REVIEWS

Prefrontal–hippocampal interactions
in episodic memory
Howard Eichenbaum
Abstract | The roles of the hippocampus and prefrontal cortex (PFC) in memory processing —
individually or in concert — are a major topic of interest in memory research. These brain areas
have distinct and complementary roles in episodic memory, and their interactions are crucial for
learning and remembering events. Considerable evidence indicates that the PFC and
hippocampus become coupled via oscillatory synchrony that reflects bidirectional flow of
information. Furthermore, newer studies have revealed specific mechanisms whereby neural
representations in the PFC and hippocampus are mediated through direct connections or
through intermediary regions. These findings suggest a model of how the hippocampus and PFC,
along with their intermediaries, operate as a system that uses the current context of experience
to retrieve relevant memories.

Oscillatory synchrony
Coordination of local field
potential oscillations and
spiking activity in two
connected brain areas.
Usually observed as a locking
of the phase of oscillatory
activity within a specific
frequency band.
Center for Memory and Brain,
Boston University, Boston,
Massachusetts 02215, USA.
hbe@bu‑edu
doi:10.1038/nrn.2017.74
Published online 29 Jun 2017
The hippocampus and prefrontal cortex (PFC) have long
been established as having important roles in episodic
memory. Studies in humans and animal models indicate
that the hippocampus plays a key part in organizing mem-
ories in the context in which they were experienced — a
defining feature of episodic memory — whereas the PFC
controls the retrieval of context-appropriate memories by
suppressing competing, context-inappropriate memories.
Over the past several years, many studies have high-
lighted interactions between the hippocampus and the
PFC as also having an essential role in episodic mem-
ory. Although the existence and importance of these
interactions are well established, until recently we knew
very little about the roles of specific pathways and func-
tional interactions between the PFC and the hippo­
campus that support memory. However, new work has
pursued the nature of these interactions using opto­
genetics and other neurobiological tools to manipulate
activity in PFC–hippocampal pathways, and suggests
specific roles for different pathways. Indeed, there is
now considerable evidence that PFC–hippocampal
interactions during episodic memory tasks are medi-
ated via oscillatory synchrony of neural activity in these
areas. One pathway for interaction involves a direct
projection from the ventral part of the hippocampus
to the PFC, and there are other indirect pathways
through intermediary thalamic and cortical routes that
are bidirectional.
Here, I aim to briefly review earlier findings about
the roles of PFC–hippocampal interactions and then
integrate the new observations towards a comprehen-
sive understanding of the functional circuitry by which
this system supports cognition and memory. I begin
with a short overview of the contributions of the hippo­
campus and PFC to memory processing, of the anatom-
ical connections between these areas and of the role of
their interactions in memory. I review new evidence on
the nature of information conveyed and when commu-
nication occurs via each of these routes. I suggest that
the ventral hippocampus (vHPC) conveys information
about contextual cues to the PFC, that the PFC exerts
top-down control over the hippocampus via a cortical
pathway and that oscillatory synchrony is mediated by
the thalamic intermediary. A synthesis of these obser-
vations suggests that these interactions contribute at
different stages of memory processing to support our
ability to use the current context to guide episodic
memory retrieval.
Distinct contributions
Hippocampus. At the outset of modern cognitive neuro-
science, observations on the patient H.M., whom, owing
to intractable epilepsy, had his hippocampus surgically
removed bilaterally and thus became amnesic, revealed
a crucial role for the hippocampus and adjacent corti-
cal areas in human memory 1. Notably, early studies on
hippocampal function in rodents and monkeys did not
readily reproduce the severe amnesia observed in H.M.2.
However, many later studies have converged on the view
that the hippocampus itself in humans and other mam-
mals supports a common kind of memory processing.
This kind of memory is characterized by a representa-
tion of relations between events and their context that
compose memories for specific experiences — known as

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Recognition memory
The ability to remember
stimuli presented earlier, by
later correctly recognizing
those stimuli and by correctly
rejecting other stimuli that
were not previously
experienced.
Wisconsin Card Sorting Test
A card-sorting task in which
participants must switch
strategies to sort cards
according to different
parameters, such as rank, suit
or colour.
episodic memory — as well as an organization of rela-
tions between memories that compose world knowledge
— so‑called semantic memory 2–4.
In rodent models, many studies have identified
a crucial role of the hippocampus when there is a strong
demand for remembering events in the spatial and tem-
poral context in which they occurred3–9. Correspondingly,
many studies have reported that hippo­campal firing
patterns represent specific objects and events within a
spatial and temporal context 10–17. For example, in a task
in which rats use the current spatial context to identify
which of two objects contains a reward, hippocampal
neurons robustly encode conjunctions of particular
objects, their reward values, their positions within a spa-
tial context and the general context in which they are
experienced12 (see ‘context-guided memory’ in BOX 1).
In addition, recent studies have revealed a topography
of the specificity of hippocampal memory representa-
tions in humans and animals. Thus, whereas neurons
in the dorsal hippocampus (dHPC) of rodents encode
highly specific locations and object–place combina-
tions, as described above, neurons in the vHPC code
for large areas of space18,19 and distinguish events that
occur in different spatial contexts in rodents, as well
as humans20–22.
Prefrontal cortex. The role of the PFC in memory was
not immediately obvious in early neuropsychological
studies on humans with prefrontal damage. For exam-
ple, H.M. performed very poorly on a facial recognition
memory test but normally in the Wisconsin Card Sorting
Test, which does not require episodic or semantic mem-
ory but relies on the ability to suppress a competing
response strategy 23. By contrast, a patient known as
K.M., who had prefrontal damage but whose hippo­
campus was spared, performed normally in face recog-
nition but poorly in card sorting. K.M. thus represented
a striking ‘control’ patient with no apparent memory
deficit despite extensive brain damage.
Subsequent to these early studies, decades of research
have provided considerable converging evidence indi-
cating that the PFC does contribute to memory by
top-down (cognitive or strategic) control of memory
processing 24–30. In particular, patients with prefrontal
damage do not have severe impairments in episodic
memory but are impaired when target information
must be remembered under various interference or
distraction conditions, or when they must distinguish
the source or context of information learned. For exam-
ple, when individuals first learn a set of verbal paired
associates (such as ‘apple–table’), then must learn new
associations using the same items (‘apple–ball’), patients
with prefrontal damage are severely impaired in learning
the new associations for the original elements, and the
impairment is marked by intrusions of the original asso-
ciates31. Even when learning two lists of unrelated associ-
ations, in patients with prefrontal damage, memory for
one list is compromised by intrusions from the other.
Parallel results have been reported on recognition
memory for lists of familiar stimuli in animals. In these
studies, dependence on the PFC or the hippocampus
is most readily detected in tasks that involve memory
for items within a specific context (for example, within
a specific list) and strong interference from prior expe-
riences (for reviews, see REFS 30,32). For example, in an
experiment in which rats were tested daily on recognition
memory for lists of odour stimuli, hippocampal lesions
impaired memory for odours that had appeared on the
list for that day 33, whereas prefrontal damage did not
reduce memory for those odours but instead resulted in
‘false’ recognition of odours from lists on the previous
days34 (FIG. 1). Of note, ageing results in a combination
of both types of memory impairment 35. PFC lesions also
result in intrusions of irrelevant memories in studies on
selective attention to specific cues36 and extinction of
conditioning to a fearful context 37, and the notion that
the PFC suppresses intrusions in memory is supported by
anatomical studies in primates and rodents that empha-
size projections from the PFC to inhibitory neurons in
cortical areas38. In addition, consistent with impairment
under conditions of high interference in humans with
PFC damage, several studies on the effects of PFC lesions
in rats have shown that the PFC is crucial for learning to
switch between memory strategies in various tasks39–43.
For example, PFC lesions impair the ability of rats to
switch between moving towards a particular place and
making a particular response at the choice point in a
plus-shaped maze40 (BOX 1). Complementary physio­
logical studies in rats44–49 and monkeys50–55 have shown
that prefrontal neuronal activity reflects the changing of
a ‘set’ or ‘rule’ that guides strategy switching. For example,
neural activity patterns in the PFC differ during place-
guided and response-guided performance as rats alternate
between those strategies in the plus-maze task45 (BOX 1).
These findings support Miller and Cohen’s56 proposal
that PFC and hippocampal functions might operate
interactively in memory processing, and this inter-
action might be understood by allusion to a ‘railroad’
metaphor in which the hippocampus is responsible for
laying down new ‘tracks’ (that is, episodic memories),
whereas the PFC is responsible for flexibly switching
between these tracks according to contextual rules. The
hippocampus and PFC may interact closely in support
of these complementary functions.
Prefrontal–hippocampal pathways
The PFC and hippocampus are strongly connected by
direct and indirect pathways. Recent studies of PFC–­
hippocampal interactions in animal models have
focused on the multiple different pathways and types
of interaction, leading to different models of functional
circuitry. Here, I provide a brief overview of the anatomy
of PFC–­hippocampal connections.
Both the hippocampus and the PFC receive and send
many projections to many cortical and subcortical areas,
so there is a very large number of pathways by which
the hippocampus and PFC could indirectly interact. In
addition, there remains uncertainty about the precise
homologies between specific prefrontal areas in rodents
and primates (BOX 2), challenging any definitive compar-
ison of pathways between the PFC and the hippocampus
in, for example, rodents versus in humans.

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Box 1 | Tests of episodic memory in rodents

Various behavioural tests have been used to assess episodic memory in
animals. Here are examples of some of the tests described in this Review that
highlight memory for a specific event within the context in which it was
experienced — a key characteristic of episodic memory (see the figure).
Context-guided memory
This task involves two spatial contexts (contexts 1 and 2, which may differ
in visual and tactile surfaces) and multiple objects that are presented in
each context (part a). Each trial has two phases. The animals first explore
one of the contexts in the absence of the object stimuli; subsequently, two
objects (A and B) are arranged in either of two left–right configurations for
the animals to sample. On trials performed in context 1, a reward is found
in object A (not B), whereas, in context 2, reward is found in object B
(not A). This task strongly tests ability to remember the reward associations
of specific cues in the context in which they were experienced and to use
the current context to guide selection of the rewarded object.
Place versus response learning
Trials in a plus-shaped maze always begin at the end of the ‘north’ (N) and
‘south’ (S) arms, and rewards are provided at the ends of ‘east’ (E) or ‘west’
(W) goal arms (part b). Under the ‘place’ rule, to obtain reward, the rat
must always go to the east arm, regardless of whether it started in the
north or south arm. Under the ‘response’ rule, the rat must turn left to
obtain reward, regardless of whether that response leads to the east or
west goal arm. Animals are tested for their ability to learn each rule and for
their ability to switch between rules when reward contingencies are
changed. This task requires memory for the appropriate response in the
context of the current rule.
Delayed non-match to place
This task involves discrete sample and choice phases in a T-maze (or
Y-maze). On each trial, in the sample phase, one of the goal arms is
blocked, and the animal goes to the open goal arm to receive reward.
Then, in the choice test phase, after a delay, both goal arms are open, and
the animal must select the arm not entered in the sample phase to receive
another reward (part c). Unlike delayed alternation, this test distinguishes
trial phases in which the animal encodes the sample from a later phase in
which its choice response is guided by memory for the sample.
Delayed spatial alternation
Animals begin each trial at the base of a T-maze (or Y-maze) and then turn
left or right to enter one of the goal arms in alternating order, with
a memory-demanding delay in between alternations (part d). This test
assesses the ability to remember the experience of the immediately
preceding trial and therefore provides a simple test of memory for
a specific episode.
Contextual fear conditioning
In this task, rodents initially explore an environment and develop a
representation of that spatial context, and then are given mild footshocks,
resulting in freezing behaviour and other signs of fear when subsequently
re‑placed in that context (part e). This test of memory for the context in
which shocks occurred is commonly used in animal models of episodic
memory. A variant of this task is the inhibitory avoidance task, in which
animals can avoid entering the spatial context associated with a shock101.
Object exploration
This test exploits the natural tendency of rodents to explore less recently
experienced objects and objects in novel locations (part f). In the
object-location version of the test, animals are initially exposed to two
objects; then, after a delay, one of the objects is moved, and the animals
tend to spend more time exploring the moved object. In the
object-recency version of the task, animals are exposed successively to
pairs of identical objects in the same places and then are presented with
one copy of each object; the animals tend to spend more time exploring
the less recently experienced object.

a Context-guided memory b Place versus response learning c Delayed non-match to place

Context 1 Context 2 Place N Response
A+ B+ W E
S
Delay

B– A–

d Delayed spatial alternation e Contextual fear conditioning

Explore Mild shock Test

Delay Delay

f Object exploration
Object location Object recency

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a Odour list memory task b Performance change following lesions or ageing

Hippocampal lesion mPFC lesion Ageing
+0.2
Study
• Lemon
• Cinnamon
• Oregano
• Cumin

Change in rate
Delay 0
Test Response
• Cinnamon Old Hit
• Coriander New Correct rejection
• Sage New Correct rejection
• Lemon New Miss
• Cumin Old Hit
• Dill Old False alarm
• Parsley New Correct rejection
• Oregano Old Hit Hit False alarm
–0.3

Figure 1 | Functions of the prefrontal cortex and the hippocampus in memory. An odour list-learning
Nature Reviews | task reveals
Neuroscience
a functional dissociation between the roles of the medial prefrontal cortex (mPFC) and and of the hippocampus in rats.
a | In the study phase of this task, rats are presented with a set of odour stimuli (with a new set chosen each day) from
a limited stimulus pool. Then, following a delay, the studied stimuli and the same number of non-studied stimuli taken
from the pool are presented in a random order. Rewards are given when the rats correctly recognize the studied stimuli
(‘hits’) and when they correctly identifies the non-studied stimuli (‘correct rejections’) but not when they fail to
recognize studied items (‘misses’) or when they incorrectly identify non-studied items as if they were studied (‘false
alarms’). Because the to‑be‑studied odours are selected each day from the same limited pool, this task demands
memory for the odours studied in the context of the current list. Memory is scored in two ways: the proportion of hits,
which indicates the strength of memory for studied items in the current list; and the proportion of false alarms, which
measures the tendency for intrusions of items studied on earlier testing days. b | Changes in performance (as
a proportion of responses) in rats following bilateral lesions of the hippocampal or bilateral lesions of the mPFC or with
age. Animals with hippocampal lesions have a decrease in the hit rate, with no change in false alarms33. Animals
with mPFC lesions have no change in hits but do show an increase in false alarms34. Notably, aged rats (24‑months old)
have both a decrease in hits and an increase in false alarms35.

Nucleus reuniens
(Re). A midline nucleus at the
centre of the thalamus that
bidirectionally connects
the prefrontal cortex with the
hippocampus.
Nevertheless, there is considerable evidence that
the basic patterns of PFC–hippocampal connections
are largely similar in rodents and primates57–60. For
the remainder of this Review, I focus on the medial
PFC (mPFC), which has been the focus of most recent
research on PFC–hippocampal interactions. Three
prominent pathways — characterized in most detail
in rats — connect the mPFC and hippocampus (FIG. 2).
A central question is whether these direct and indi-
rect pathways have distinct functional roles in PFC–­
hippocampal interactions (see below).
The first is a well-known monosynaptic projection
from area CA1 of the vHPC and proximal subiculum
(extending to the portion of the hippocampus inter-
mediate between the vHPC and dHPC, but commonly
referred to as part of the vHPC pathway) broadly to all
layers of the mPFC, as well as the orbital PFC61–63. This
projection provides the most immediate access of PFC
areas to information processed by the hippocampus.
What is the nature of that information? Whereas neu-
rons in the dHPC seem to have firing patterns that are
highly spatially localized, neurons in the vHPC that
project to the PFC show much broader spatial and
contextual coding 18–20 (see also REF. 64). Therefore, the
signals that are sent from the hippocampus directly
to the PFC may concern global information about
the context of current events rather than detailed
memories.
There are two main pathways that involve a single
intermediary between the hippocampus and the mPFC:
one via the thalamus and the other via a cortical route.
The thalamic pathway includes bidirectional connec-
tions between the thalamic nucleus reuniens (Re) and all
mPFC areas, and bidirectional connections between the
Re and hippocampal CA1 throughout its dorsal–­ventral
extent, as well as the perirhinal cortex (PRC) and
entorhinal cortex 65–69. The Re is believed to be part of
the thalamocortical circuitry that probably has a global
role in synchronizing interactions between the PFC and
hippocampal areas69–71. This anatomical and physio­
logical evidence suggests that the Re is well placed to
couple the mPFC, the hippocampus and related areas,
supporting the transfer of information that underlies
their interactions in cognitive processing.
With regard to cortical pathways, the mPFC is con-
nected with many cortical areas through which extended
pathways can influence the hippocampus. Of these con-
nections, the mPFC is most directly, and bidirection-
ally, connected to the PRC and lateral entorhinal cortex
(LEC), which in turn are strongly connected bidirection-
ally with the hippocampus72–75. The mPFC projects to
superficial layers of the PRC and deep layers of the LEC,
and the reciprocal projections terminate in layers I, II and
VI of the mPFC74,75. Areas of the mPFC also project to the
medial entorhinal cortex (MEC), but more weakly than
to the LEC72. Given that the PRC and LEC are specialized

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Crossed lesions
Unilateral inactivation or
lesion of each of two areas in
opposing hemispheres, thus
leaving each area intact in
one hemisphere but
eliminating ipsilateral
connections between them.
Theta oscillations
Oscillations in the local field
potential or spiking activity in
the 4–12 Hz frequency band
originating in the medial
septum.
Local field potentials
Recorded electrical activity
patterns that reflect both
synaptic potentials and spiking
activity of many neighbouring
neurons within a brain area.
Oscillatory patterns in local
field potential reflect
synchronous neural activity at
particular frequencies.
for representing information about objects and specific
behavioural events76–78, mPFC–­hippocampal interactions
via this route may be better suited for the processing of
object and event representations than for spatial coding.
Interactions in memory
Direct evidence that the mPFC and hippocampus inter-
act in support of memory comes from studies on the
effects of disconnecting these areas and from studies
on oscillatory synchronization associated with memory
processing.
Disconnection studies. Some studies have explored the
role of mPFC–hippocampal interactions by testing
the behavioural effects of crossed lesions that disconnect
ipsilateral PFC and hippocampal areas in rats (FIG. 3a).
Typically, these studies first show that bilateral lesions
or inactivation of either the mPFC or the hippo­campus
either before learning or the memory test produce
a memory deficit in a particular task, thereby confirm-
ing that both areas play essential parts. By contrast, uni-
lateral lesions of both the PFC and hippocampus in the
same hemisphere are typically found to spare the studied
aspect of memory, indicating that a unilateral combina-
tion of these areas and the pathways between them is
sufficient to support memory. Disconnecting the mPFC
and the hippocampus — by inactivating or removing
the mPFC in one hemisphere and the hippocampus in
the other hemisphere — impairs memory, thereby indi-
cating that ipsilateral mPFC–hippocampal interactions
are crucial.
Such disconnection analyses have revealed that
mPFC–hippocampal interactions are crucial to remem-
bering where79 and when80–82 stimuli were previously
experienced in tasks in which rats normally prefer to
spend more time exploring objects that are in novel
locations or that were experienced longer ago than other
objects (BOX 1). In addition, disconnection of the mPFC
and hippocampal areas also impairs delayed non-­
matching to place memory 83 and delayed spatial alter-
nation84 (BOX 1). These studies provide robust evidence
that the mPFC and hippocampus support memory via
an ipsilateral pathway.
Oscillatory synchrony. Complementary evidence of cru-
cial PFC–hippocampal interactions in memory comes
from several studies that have described strong oscillatory
synchrony between the mPFC and the hippo­campus,
specifically of theta oscillations (4–12 Hz), which sup-
ports accurate memory (FIG. 3b). These studies typically
involve correlating spiking activity in the mPFC with
the local field potentials in the theta band recorded from the
dHPC. An initial study 85 reported that spiking activity
in the mPFC was synchronized to hippocampal theta
as animals performed various spatial tasks, including
a spatial working-memory test on an eight-arm maze,

Box 2 | Do rats have a prefrontal cortex?

In primates, the prefrontal cortex (PFC) is characterized by an internal granular layer, but this defining cytoarchitectural
marker is lacking in the rodent prefrontal areas118,119. Also, in primates (see part a in the figure), areas in the dorsolateral
PFC (dlPFC), ventromedial PFC (vmPFC) and orbital PFC (OFC) are distinguished on the basis of topographical
connections with areas in the mediodorsal thalamic nucleus118,119. In the rat, neurons located in the mediodorsal thalamus
also project to the anterior cortex in an organization that distinguishes medial PFC (mPFC) areas (the anterior cingulate
(aCg), prelimbic area (PL) and infralimbic area (IL)) and the OFC (parts b,c). However, rodents lack mediodorsal thalamic
connections to a dorsolaterally positioned prefrontal area that is the focus of many studies of PFC in primates. These
observations have led to doubts about whether rats have a ‘PFC’ and, even if they do, whether prefrontal areas are
homologous in rodents and primates. Thus, one possibility is that areas of the rodent mPFC compose the homologue of
the vmPFC in primates42,120–122, but it is also possible that the rodent mPFC is simply ‘undifferentiated’ between areas that
are distinguished as vmPFC and dlPFC in primates123.
It is unlikely that the issue can be resolved on anatomical grounds alone. More important, with regard to models of
functional circuitry, is evidence that there are strong parallels in the roles of prefrontal areas in rodents and in primates. In
rodents, there is strong evidence for selective involvement of the mPFC in switching between stimulus domains — as
contrasted with involvement of the OFC in switching reward contingencies — and these findings parallel the same
distinctions in the dlPFC and OFC in monkeys124,125. There are also strong similarities in the functions of the mPFC in rodents
and of the dlPFC in primates in
examples of executive function, a b c
including in visuospatial delayed vmPFC mPFC
responses, in attention and in
decision making126,127. There is also
strong evidence that the rodent aCg
mPFC and the human vmPFC play PL
similar parts in the integration of
IL
memories29. These findings support OFC OFC
the tentative conclusion that the
rodent mPFC supports the same
fundamental cognitive processing
functions as those served by
dlPFC
a combination of the vmPFC and
dlPFC in primates. Adapted with
permission from REF. 128, Frontiers.

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Hippocampus PFC In addition, a magnetoencephalography study in

CA1
PL
iHPC
OFC
CA3 Re
IL
PRC
LEC vHPC
Direct hippocampus-to-PFC pathway
Bidirectional pathway via the Re
Bidirectional pathway via the PRC and LEC
Nature Reviews
Figure 2 | Indirect and direct prefrontal–hippocampal pathways. | Neuroscience
The ventral
hippocampus (vHPC) (as well as some more dorsal regions of the hippocampus such
as the intermediate hippocampus (iHPC)) sends direct connections to different regions
of the prefrontal cortex (PFC), including the orbital PFC (OFC), the prelimbic cortex (PL)
and infralimbic cortex (IL). In addition, two bidirectional connections between the
PFC and the hippocampus exist: one via the thalamic nucleus reuniens (Re) to
hippocampal area CA1 and the other via the perirhinal cortex (PRC) to hippocampal area
CA1 and lateral entorhinal cortex (LEC) to hippocampal areas CA1 and CA3.
delayed alternation on a T-maze (BOX 1) and running on
linear or circular tracks. Extending these findings, a sep-
arate study 86 (see also REF. 87) observed increased theta
synchrony between spiking in the hippocampus and
mPFC as animals performed a delayed non-matching
to place task (which tests memory for a recently visited
place (BOX 1)) and showed that mPFC spiking was more
strongly correlated with dHPC theta when animals were
remembering a visited place than during the initial visit
to the place.
Furthermore, mPFC cells with specific behavioural
correlates during spatial behaviour (for example, neu-
rons that are activated when the animal makes a specific
turn or runs in a specific direction) are predominantly
synchronized with hippocampal theta88. In a delayed
matching to place task, the proportion of mPFC cells
entrained to theta is much higher during both encoding
and retrieval phases on trials when recall is accurate than
during error trials, despite no difference in the firing
rates of these cells between accurate and error trials89.
This increase in theta coherence between the mPFC
and the hippocampus was confirmed in animals as they
successively learned two reward-contingency rules on
a Y-maze (first, go to the arm on the right, then go to
the illuminated arm), with peak theta coherence and
Phase shifts
phase locking observed when animals were at the criti-
Changes in the temporal cal choice point in the maze90. In addition, these mPFC
coordination of spiking activity neurons showed theta phase shifts as animals learned
that, in many brain areas, is the new rule90. Strong mPFC–hippocampal coherence
closely time-locked to the
has also been observed in tasks in which spatial context
phase of a particular oscillation
in the local field potential. determines object–reward associations91,92. A separate
study 93 extended the findings on mPFC–hippocampal
Gamma synchrony to the vHPC, confirming that synchrony is
Oscillations in the local field associated with successful delayed non-match to place
potential in low (30–80 Hz) or
high (80–140 Hz) frequency
performance and showing that PFC–vHPC synchrony
bands (defined differently supports performance even when the influence of dHPC
among different studies). is removed.
humans revealed that, as participants successfully inte-
grated associations that contained common elements
(for example, if A is associated with B, and B is asso-
ciated with C, inferring that A and C are also related),
hippocampal theta power and coherence with mPFC
theta increased94.
Directional flow of information. It is generally believed
that the purpose of cross-area synchronization is to sys-
tematically transfer information from one area to the
other, and potentially in both directions95–97. Directional
flow has been explored in several studies using an analy-
sis in which the maximal correlation of signals between
two areas is determined by calculating the magnitude
of correlation when the signal from one area is artifi-
cially time-shifted compared with the other incremen-
tally over a large range of shifts. For example, in an early
report85 of mPFC–hippocampal synchrony, such ana­lysis
showed maximal correlation when hippocampal theta
was shifted earlier than mPFC spiking by ~30 ms, sug-
gesting that information flows from the hippo­campus
to the mPFC, and this was confirmed in studies on
increased synchrony with learning 98.
In addition, two recent studies have provided evi-
dence of communication in both directions between
the hippocampus and the mPFC during different phases
of memory processing. In one of these two studies, the
authors trained rats in both a delayed spatial alternation
task (BOX 1), which demands memory for the immedi-
ately preceding experience over a delay, and a conditional
spatial discrimination task, which does not demand
trial-­specific memory 98. Coherence of theta in the dHPC
and mPFC correlated with choice accuracy only on the
memory-demanding task. Furthermore, when animals
waited in a start box during the memory delay before
each alternation trial, dHPC theta preceded theta in the
mPFC by ~30 ms on correct trials but not on incorrect
trials. By contrast, when animals traversed the maze
choice point in making the memory-driven decision, the
mPFC preceded the dHPC in the low-­frequency gamma
range (30–80 Hz), again only on correct trials. Neither
direction of communication was observed in the task
that did not demand memory on each trial. Thus, main-
taining the memory of the previous trial during the delay
involved dHPC‑to‑mPFC communication, whereas
retrieving the previous memory or planning the choice
response involved mPFC‑to‑dHPC communication.
In the other study of the directional flow of infor-
mation between the mPFC and the hippocampus92,
the authors explored mPFC–hippocampal functional
connectivity in a task in which rats learned that each
of two different spatial contexts cued different object–
reward associations (context-guided memory (BOX 1)).
During task performance, theta activity in the mPFC
and hippo­campus are strongly coherent, both when
animals entered a context and when they sampled the
objects before making the choice response (FIG. 3b). Upon
context entry, functional connectivity analysis indicated
that hippocampal theta preceded that in the mPFC by
~30 ms, indicating a flow of contextual information from

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a Crossed lesions information flow 85, were on the order of 30 ms, a period
Memory impaired Memory impaired Memory intact Memory impaired that exceeds the delay for a monosynaptic connection
(15 ms (REF. 99)). This observation suggests a more com-
plex network phenomenon in which the theta rhythm
synchronizes activity between brain areas, and the infor-
mation might be transferred in segments of about 30 ms,
which corresponds to a gamma cycle. Alternatively, this
relatively long delay might reflect polysynaptic effects
even in the monosynaptic pathway, if information is con-
veyed via multisynaptic connections from interneurons
Intact Lesioned to pyramidal cells within the mPFC85.
b Oscillatory synchrony
~30 ms ~30 ms The roles of specific pathways
Context cue Memory retrieval
Several recent studies using state‑of‑the-art neuro­
biological approaches have begun to identify the func-
Voltage

Voltage

tional roles of the specific pathways between the mPFC

and the hippocampus.

0 20 40 60 80 100 120140 160180 200 0 20 40 60 80 100 120 140 160 180 200
Time (ms) Time (ms)
PFC Hippocampus
Nature Reviews
Figure 3 | Prefrontal–hippocampal interactions. a | Crossed-lesion | Neuroscience
studies have shown
that bilateral lesions of the medial prefrontal cortex (mPFC) or hippocampus result in
impairment in various episodic memory tasks (see main text), implying that each plays
a crucial part in memory. Unilateral lesions in one hemisphere have no effect, showing
that an intact unilateral pathway between the mPFC and the hippocampus in the
non-lesioned hemisphere is sufficient to support memory. Crossed lesions (that is,
damage to the mPFC in one hemisphere and to the hippocampus in the other
hemisphere) impair memory, indicating that an ipsilateral mPFC–hippocampal pathway
is necessary. b | Oscillatory synchrony is a key feature of interactions between the
hippocampus and the mPFC92. During presentation of a contextual cue and during
a memory delay, hippocampal theta precedes that in the mPFC. By contrast, during
memory retrieval, theta oscillations in the mPFC precede those in the hippocampus. The
bidirectional information flow carried in synchrony involves leads of approximately
30 ms, which is equivalent to the length of one gamma cycle.
the hippocampus to the mPFC. Conversely, when ani-
mals began to sample an object before their decision, the
direction of information flow reversed, with mPFC theta
leading hippocampal theta by ~30 ms, consistent with
the flow of information from the mPFC to the hippo­
campus. Furthermore, both directions of functional
connectivity were observed only on trials in which the
animal subsequently made the correct response, indicat-
ing that the increase in functional connectivity predicted
memory accuracy. Importantly, the comparison between
correct trials and errors was restricted to those trials in
which the animals made the same behavioural response,
either to the correct (rewarded) or to the incorrect
(non-rewarded) object, thus eliminating the possibility
that the differences in connectivity were due to distinct
behaviours or different expectations of reward.
Although the reason why these two studies92,98 differed
in the maximal frequency band of functional connec-
tivity observed during the decision phase of their tasks
remains unclear, both studies indicated that communi-
cation between the hippocampus and the mPFC is bidi-
rectional and suggest that distinct memory processes are
associated with opposing directions of the flow of infor-
mation. Note also that the leads observed in both of
these studies, as well as in the earlier report of directional
The direct hippocampus-to‑mPFC pathway. This
pathway was recently studied using a delayed non-
match‑to‑place task (BOX 1) in which a sample spatial cue
signalled the correct response in the subsequent choice
phase100 (much as the spatial context signals the object–
reward associations in the context-guided memory task).
During task performance, vHPC terminals in the mPFC
were optogenetically inactivated for brief periods dur-
ing the sample phase or during the subsequent memory
delay or choice phase. Inactivation of vHPC terminals
in the mPFC during the sample period disrupted coding
of the sample location by mPFC cells and impaired sub-
sequent choice accuracy, whereas the same inactivation
was ineffective when applied during the delay or choice
phase. An additional analysis of functional connectivity
in the same study showed that gamma-locked spiking
activity in the vHPC preceded that in the mPFC dur-
ing the sample phase, whereas mPFC theta oscillations
preceded those in the vHPC during the choice phase.
Furthermore, vHPC-terminal inactivation disrupted
the vHPC‑to‑mPFC connectivity (but not reciprocal
connectivity), and vHPC‑to‑mPFC connectivity was
stronger during the sample phase and correlated with
memory accuracy. These findings indicate that informa-
tion from the vHPC was crucial for encoding the sample
location but not for maintaining the memory during the
delay or for subsequent memory expression and that
the functional connectivity during this sample phase
arose via the direct vHPC‑to‑mPFC pathway. An addi-
tional confirmation of a role for hippocampus-to‑mPFC
projections was demonstrated in a study using a vari-
ant of contextual fear conditioning. In this experiment,
chemo­genetic inactivation of terminals in the prelim-
bic area that arose from the dHPC blocked reminder-­
induced fear memory, whereas inactivation of dHPC
terminals in the infralimbic area blocked extinction101
(for a general review of the PFC in fear conditioning,
see REF. 37).
The pathway via the nucleus reuniens. Other stud-
ies have focused on the indirect pathway between the
mPFC and the hippocampus via the thalamic Re. A tet-
anus toxin molecular control system was used in mice to

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reversibly inactivate specific projections from the mPFC
that influenced the acquisition of the standard version
of contextual fear conditioning (BOX 1) and subsequent
generalization of fear to a different spatial context 102.
Inactivation of the mPFC or the mPFC‑to‑Re pathway
did not affect contextual fear acquisition but instead
caused an overgeneralization from the training context
to another context; furthermore, this inactivation was
effective only if applied during the initial training and
not if applied during fear expression. This finding sug-
gests that PFC–hippocampal interactions are important
in distinguishing a context during initial learning just as
they are during memory retrieval.
In addition, optogenetic stimulation of the Re that
resulted in predominant excitation caused increased
freezing in the new context, whereas stimulation that
resulted in predominant inhibition reduced freezing 102.
These results identified an essential role for the Re in
mPFC–hippocampal interactions in the specificity of
memory encoding. However, because the manipulation
of the Re involved artificial patterns of excitation and
inhibition, it is possible that, rather than directly com-
municating specific information between areas, the Re
may exert a general modulatory influence required for
specificity of memory coding.
The role of the Re in the specificity of memories was
also studied in rats performing a continuous spatial
alternation task (as in ‘delayed spatial alternation’ shown
in BOX 1, but without delays between trials)103. Neurons in
the mPFC, Re and CA1 fired at different rates as animals
traversed the common segment of left-turn and right-
turn routes through the maze. In CA1, this ‘rate coding’
of memories for specific trajectories was eliminated by
halorhodopsin-mediated optogenetic inactivation of the
Re. Furthermore, memory-specific firing increased in
the Re and CA1 as the animal reached the end of the
common segment of the maze, suggesting that the Re
coordinates mPFC–hippocampal communication as the
critical choice is engaged. In a delayed spatial alternation
task (BOX 1), muscimol-mediated inactivation of the Re
during the memory delay or the choice phase decreased
phase-locking of mPFC spiking to dHPC theta and elim-
inated bidirectional functional connectivity between the
dHPC and the mPFC98.
The combined findings of these studies indicate that
the Re supports bidirectional synchronization and com-
munication important for the specificity of memory. In
particular, the finding that artificial activation by opto­
genetic stimulation can enhance memory 102 suggests that,
rather than bearing information about specific memories,
the Re has a modulatory role. Also, although Re firing
rates differentiated maze routes, Re firing patterns did not
contain detailed information about spatial trajectories103,
suggesting that Re neuronal activity may instead reflect
a general biasing of mPFC and hippocampal ensem-
bles that do represent spatial trajectories. Moreover, the
results of these studies differ on whether the Re is more
important during encoding or retrieval periods, suggest-
ing that different memory processing demands in these
behavioural paradigms may differentially engage the flow
of mPFC–hippocampal communication.
Top-down control via other routes from the mPFC
to the hippocampus. Other pathways from the mPFC
to the hippocampus can mediate both a general modu-
lation and specific control of hippocampal representa-
tions. One study reported discovery of a direct pathway
from the anterior cingulate cortex, which is considered
to be a part of the mPFC area, to hippocampal areas CA1
and CA3 (REF. 101) (see also REF. 104). Using a variant of
a contextual fear-conditioning paradigm, the authors
of this study found that optogenetic activation of anterior
cingulate projections to CA3 modulated the engagement
of memory-specific CA3 neuronal representations and
expression of fear memories. This finding suggests that an
anterior cingulate projection may have direct top-down
control over the hippocampal memory processing.
Early in training on a context-guided memory task
(BOX 1), many dorsal CA1 neurons initially fire at low
rates during the sampling of an object in a particular
place; then, associated with successful learning, some
of these neurons begin to fire selectively in response
to one object in a particular place and context 12. One
study building on this research examined the influ-
ence of the mPFC and MEC on memory performance
and on firing patterns of dorsal CA1 neurons in rats
performing a context-guided memory task105 (see also
REF. 106). The firing patterns of these CA1 neurons
were characterized before and after either the mPFC
or the MEC was inactivated by muscimol infusion. This
approach revealed that bilateral inactivation of either
the mPFC or the MEC strongly reduced memory per-
formance (as does mPFC–hippocampal disconnec-
tion106), whereas unilateral inactivation of either area
had no effect 105. In addition, bilateral inactivation of
the mPFC, or unilateral mPFC inactivation ipsilat-
eral (but not contralateral) to the recorded CA1 cells,
resulted in a specific loss of object selectivity of the
responses of these cells without affecting their spatial
specificity. That is, the CA1 neurons fired robustly in
response to multiple objects sampled in the same place
where, before treatment, they were activated for a sin-
gle object. By contrast, MEC inactivation resulted in
a broad ‘remapping’ of both object and spatial coding
in the dHPC, such that dHPC neurons stopped fir-
ing, developed firing in response to places or objects,
or changed their firing pattern unpredictably. Thus,
whereas the MEC determines the overall organization
of CA1 firing patterns, the mPFC has a selective role
in determining the specificity of object (though not
spatial) memory representations and, consistent with
the crossed-lesion studies (see above), this influence is
mediated via an ipsilateral pathway.
Towards a new model
How might the findings described above inform our
understanding of the nature of mPFC–hippocampal
interactions that support memory? Here, I present
a tentative model that focuses on context-guided mem-
ory, a common situation in which a current contextual
cue or another recent experience guides the retrieval of
specific memories (FIG. 4). When a subject is presented
with a specific contextual cue12, or is cued by a previous

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Post-learning consolidation experience98,100, the Re coordinates the vHPC‑to‑mPFC
A prolonged period (hours to flow of information, and the vHPC sends information
months) after learning, over relating to the contextual cues or previous experi-
which memories that are ence to the mPFC via the direct pathway. Then, when
initially unstable become
stable. This process is thought
the animal must make a choice between alternative
to involve the integration of memory-­g uided responses 92,98, the Re reverses the
new episodic memories into flow of information by coordinating the mPFC‑­to‑­
a semantic memory network. hippocampus pathways, and the mPFC suppresses
context-­inappropriate representations in the PRC
and LEC to provide top-down control over retrieval of
specific memories in the dHPC.
This bidirectional dialogue is consistent with the
experimental findings described above. Flow of con-
textual cues from the vHPC to the mPFC is consist-
ent with the observation that the vHPC represents
the specific contexts in which particular events have
occurred20 and with anatomical evidence on the direct
pathway from the vHPC to the mPFC61. The flow of
rule-based, top-down influences from the mPFC to the
hippocampus is consistent with: observations that
the PFC develops abstract rule-like representations49,56;
a Context presentation
Re synchrony
mPFC dHPC
Re
vHPC
Contextual cues
b Memory retrieval Bias memory retrieval
A+
mPFC dHPC
Re
B–
vHPC
PRC and LEC
Nature Reviews | Neuroscience
Figure 4 | A model of prefrontal–hippocampal functional interactions. Here, a model
of medial prefrontal cortex (mPFC)–hippocampal interactions in episodic memory is
illustrated using the example of the context-guided memory task (BOX 1). a | When
contextual cues are presented, the nucleus reuniens (Re) engages synchrony directed
from the hippocampus to the mPFC to send contextual information from the ventral
hippocampus (vHPC) to the mPFC. b | Subsequently, during context-guided memory
retrieval, the Re engages synchrony directed from the mPFC to the hippocampus such
that the mPFC biases retrieval of specific memories in the hippocampus. dHPC, dorsal
hippocampus; LEC, entorhinal cortex; PRC, perirhinal cortex.
evidence that the mPFC projects directly to the PRC
and LEC, which contain neurons that encode specific
objects and events59,77; evidence that the PRC and LEC
gate information entering the hippocampus107; and
reports that the mPFC suppresses irrelevant memories
in rats34,105. In addition, the model is consistent with
findings indicating that the direction of communi-
cation is from the hippocampus (and specifically the
vHPC) during a memory delay 98 or when cued by
a context 92 or prior experience100, whereas communi-
cation is directed from the mPFC to the hippocampus
during memory retrieval and choice making 91,92,98, and
with findings implicating the Re as being crucial for
directional synchronization98.
Acquisition, consolidation and recall
Although this Review has focused on the role of mPFC–
hippocampal interactions in memory retrieval, other
studies have focused on the contributions of this system
during the acquisition and post-learning consolidation
of memories. There is strong evidence in rodents and
humans that the mPFC and the hippocampus are jointly
involved during the integration of new information
into existing knowledge organizations (known as
schema building)108–110. In these tasks, the mPFC may
play a key part in reconciling conflicts between new
and existing associations during the course of learn-
ing to facilitate assimilation of the new memories into
an updated memory organization44. Such a function
parallels the role of mPFC–hippocampal interactions
in reconciling competing memory during retrieval, as
discussed above29.
There is also evidence that the mPFC has a role in
memory consolidation, in that it supports remotely
acquired memories. Immediately after the learning
phase in various memory tasks, the engagement of the
mPFC and other cortical areas is relatively low, whereas
hippocampal activation is high. However, over several
days, these levels of engagement reverse such that the
mPFC and other cortical areas become more acti-
vated during retrieval of remotely acquired memories,
whereas the hippocampus becomes less activated; after
this point, mPFC damage selectively blocks remotely
acquired memories111–113. Further studies have observed
markers of plasticity within the mPFC during initial
learning, even though the mPFC does not become cru-
cial for representing memories until several days after
initial encoding 114,115. One possibility consistent with the
role of the mPFC described above is that, in some tasks
in which a newly acquired memory is very strong (for
example, in contextual fear conditioning), other earlier
acquired memories do not initially compete for expres-
sion. Yet, over time, as the strength of the new mem-
ory fades somewhat, the mPFC becomes increasingly
more important in integrating these remotely acquired
memories with other stored information (for example,
the initial exposure to a neutral context before shock)
during retrieval49. This idea is very speculative, and
our understanding of the precise roles of the mPFC
and interactions with the hippo­campus during learn-
ing and remote memory expression will be improved

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Box 3 | Implications for psychiatric disorders Conclusions

Several lines of converging evidence indicate that the
Characteristics of the prefrontal cortex (PFC)–hippocampal system offer promise mPFC and hippocampus have complementary roles
for understanding and developing new treatments for psychiatric disorders. in memory processing. The hippocampus is crucial for
In particular, three key features of schizophrenia could be related to a dysfunction of organizing memories within the context in which they are
PFC–hippocampal interactions emphasized in this Review.
experienced, whereas the mPFC has an essential role in the
First, the PFC and hippocampus are most strongly implicated in the neuropathology
retrieval of context-appropriate memories. Furthermore,
of the schizophrenic brain129–131. Correspondingly, the cognitive deficits that are
highlighted in the neuropsychology of schizophrenia parallel deficits observed in
the mPFC and hippocampus interact to serve memory via
people who have sustained damage to these brain areas4. Thus, individuals with multiple pathways that support synchronization and bidi-
schizophrenia are impaired in working-memory tasks and several aspects of rectional exchange of specific information. Based on evi-
executive function and cognitive control132, similar to deficits found in patients with dence from recent studies of the roles of specific pathways,
PFC lesions30. In addition, individuals with schizophrenia have impaired episodic a tentative model suggests that the Re mediates the occur-
memory and are specifically deficient in memory for items in context and in rence of oscillatory synchrony and direction of informa-
several tests of memory organization133–139, similar to deficits following damage tion transfer; the direct vHPC‑to‑mPFC pathway supports
to the hippocampus3. transfer of contextual cues to the mPFC; and the pathway
Second, there is substantial evidence of diminished functional connectivity between through the PRC and LEC supports top-down control
the PFC and the hippocampus in schizophrenia and of an association between this by the mPFC in the retrieval of context-appropriate
reduction and cognitive impairment140,141, paralleling the effects of PFC–hippocampal memory representations in the dHPC.
disconnection in rats79 and consistent with findings on PFC–hippocampal oscillatory
There remain several missing elements of the model
coherence and memory in normal cognitive and memory function90,92, and in a rodent
that could confirm or refute this model. In particular, the
model of schizophrenia87. Thus, symptoms of schizophrenia are associated with
abnormal PFC–hippocampal interactions, as measured in various neurophysiological
specific role of the bidirectional PRC and LEC pathway
and functional imaging studies140–143. has not been determined. The model predicts that the
Third, there is an emerging consensus that a core cognitive disturbance in mPFC controls the specificity of memory representa-
schizophrenia is a failure to use context to control the activation of appropriate tions in these cortical areas and that this information is
stored associations — the fundamental mechanism of PFC–hippocampal interactions then passed on to the dHPC116. Thus, mPFC inactivation
in the model proposed here144,145. Thus, individuals with schizophrenia are impaired at should reduce the specificity of memories in the PRC
tasks in which they must use context-setting cues to determine the appropriate and LEC, whereas inactivation of the PRC and/or LEC
response to a following stimulus144,146,147. Impairment in this fundamental capacity should reduce the capacity of dHPC neurons to respond
could contribute to the intrusions of inappropriate and unwanted thoughts that to specific stimuli. Also, the studies discussed above
are characteristic of hallucinations, delusions and disorganization of thoughts vary in the synchronizing frequencies that carry signals
in psychosis145. between the mPFC and the hippocampus in different
These observations suggest that the neurobiological mechanisms and pathways
behavioural paradigms, suggesting that a more detailed
highlighted in the model offered here could guide further application of new
analysis of the particular cognitive functions that involve
neurobiological tools to examine the roles of specific neuron types and their
connections within local circuits that support the contributions of each component of these synchronizations is needed.
this system148, as well as studies on their interactions. This enterprise could ultimately The application of the proposed model to differen-
constitute the new endeavour in circuit psychiatry through which new treatments are tiate periods of context processing and encoding and
developed based on aberrant neural processing within and between PFC and retrieval of phases of memory processing different
hippocampal circuits117. memory tasks offers a guide to future research on the
functional circuitry that underlies memory and deci-
sion making supported by the mPFC–hippocampal
Circuit psychiatry by further studies on information processing by mPFC system. Furthermore, because this system is implicated
The use of powerful neuronal networks during learning and retrieval at in major psychiatric disorders, the application of mod-
neurobiological tools to identify, different times, and by studies that aim to inform us els of mPFC–hippocampal interactions holds consid-
monitor and manipulate specific
brain circuits to advance
about the contributions of the mPFC to development of erable promise for understanding the circuit basis for
knowledge of normal brain network representations in the hippocampus and other mental disorders, offering promise of new circuit-based
function and mental disorders. cortical areas. approaches to therapy development 117 (BOX 3).

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Acknowledgements
The author acknowledges funding from the US National
Institute of Mental Health (grant numbers MH094263,
MH051570 and MH052090).
Competing interests statement
The author declares no competing interests.
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional
claims in published maps and institutional affiliations.

558 | SEPTEMBER 2017 | VOLUME 18 www.nature.com/nrn

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