlying mechanisms are very like to subserve
multiple cognitive (memory) processes.
In the recent decade studies have further investigated O’Keefe and Nadels’ (1978)
proposal that the hippocampus is a neural substrate of a ‘cognitive map’ and how place-cell
activity is linked to spatial memory traces. A cognitive map is usually defined as an internal
representation of the outside world (Marozzi & Jeffery, 2012). It is a crucial part of spatial
cognition and place cells are said to play an important role by representing specific locations
in the environment. The discovery of other spatially sensitive neurons provided even more
knowledge on how this internal representation might looks like. Head-direction cells, grid
cells and border cells were named after their respective functions; head-directions cells
showed preferred firing when the animal faced a particular direction, grid cells showed ‘firing
fields’ that were evenly spaced representing distance information, finally border cells mark
out boundaries of an environment (Marozzi & Jeffery, 2012). Figure 1 shows the firing
patterns of the cell types underlying the cognitive map.
Fig 1. Firing patterns of the different cell types underlying the cognitive map; (A) place cells show preferred firing at certain
locations, (B) head direction cells when facing a particular direction, (C) grid cells provides distance information by evenly
spaced ‘firing fields’ and (D) border cells mark out boundaries. Adapted from Marozzi & Jeffrey (2012) and Bird & Burgess
(2008) without permission.
An important question is how these cells function and interact to encode and represent spatial
properties of the environment. Besides incoming perceptual information, place cells also rely
on interoceptive signals related to self-motion (Bird & Burgess, 2008). Combined, the many
sensory systems that provide input to the place cells converge to supramodal representations
of our environment (Marozzi & Jeffrey, 2012). Marozzi & Jeffrey (2012) divided these
representations into three broad categories; external positional information (e.g. landmarks,
boundaries), diffuse non-positional contextual cues (e.g. color, task instructions) and selfmotion information. Place cells usually have one or two place fields (i.e. a ‘receptive field’ in
this case the location to which a place cell responds). These place fields are thought to be
generated by different receptive fields from the grid cells, called ‘grid fields’ (Moser, Kropff
& Moser, 2008).
Spatial properties of grid, head-direction and border cells
As can be seen in figure 1, grid cells have multiple receptive fields ‘mapping’ the floor of an
environment. Because grid fields have different spacing, ranging from approximately 25 cm
for cells situated dorsally, to several meters for the ventral cells (Marozzi & Jeffrey, 2012), it
has been proposed that the different grid fields combine linearly to generate the place fields
(O’Keefe & Burgess, 2005; Moser, Kropff & Moser, 2008). Cells that are in close vicinity of
each other have similar receptive fields regarding spacing and orientation but are offset
relative to each other (Marozzi & Jeffrey, 2012). The combined activation of several grid cells
would result in a peak of activation at the location where most of the grid cells are in phase,
resulting in a place field (Moser, Kropff & Moser, 2008). The fact that grid cells are found in
the entorhinal cortex (EC), which is the main cortical input to the hippocampus where the
place cells reside, further supports this idea.
Grid cells are also important in a process known as ‘path integration’. Path integration
relies on proprioceptive, vestibular and efference copies from intended movements to provide
information about self-motion. It contains information about the location of the animal, based
on its own movement. Besides information on self-motion, grid cells also use environmental
information to create and adjust their grid fields. Initially, the fields are determined by
intrinsic self-motion information, however, grid fields can be altered after changes in a
familiar environment (Marozzi & Jeffrey, 2012). Nevertheless grid cells maintain their firing
pattern even when completely deprived of environmental cues (e.g. dark room). This ability to
mediate between self-motion based information and information from the environment is
why grid cells are likely to play an important role in path integration.
Not only the grid cells but also the head-direction and border cells are important parts
of the cognitive map as spatial sensitive neurons that help explain how space is represented in
the brain. Head-direction cells act as a neural compass, and show the same mediating
properties as grid cells that make them likely to be important in the path integration process.
Although less is known about how border cells interact with the other spatial sensitive cells, it
has been proposed be important for grid cells since the grid fields can be deformed after
changes to the environment. Border cells do not show this remapping (Marozzi & Jeffrey,
2012). Reacting to changes is an important ability of these cells, since our environment is
subject to constant changes.
Updating the cognitive map
Our environment is far from static and animals have to constantly adapt to changes. An
impressive feat of place cells is the ability to adjust to alterations in our environment. The
degree of change varies however, warranting the need for a system that can react to different
environmental changes. If the environment has changed significantly, the cognitive map
should be able to distinguish it as novel. Indeed Marozzi & Jeffrey (2012) stated that about
50% of the cells keep expressing place fields after significant changes. However, their place
fields are unrelated to the locations they coded in the previous environment. Apparently the
cells are used to generate a new map of the unfamiliar environment, a process called
‘remapping’.
Small changes however, should not lead to complete remapping for obvious reasons.
In 2005, Leutgeb and colleagues differentiated between two kinds of remapping: rate
remapping and global remapping. Global remapping is a complete reorganization of
hippocampal place cells which normally happens when an environment changes completely,
for instance when moving from one environment to another (McNaughton, Battaglia, Jensen,
Moser & Moser, 2006). It allows us to recognize similar experiences that occur in different
spatial contexts (Leutgeb et al., 2005). In contrast, rate remapping allows us to distinguish
different kinds of experiences that take place in the same environment. Place cells do this by
either changing only the firing rates of the cells while maintaining the location of the place
fields (rate remapping) or, in case of global remapping, changing both the firing rate and the
location to statistically independent values (Leutgeb et al., 2005).
Concluding, place cells have the ability to decide if environmental changes are
substantial enough to warrant remapping, and if so, distinguish between rate remapping and
only change firing rate and global remapping by changing both firing rate and location. To do
so we need memory traces. Sensory information accompanying the experience has to be
compared to the memory trace to decide if the environment is; constant (recognized), changed
(familiar) or completely novel. The hippocampus is likely to be an important structure in this
process, as small differences in cortical input are hypothesized to be amplified as they
propagate through the hippocampal network (McNaughton et al., 2006). Importantly, there is
evidence that strongly suggest that place cells and other spatially sensitive cells represent
memory traces.
Hippocampal memory system and spatially sensitive neurons
A long tradition of research on hippocampal involvement in episodic memory combined with
the discovery of place cells led to the suggestion that the physiology of spatial encoding
allowed the cells to function as a memory trace (Moser, Kropff & Moser, 2008; Marozzi &
Jeffery, 2012). Several findings supported this hypothesis, more or less indirectly. First, Lever
and colleagues (2002) found that place fields are able to remain stable for several weeks.
Second, by using ‘pattern completion’, place cells can hold this stability after minor changes
to an environment. This allows the animal to stay orientated in familiar environments even
when certain landmarks or features have changed. In contrast, when the environment changes
too much, ‘pattern separation’ helps create distinct representations (Bird & Burgess, 2008).
Bird & Burgess (2008) defined pattern separation as “a process by which small differences in
patterns of input activity are amplified as they propagate through a network”, similar to the
definition of McNaughton et al. (2006). Pattern completion/separation and memory processes
have often been associated with an attractor network. This is a network of neurons that have
recurrent connections and one or more preferred patterns of firing rates called ‘stable states’.
The stable states depend on the strength of the connections. Pattern completion occurs when
the network ends up in one of the stable states (Bird & Burgess, 2008). This is related to the
earlier discussed rate remapping, the environment has to be compared to memory traces
before they can signal whether or not the animal is in a novel or familiar environment.
Nakazawa and colleagues (2004) listed four necessary attributes of memory traces.
First, the memory trace should be experience dependent; place cells should only encode for
spatial locations after an environment has been experienced. This is a relative straightforward
attribute, but it has been difficult to prove; Nakazawa et al. (2004) stated that the code of a
novel space improves rapidly with exploration of the environment but monitoring of single
cells proves to be difficult because the speed of improvement in the coding is too fast.
Furthermore, Marozzi & Jeffery (2012) described sequences of place cell activation during
sleep that was highly correlated with the sequence of activation during the original experience
in wakefulness. It was proposed that this is part of the consolidation process; by replaying the
experiences, memories can be transferred or copied to the neocortex (Marozzi & Jeffrey,
2012). However, these sequences have also been observed even before an environment has
been explored. This is a correlation between sleep and waking place cell activation sequences
and the function of this phenomenon is not yet clear. The second, third and fourth attribute are
supported by more convincing results. After re-exposure to an environment a unique set of
place cells is reactivated (criterion 2). Furthermore, the firing patterns are persistent and
remain stable after the animal is exposed to the information (criterion 3). Finally, when an
animal is presented with a subset of the original cues, the same set of place cells are
reactivated (criterion 4) (Nakazawa et al., 2002; Muller & Kubie, 1987; Nakazawa, McHugh,
Wilson & Tonegawa, 2004).
Another reason why place cells are suggested to be neural memory traces is the role of
long term potentiation (LTP) in the formation place fields and the activity of place cells. The
first clue was that NMDA receptor (NMDAR)-dependent LTP is essential in the hippocampal
memory system (Nakazawa et al., 2004; Isaac, Buchanan, Muller & Mellor, 2009). LTP is an
enhancement of signal transmission due to a synchronous stimulation of neurons and it has
been widely proposed to play a crucial role in learning and memory. This synaptic plasticity is
important because this chemical process allows for a strengthening of the synapse. Hebb
(1949) already proposed memory might be encoded this way. It has been proposed that place
fields emerge through LTP like mechanisms (Moser, Kropff & Moser, 2008; Isaac et al.,
2009). Indeed, NMDAR-dependent LTP has been observed in place cell firing patterns, but
only when the place cells showed overlapping place fields. The same study also showed that
LTP in place cell firing patterns rely on cholinergic tone, which increases in behavioral
conditions such as exploration (Isaac et al., 2009). Both pharmacological intervention and
gene knock-out studies have been performed to study LTP and place cell activity with mixed
results. Kentros et al. (1998) blocked NMDAR using an antagonist on CA1 place cell
formation and maintenance called CPP. They found that the formation and short term stability
of the place fields were independent of NMDAR activation. In contrast, long-term stability of
newly formed place fields relied on NMDAR functioning (Kentros et al., 1998). This
contrasts gene knock out studies who did find NMDAR dependent LTP in place field
formation (Nakazawa et al., 2003). Nakazawa and colleagues (2004) explained this difference
by highlighting the methodological differences of gene knock-out and pharmacological
studies. Pharmacological studies show less regional specificity but have superior temporal
control. The exact role of NMDAR dependent LTP in place fields formation and maintenance
is not yet entirely clear. For now, the consensus is that new place cell activity can be initiated
even when NMDARs are blocked, however, NMDAR-dependent plasticity is thought to be
crucial for place cell map stability (Kentros et al., 1998; Isaac et al., 2009; Nakazawa et al.,
2004). Importantly, these studies support the hypothesis that place cells are neural memory
traces. Next, I will focus on the temporal properties of the place cells and discuss the recently
discovered (and possibly related) ‘time cells’.
Temporal processing in the hippocampus
Already since Hebb (1949) described his cell assembly theory it has become clear that the
temporal dimension of neural representations is important in our thought as well as our
learning and memory capabilities. His theory stated that persistent or repetitive activity of cell
assemblies induces lasting cellular changes that add to its stability. He emphasized that
temporal precedence is a requirement in this process. The hippocampus has been implicated
in both recollection and episodic memory making it a likely candidate to play an important
role in the temporal processing of memories.
Interestingly, evidence also suggests that place cells have a temporal aspect to them.
Neuronal populations in the hippocampus show membrane oscillations in the theta range (612 Hz). Place cells show theta phase precession when animals run through its place fields.
This means that place cells fire at progressively earlier phases of the theta rhythm when
animals follow a fixed path (O’Keefe & Recce, 1993; Marozzi & Jeffery, 2012; Moser,
Kropff & Moser, 2009). This phase precession is highly correlated with an animal’s location
(Marozzi & Jeffery, 2012). Thus, using the phase of the theta oscillation the brain can
determine the relative locations of the place fields. The precise neuronal mechanisms behind
temporal processing of place cells are not yet clear, but temporally sensitive neurons have
been discovered that are suggested to bridge the gap (MacDonald, Lepage, Eden &
Eichenbaum, 2011).
Time cells
In 2011, MacDonald and colleagues discovered pyramidal cells in the same region of the
hippocampus where the place cells are found. These cells responded to specific moments in a
temporally structured sequence. They were dubbed ‘time cells’ because they are thought to be
analogous to place cells in the sense that where place cells encode locations of a spatially
structured environment, time cells encode moments in a temporally structured period
(Eichenbaum, 2013). The task that MacDonald et al. (2011) used involved rats that had to
learn associations between specific objects and certain odors with a 10 second delay. Initially,
rats were presented with an object which they had to poke with their nose. When they poked
the object a 10 second delay followed after which the rat had to respond to one of two odors
to get a reward. Figure 2 shows the task and the hippocampal neurons that fire sequentially,
together filling the 10 second delay period.
Fig 2. In the task (left), rats had to poke the object and, after a 10 second delay, respond to an odor. The neuronal firing sequence (right)
suggest that this assembly of neurons encode moments in time. Taken from Eichenbaum (2013) without permission.
The firing sequence reflected the passage of time even after controlling for location, head
direction and movement speed (MacDonald et al., 2011; Eichenbaum, 2013). Time cells seem
to show the same characteristics of memory traces, described by Nakazawa et al. (2004), as
place cells do. First, time cell activation patterns are experience dependent. In a typical
experiment, rats are taught that a specific delay of time exists between two events (for
example, exposure of an object followed by a scent; Eichenbaum, 2013). Time cells become
sensitive for a specific moment in time within this delay. Second, time cell activation patterns
are unique for each moment within this delay (MacDonald et al., 2011).
Similarities and differences between place and time cells
Time and place cells show some striking similarities. First, time cells parse temporally
defined periods in specific chunks, just like place cells parse spatially defined environments.
Thus, these cells are either responsive to a moment in time or a specific place in the
environment. The spatial or temporal receptive fields of these cells are referred to as ‘placefields’ and ‘time-fields’ respectively. Although ‘re-timing’ has not yet been looked at so
extensively as remapping, alterations in the temporal dimension of the task do seem to cause
re-timing of hippocampal time cells (MacDonald et al., 2011). Eichenbaum (2013) also noted
that that the properties of the time cells parallel the properties of place cells in other ways. He
stated that place and time cells could have a similar input source; the medial entorhinal cortex,
which is an important relay station for neocortical input to the hippocampus (Eichenbaum,
2013). Furthermore, time and place cells have been found to incorporate both temporal and
spatial information. Whether a time/place cell becomes sensitive to spatial or temporal
information is thought to depend on the context in which learning occurs (Eichenbaum, 2013).
Finally, both place and time cells have been found in the CA1 sub region of the hippocampus.
(MacDonald et al., 2011; O’Keefe & Dostrovsky, 1973). Eichenbaum (2013) concluded two
important things that warrant more discussion. First, I will discuss his idea that time and place
cells are not distinct cell type. Although some evidence has been brought forward, it remains
circumstantial. The interaction with the spatially sensitive cells described above will be of
special interest. Second, Eichenbaum (2013) claims that these cells establish a spatial and
temporal framework for organizing episodic memories. The spatial processing of episodic
memory and its neural underpinnings have been discussed and studied at length, the evidence
for time cells as a neural mechanism for temporal aspects of episodic memories is weaker
Distinct or similar cells
Summarizing the similarities described above, Eichenbaum (2013) concluded that the
distinction between temporal or spatial encoding of pyramidal cells in the hippocampus is
caused by the experimental designs of the different studies. Although some evidence supports
this notion, ‘pure’ time cells have been discovered in the hippocampus (Kraus, Robinson,
White, Eichenbaum & Hasselmo, 2013). In an attempt to dissociate time and distance as much
as possible, Kraus et al. (2013) used an experimental design in which rats ran through a
modified version of the T-maze. At the start of maze, instead of roaming free, the rats had to
run in a treadmill, while also holding in working memory whether to go left or right. Trials
varied between ‘time-fixed’, where rats had to run for a certain amount of time and ‘distancefixed’, where they had to run a certain distance. Using different treadmill speeds, they argued
that time and distance were sufficiently dissociated (Kraus et al., 2013). The majority of the
cells (70%) activity was best explained by both time and distance. A minority of neurons
responded exclusively to time (8%) or distance (11%), suggesting ‘pure’ time and/or place
cells do exist. However, the majority of cells seem to have the characteristic that Eichanbaum
(2013) proposed. It is not yet known how this switching or differentiating of cells occurs.
Jezek, Henriksenm, Treves, Moser & Moser (2011) suggested a role for theta cycles and
thought time and distance information could be represented by different phases of the theta
oscillation, but Kraus et al. (2013) found no such distinction.
As described above, a substantial part of our spatial processing relies on interactions
between the spatially sensitive neurons. If time and place cells’ sensitivity to temporal or
spatial information is interchangeable, it follows that time cells may also interact with the
neurons that were thought to be exclusively sensitive to space. This begs the question whether
grid/head-direction/border cells are also involved in temporal processing. Of these cells, grid
cells are the most likely to be involved in temporal processes. Grid cells are also the most
interesting because it has been suggested that grid fields combine linearly to directly inform
the place cells about where to fire (Marozzi & Jeffery, 2012; Moser, Kropff & Moser, 2008).
Importantly, if grid fields, through Hebbian learning, contribute to a certain place field and
place fields can also be time fields depending on the context then grid fields are likely to
contribute to time fields as well. If a given cell can switch between place and time cells, either
the grid cells have to discriminate between signaling spatial and temporal information or they
too can signal both spatial and temporal information depending on context. Nevertheless,
somewhere the information needs to be classified as spatial or temporal. Where and how this
happens has yet to be solved. After place and time cells’ supposed role in episodic memory, I
will return to the importance of the hippocampal-entorhinal cortex system.
Place & Time cells and episodic memory
One network state of place cells activation in the hippocampus is suggested to play an
important role in consolidating memories. Sharp-wave/ripple (SWR) events are sequences of
place cell activation that are highly similar to the ones observed during wakefulness
exploration (Marozzi & Jeffery, 2012). Perhaps this place cell ‘replay’ contributes to the
transferring of these memories to the neocortex, enabling us to recall the environment without
having to be there. However, this replay can occur both forwards and backwards (future
exploration) and so the function of SWR-associated replay still has to be determined.
Eichenbaum (2013) argues that time cells are able to bridge the gap in the current
literature on hippocampal function in episodic memory and spatial mapping. The time cells
are hypothesized to provide a temporal framework for episodic memory. This is a tempting
conclusion since place cells show a prominent role in both spatial processing and episodic
memory. However paradigms investigating time cells all have used relatively short delay
periods and MacDonald et al. (2011) made the safer conclusion that it is mainly a way to
bridge small temporal gaps in events.
If time cells provide a temporal framework of episodic memory, then they should
show the same stability over time but they should also extend their activation longer delay
periods. Indeed Hassabis & Maguire (2007) already pointed out that when we talk about time
in episodic memory, there are at least 2 types that are relevant. The moment by moment order
of a certain event of sequence is called ‘micro-time’. The experiments used for time cell
research have a relatively short temporal dimension, so when time cells are discussed in the
light of episodic memory, it is most probably micro-time that is discussed. Hassabis and
Maguire (2007) conclude it is an intrinsic property of episodic memory. Micro-time ensures
that episodic memories are recalled in the same or reverse sequence in which they were
encoded. The second type is called ‘macro-time’ concerns our subjective sense of time,
closely related to the autonoetic awareness described by Tulving (2002) and explained above.
It has been proven difficult to provide evidence that suggest a distinct neural mechanism for
this kind of time in episodic memory (Hassabis & Maguire, 2007). Here again, the neural
mechanisms seem to underlie multiple cognitive processes. At the moment, macro-time is
somewhat elusive and sometimes viewed as a reconstructive process of a particular memory
and its semantic knowledge (Hassabis & Maguire, 2007).
For now, it is unlikely that time-cells are able to provide our subjective sense of time
in episodic memories. One line of research argues that temporal processes and episodic
memory is supported by the gradual changes of neural representation over time. Recovering
this variable neural representation enables us to jump back in time, accompanied by our
subjective experience of mental time travel. It is not entirely clear how the different
timescales, episodic memory and the hippocampus are related. One study argued that the
hippocampus is necessary for keeping track of elapsed time since an event, on fine temporal
discriminations, between long intervals (8 vs. 12 min), but not for the same temporal
resolution on a shorter timescale (1 vs. 1.5 min) (Jacobs, Allen, Nguyen & Fortin, 2013). So
then, time cells are not critical for the timescales generally used in the time cell paradigm.
Instead, Jacobs and colleagues (2013) state that they are important for “temporally
segregating individual events within the context of an unfolding sequence of events”.
Arguably, this is exactly what happens in the 10 second delay period described earlier. For
longer intervals, hippocampal-entorhinal interactions could be important.
The hippocampal-entorhinal cortex system
Combining different studies we are left with three different mechanisms for the broad range
of intervals of temporal processing in the medial temporal lobe. First, the time cells described
above provide a way of temporal ordering of events on a second to minute’s timescale. Like
Eichenbaum (2013) argued, the mechanisms that keep information about past memories,
spatial processes and planned goals are also able to keep track of time and bridge
noncontiguous events (Buzsáki & Moser, 2013). Time cells do not seem to just ‘mindlessly’
keep track of time, but also provide a temporal context. This is supported by findings that the
firing sequences change when the delay between cue and response is changed. Combined with
Kraus’ et al. (2013) finding that the majority of cells firing patterns are explained by both
spatial and temporal processes, it provides support for Eichenbaum’s (2013) hypothesis that
these are not (always) distinct cell types. However, other mechanisms are thought to be
important for longer intervals.
The second mechanism was described by Mankin and colleagues (2012). Here, they
looked at firing consistency and similarity over time. This consistency over longer intervals is
a necessity for Eichenbaum’s hypothesis that these cells function as a temporal framework for
episodic memory. Mankin et al. (2012) looked at intervals of hours and days and found a
distinction between the CA1 and CA3 region of the hippocampus. They found that neuronal
activity in the CA1 diverges after longer intervals (i.e. 6-h compared to 1-h). This diverging
provides a way for events that are separated by longer intervals to be represented by distinct
neuronal representations. This contrasted cell assemblies in the CA3 regions which showed a
high degree of similarity in their firing patterns over both longer and shorter intervals
(Mankin et al., 2012). Thus, they concluded that the CA1 region of the hippocampus is
required for the temporal coding over extended time periods. This is reflected by the
decreasing similarity of firing patterns over longer delay intervals. The stability in firing
patterns of the CA3 region is thought to provide a stable spatial and contextual representation,
often associated with pattern completion (Mankin et al., 2012). So far, this supports
Eichenbaum’s (2013) hypotheses, since time cells were discovered in the CA1 region of the
hippocampus, just as the variability on the firing patterns were found in the CA1 region and
not the CA3 region. Arguably, this could also subserve our re-experiencing of past events.
Even though recollecting our personal past appears as a continuous process, it usually
involves chunks or parts of an episode at any one time. Another study provided insight into
how item (what) and timing (when) information are integrated for episodic memories (Naya
& Suzuki, 2011). The hippocampus provides “a robust incremental timing signal” that
anchors temporal information to events within an episode. This time information flows to the
entorhinal cortex and perirhinal cortex. Here it is integrated with item information from visual
cortices (Naya & Suzuki, 2011).
However, the question remains on how the different (sub)structures and firing patterns
are related. For instance, the variable firing patterns of the CA1 receive input from the CA3
region, which show similar firing patterns over time. Here, it is thought that input from the
entorhinal cortex contributes to CA1’s variable firing pattern (Mankin et al., 2012). Indeed,
the third layer of the entorhinal cortex has been associated with processing timing
information, although possibly to a lesser extent than in the hippocampus (Suh, Rivest,
Nakashiba, Tominaga & Tonegawa, 2011; Naya & Suzuki, 2011). However, the direction of
flow is unclear. According to Naya & Suzuki (2011) timing information in the service of
episodic memory flows from the hippocampus to the entorhinal cortex. In contrast, Mankin
and colleagues (2012) suggested that information from the entorhinal cortex contribute to the
firing patterns in the hippocampus. There are two closed loop networks present in the
hippocampal-EC network. The preforant path
(PP) is the main input source from the EC to
the hippocampus. It has two major projections
(figure 3). One originating in layer II of the
EC which project to granule cells of the
dentate gyrus (DG) and pyramidal cells of the
CA3 region (trisynaptic pathway; TSP). The
other originates in layer III of the EC and
projects to the subiculum and the CA1 region
(monosynaptic pathway; MSP). Furthermore,
axons from CA3 region project to the CA1
region
which
in
turn
send
the
main
Fig 3. The main input pathways of the hippocampus; the
preforant path (PP). Layer III of the EC to subiculum
(Sub) and CA1 (red line, MSP) and layer II of the EC to
DG and CA3 (blue line, TSP). Axons from CA3 project
to CA1, where output is being send back to the EC
through the Sub using two pathways, forming two
closed loops. Taken without permission from Suh et al.
(2011).
hippocampal output back to the EC through
the subiculum via two pathways, forming two closed loop networks. Given these connections
between the hippocampal-entorhinal cortex network, reciprocal communication is inevitable
and brain systems involved in spatial processes, memory and temporal processes have been
found to overlap to a great extent (O’Keefe & Nadel, 1978; Burgess, Maguire & O’Keefe,
2002; Buzsáki & Moser, 2012). However, how these connections and the direction of flow are
connected to function is not entirely understood.
Conclusion
There has been a long tradition of research on hippocampal involvement in episodic memory,
spatial memory processes and, more recently, temporal processes of memory. The discovery
of space cells and other spatially sensitive neurons greatly boosted our knowledge on spatial
processes in the hippocampus and episodic memory. The more recent discovery of time cells
seems to do the same for temporal processes in the hippocampus. Similarities between time
and place cell characteristics led to the proposition that they are not distinct cell types, but
rather that these cells become sensitive to either spatial or temporal information based on the
context in which learning occurs (Eichenbaum, 2013). This is an interesting suggestion since
we know a lot more about place cells than we do about time cells. Although some evidence
support this idea (Kraus et al., 2013), a notable difference is the range of spacing for spatially
and temporally defined environments. Spatially defined environments are somewhat limited
in range; place and or grid fields of centimeters to meters are sufficient to “map” the
environment spatially. This is accounted for by the topographical organization of place and
grid cells. In contrast, a temporal environment, especially in human episodic memory, has a
larger reach and it is unclear how this can be accounted for. Furthermore, somewhere the
information needs to be classified as spatial or temporal. For both these issues, the
hippocampal-entorhinal cortex system might be interesting to look at for several reasons.
First, it has been suggested that grid fields in the entorhinal cortex combine linearly to directly
inform the place cells about where to fire (Moser, Kropff & Moser, 2008; Marozzi & Jeffery,
2012). However, in transgenic mice in which the layer III input of the entorhinal cortex to the
hippocampus (i.e. the monosynaptic pathway) are specifically inhibited, place fields’ basic
properties were unaffected (Suh et al., 2011). Arguably, the other afferent projection from the
EC to the hippocampus (i.e. the trisynaptic pathway) is important for place cell properties.
Second, the different temporal scales (e.g. minutes/hours/days) have been related to the
variable EC input to the hippocampus. If place and time cells are the same cells that
differentiate based on context of the learning phase, then time cells should also be unaffected
by inhibiting the MSP providing entorhinal input to the hippocampus. This is a counterintuitive hypothesis, since the MSP provides the more direct route to the CA1; the region
where time cells have been discovered.
Figure 4 depicts the discussed findings. The colored arrows indicate the need for more
evidence. Nevertheless, just like place cells’ topographical arrangement provides them with a
way to represent multiple spatial domains, it can be argued that with varying their firing
sequence, time cells also have this ability (Mankin et al., 2012). Although this mechanism
does not exclude other mechanisms to account for the multiple domains it is a great step
forward in arguing the role for these cells in episodic memory. As already stated, although the
recollections of our episodic memories appear continuous, it often involves chunks or parts.
This emphasized the need for these multiple domains. Together, it supports the idea that the
multiple aspects of memories (what, where & when) coexist in the hippocampus. Even though
time stamps over days or weeks or the integration of this time information with the other
aspects of episodic memories might be explained by other mechanisms, it could still be able
to account for a substantial amount of temporal processes in episodic memory. Especially
since it has been argued that the order of a sequence (micro-time) is an intrinsic property of
episodic memory (Hassabis & Maguire, 2007). In contrast, it has been questioned whether
macro-time (subjective time) can be distinguished from other processes in episodic memory.
Furthermore, temporal information has also been proven to be a poor retrieval cue for
episodic memory (Hassabis & Maguire, 2007). Thus, a crucial part of temporal properties of
episodic memories is the order of events, for which these cells are particular well suited.
Hippocampus
Domains
Seconds – hours
Time cells (CA1)
Entorhinal
interactions with HC
Firing sequence
variability
Spatiotemporal
properties of
Episodic memory
Context
Centimeters - meters
Place cells (CA1/3)
Topographical
arrangement
Fig 4. Schematic overview of the discussed findings. The colored arrows indicate the need for more evidence. Entorhinal input to
the hippocampus has been related to the creation of place fields, but this has been questioned by genetic studies. It has been
proposed that cells become sensitive to either temporal or spatial information depending on the context in which learning occurs
(red arrow). However, both cells seem to have the ability to represent multiple domains. Together they are thought to underlie a
substantial part of the spatiotemporal properties of episodic memory
Concluding, there is substantial evidence that supports the idea that temporally
sensitive neurons in the hippocampus are an important component of episodic memory,
reflected by mechanisms for multiple time domains. However, the interaction between the
hippocampus and the EC needs to be investigated further. Studies investigating the
importance of this interaction for the basic properties of time and place cells showed mixed
results. Importantly, EC input to the hippocampus has been related to both the creation and
stability of place fields as well as providing a way for time cells to parse events with longer
intervals with distinct (variable) neural representations. Even though this supports
Eichenbaum’s (2013) hypothesis that time and place cells are not distinct cells, the
importance of the hippocampal-EC connections for the basic properties of both time and place
cells is not entirely clear.
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