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Prefrontal-Hippocampal Interactions in Episodic Memory: Howard Eichenbaum
Prefrontal-Hippocampal Interactions in Episodic Memory: Howard Eichenbaum
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 The hippocampus and prefrontal cortex (PFC) have long this system supports cognition and memory. I begin
Coordination of local field been established as having important roles in episodic with a short overview of the contributions of the hippo
potential oscillations and memory. Studies in humans and animal models indicate campus and PFC to memory processing, of the anatom-
spiking activity in two that the hippocampus plays a key part in organizing mem- ical connections between these areas and of the role of
connected brain areas.
Usually observed as a locking
ories in the context in which they were experienced — a their interactions in memory. I review new evidence on
of the phase of oscillatory defining feature of episodic memory — whereas the PFC the nature of information conveyed and when commu-
activity within a specific controls the retrieval of context-appropriate memories by nication occurs via each of these routes. I suggest that
frequency band. suppressing competing, context-inappropriate memories. the ventral hippocampus (vHPC) conveys information
Over the past several years, many studies have high- about contextual cues to the PFC, that the PFC exerts
lighted interactions between the hippocampus and the top-down control over the hippocampus via a cortical
PFC as also having an essential role in episodic mem- pathway and that oscillatory synchrony is mediated by
ory. Although the existence and importance of these the thalamic intermediary. A synthesis of these obser-
interactions are well established, until recently we knew vations suggests that these interactions contribute at
very little about the roles of specific pathways and func- different stages of memory processing to support our
tional interactions between the PFC and the hippo ability to use the current context to guide episodic
campus that support memory. However, new work has memory retrieval.
pursued the nature of these interactions using opto
genetics and other neurobiological tools to manipulate Distinct contributions
activity in PFC–hippocampal pathways, and suggests Hippocampus. At the outset of modern cognitive neuro-
specific roles for different pathways. Indeed, there is science, observations on the patient H.M., whom, owing
now considerable evidence that PFC–hippocampal to intractable epilepsy, had his hippocampus surgically
interactions during episodic memory tasks are medi- removed bilaterally and thus became amnesic, revealed
ated via oscillatory synchrony of neural activity in these a crucial role for the hippocampus and adjacent corti-
areas. One pathway for interaction involves a direct cal areas in human memory 1. Notably, early studies on
projection from the ventral part of the hippocampus hippocampal function in rodents and monkeys did not
to the PFC, and there are other indirect pathways readily reproduce the severe amnesia observed in H.M.2.
through intermediary thalamic and cortical routes that However, many later studies have converged on the view
Center for Memory and Brain,
Boston University, Boston,
are bidirectional. that the hippocampus itself in humans and other mam-
Massachusetts 02215, USA. Here, I aim to briefly review earlier findings about mals supports a common kind of memory processing.
hbe@bu‑edu the roles of PFC–hippocampal interactions and then This kind of memory is characterized by a representa-
doi:10.1038/nrn.2017.74 integrate the new observations towards a comprehen- tion of relations between events and their context that
Published online 29 Jun 2017 sive understanding of the functional circuitry by which compose memories for specific experiences — known as
episodic memory — as well as an organization of rela- is most readily detected in tasks that involve memory
tions between memories that compose world knowledge for items within a specific context (for example, within
— so‑called semantic memory 2–4. a specific list) and strong interference from prior expe-
In rodent models, many studies have identified riences (for reviews, see REFS 30,32). For example, in an
a crucial role of the hippocampus when there is a strong experiment in which rats were tested daily on recognition
demand for remembering events in the spatial and tem- memory for lists of odour stimuli, hippocampal lesions
poral context in which they occurred3–9. Correspondingly, impaired memory for odours that had appeared on the
many studies have reported that hippocampal firing list for that day 33, whereas prefrontal damage did not
patterns represent specific objects and events within a reduce memory for those odours but instead resulted in
spatial and temporal context 10–17. For example, in a task ‘false’ recognition of odours from lists on the previous
in which rats use the current spatial context to identify days34 (FIG. 1). Of note, ageing results in a combination
which of two objects contains a reward, hippocampal of both types of memory impairment 35. PFC lesions also
neurons robustly encode conjunctions of particular result in intrusions of irrelevant memories in studies on
objects, their reward values, their positions within a spa- selective attention to specific cues36 and extinction of
tial context and the general context in which they are conditioning to a fearful context 37, and the notion that
experienced12 (see ‘context-guided memory’ in BOX 1). the PFC suppresses intrusions in memory is supported by
In addition, recent studies have revealed a topography anatomical studies in primates and rodents that empha-
of the specificity of hippocampal memory representa- size projections from the PFC to inhibitory neurons in
tions in humans and animals. Thus, whereas neurons cortical areas38. In addition, consistent with impairment
in the dorsal hippocampus (dHPC) of rodents encode under conditions of high interference in humans with
highly specific locations and object–place combina- PFC damage, several studies on the effects of PFC lesions
tions, as described above, neurons in the vHPC code in rats have shown that the PFC is crucial for learning to
for large areas of space18,19 and distinguish events that switch between memory strategies in various tasks39–43.
occur in different spatial contexts in rodents, as well For example, PFC lesions impair the ability of rats to
as humans20–22. switch between moving towards a particular place and
making a particular response at the choice point in a
Prefrontal cortex. The role of the PFC in memory was plus-shaped maze40 (BOX 1). Complementary physio
not immediately obvious in early neuropsychological logical studies in rats44–49 and monkeys50–55 have shown
studies on humans with prefrontal damage. For exam- that prefrontal neuronal activity reflects the changing of
ple, H.M. performed very poorly on a facial recognition a ‘set’ or ‘rule’ that guides strategy switching. For example,
memory test but normally in the Wisconsin Card Sorting neural activity patterns in the PFC differ during place-
Test, which does not require episodic or semantic mem- guided and response-guided performance as rats alternate
ory but relies on the ability to suppress a competing between those strategies in the plus-maze task45 (BOX 1).
response strategy 23. By contrast, a patient known as These findings support Miller and Cohen’s56 proposal
K.M., who had prefrontal damage but whose hippo that PFC and hippocampal functions might operate
campus was spared, performed normally in face recog- interactively in memory processing, and this inter-
nition but poorly in card sorting. K.M. thus represented action might be understood by allusion to a ‘railroad’
a striking ‘control’ patient with no apparent memory metaphor in which the hippocampus is responsible for
deficit despite extensive brain damage. laying down new ‘tracks’ (that is, episodic memories),
Subsequent to these early studies, decades of research whereas the PFC is responsible for flexibly switching
have provided considerable converging evidence indi- between these tracks according to contextual rules. The
cating that the PFC does contribute to memory by hippocampus and PFC may interact closely in support
top-down (cognitive or strategic) control of memory of these complementary functions.
processing 24–30. In particular, patients with prefrontal
damage do not have severe impairments in episodic Prefrontal–hippocampal pathways
memory but are impaired when target information The PFC and hippocampus are strongly connected by
must be remembered under various interference or direct and indirect pathways. Recent studies of PFC–
distraction conditions, or when they must distinguish hippocampal interactions in animal models have
Recognition memory the source or context of information learned. For exam- focused on the multiple different pathways and types
The ability to remember
stimuli presented earlier, by
ple, when individuals first learn a set of verbal paired of interaction, leading to different models of functional
later correctly recognizing associates (such as ‘apple–table’), then must learn new circuitry. Here, I provide a brief overview of the anatomy
those stimuli and by correctly associations using the same items (‘apple–ball’), patients of PFC–hippocampal connections.
rejecting other stimuli that with prefrontal damage are severely impaired in learning Both the hippocampus and the PFC receive and send
were not previously
the new associations for the original elements, and the many projections to many cortical and subcortical areas,
experienced.
impairment is marked by intrusions of the original asso- so there is a very large number of pathways by which
Wisconsin Card Sorting Test ciates31. Even when learning two lists of unrelated associ- the hippocampus and PFC could indirectly interact. In
A card-sorting task in which ations, in patients with prefrontal damage, memory for addition, there remains uncertainty about the precise
participants must switch one list is compromised by intrusions from the other. homologies between specific prefrontal areas in rodents
strategies to sort cards
according to different
Parallel results have been reported on recognition and primates (BOX 2), challenging any definitive compar-
parameters, such as rank, suit memory for lists of familiar stimuli in animals. In these ison of pathways between the PFC and the hippocampus
or colour. studies, dependence on the PFC or the hippocampus in, for example, rodents versus in humans.
B– A–
Delay Delay
f Object exploration
Object location Object recency
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.
Nevertheless, there is considerable evidence that There are two main pathways that involve a single
the basic patterns of PFC–hippocampal connections intermediary between the hippocampus and the mPFC:
are largely similar in rodents and primates57–60. For one via the thalamus and the other via a cortical route.
the remainder of this Review, I focus on the medial The thalamic pathway includes bidirectional connec-
PFC (mPFC), which has been the focus of most recent tions between the thalamic nucleus reuniens (Re) and all
research on PFC–hippocampal interactions. Three mPFC areas, and bidirectional connections between the
prominent pathways — characterized in most detail Re and hippocampal CA1 throughout its dorsal–ventral
in rats — connect the mPFC and hippocampus (FIG. 2). extent, as well as the perirhinal cortex (PRC) and
A central question is whether these direct and indi- entorhinal cortex 65–69. The Re is believed to be part of
rect pathways have distinct functional roles in PFC– the thalamocortical circuitry that probably has a global
hippocampal interactions (see below). role in synchronizing interactions between the PFC and
The first is a well-known monosynaptic projection hippocampal areas69–71. This anatomical and physio
from area CA1 of the vHPC and proximal subiculum logical evidence suggests that the Re is well placed to
(extending to the portion of the hippocampus inter- couple the mPFC, the hippocampus and related areas,
mediate between the vHPC and dHPC, but commonly supporting the transfer of information that underlies
referred to as part of the vHPC pathway) broadly to all their interactions in cognitive processing.
layers of the mPFC, as well as the orbital PFC61–63. This With regard to cortical pathways, the mPFC is con-
projection provides the most immediate access of PFC nected with many cortical areas through which extended
areas to information processed by the hippocampus. pathways can influence the hippocampus. Of these con-
What is the nature of that information? Whereas neu- nections, the mPFC is most directly, and bidirection-
rons in the dHPC seem to have firing patterns that are ally, connected to the PRC and lateral entorhinal cortex
highly spatially localized, neurons in the vHPC that (LEC), which in turn are strongly connected bidirection-
project to the PFC show much broader spatial and ally with the hippocampus72–75. The mPFC projects to
Nucleus reuniens contextual coding 18–20 (see also REF. 64). Therefore, the superficial layers of the PRC and deep layers of the LEC,
(Re). A midline nucleus at the signals that are sent from the hippocampus directly and the reciprocal projections terminate in layers I, II and
centre of the thalamus that
bidirectionally connects
to the PFC may concern global information about VI of the mPFC74,75. Areas of the mPFC also project to the
the prefrontal cortex with the the context of current events rather than detailed medial entorhinal cortex (MEC), but more weakly than
hippocampus. memories. to the LEC72. Given that the PRC and LEC are specialized
Crossed lesions for representing information about objects and specific the other hemisphere — impairs memory, thereby indi-
Unilateral inactivation or behavioural events76–78, mPFC–hippocampal interactions cating that ipsilateral mPFC–hippocampal interactions
lesion of each of two areas in via this route may be better suited for the processing of are crucial.
opposing hemispheres, thus object and event representations than for spatial coding. Such disconnection analyses have revealed that
leaving each area intact in
one hemisphere but
mPFC–hippocampal interactions are crucial to remem-
eliminating ipsilateral Interactions in memory bering where79 and when80–82 stimuli were previously
connections between them. Direct evidence that the mPFC and hippocampus inter- experienced in tasks in which rats normally prefer to
act in support of memory comes from studies on the spend more time exploring objects that are in novel
Theta oscillations
effects of disconnecting these areas and from studies locations or that were experienced longer ago than other
Oscillations in the local field
potential or spiking activity in
on oscillatory synchronization associated with memory objects (BOX 1). In addition, disconnection of the mPFC
the 4–12 Hz frequency band processing. and hippocampal areas also impairs delayed non-
originating in the medial matching to place memory 83 and delayed spatial alter-
septum. Disconnection studies. Some studies have explored the nation84 (BOX 1). These studies provide robust evidence
Local field potentials
role of mPFC–hippocampal interactions by testing that the mPFC and hippocampus support memory via
Recorded electrical activity the behavioural effects of crossed lesions that disconnect an ipsilateral pathway.
patterns that reflect both ipsilateral PFC and hippocampal areas in rats (FIG. 3a).
synaptic potentials and spiking Typically, these studies first show that bilateral lesions Oscillatory synchrony. Complementary evidence of cru-
activity of many neighbouring
or inactivation of either the mPFC or the hippocampus cial PFC–hippocampal interactions in memory comes
neurons within a brain area.
Oscillatory patterns in local
either before learning or the memory test produce from several studies that have described strong oscillatory
field potential reflect a memory deficit in a particular task, thereby confirm- synchrony between the mPFC and the hippocampus,
synchronous neural activity at ing that both areas play essential parts. By contrast, uni- specifically of theta oscillations (4–12 Hz), which sup-
particular frequencies. lateral lesions of both the PFC and hippocampus in the ports accurate memory (FIG. 3b). These studies typically
same hemisphere are typically found to spare the studied involve correlating spiking activity in the mPFC with
aspect of memory, indicating that a unilateral combina- the local field potentials in the theta band recorded from the
tion of these areas and the pathways between them is dHPC. An initial study 85 reported that spiking activity
sufficient to support memory. Disconnecting the mPFC in the mPFC was synchronized to hippocampal theta
and the hippocampus — by inactivating or removing as animals performed various spatial tasks, including
the mPFC in one hemisphere and the hippocampus in a spatial working-memory test on an eight-arm maze,
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
0 20 40 60 80 100 120140 160180 200 0 20 40 60 80 100 120 140 160 180 200 The direct hippocampus-to‑mPFC pathway. This
Time (ms) Time (ms) pathway was recently studied using a delayed non-
PFC Hippocampus match‑to‑place task (BOX 1) in which a sample spatial cue
signalled the correct response in the subsequent choice
Nature Reviews
Figure 3 | Prefrontal–hippocampal interactions. a | Crossed-lesion | Neuroscience
studies have shown phase100 (much as the spatial context signals the object–
that bilateral lesions of the medial prefrontal cortex (mPFC) or hippocampus result in reward associations in the context-guided memory task).
impairment in various episodic memory tasks (see main text), implying that each plays
During task performance, vHPC terminals in the mPFC
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 were optogenetically inactivated for brief periods dur-
non-lesioned hemisphere is sufficient to support memory. Crossed lesions (that is, ing the sample phase or during the subsequent memory
damage to the mPFC in one hemisphere and to the hippocampus in the other delay or choice phase. Inactivation of vHPC terminals
hemisphere) impair memory, indicating that an ipsilateral mPFC–hippocampal pathway in the mPFC during the sample period disrupted coding
is necessary. b | Oscillatory synchrony is a key feature of interactions between the of the sample location by mPFC cells and impaired sub-
hippocampus and the mPFC92. During presentation of a contextual cue and during sequent choice accuracy, whereas the same inactivation
a memory delay, hippocampal theta precedes that in the mPFC. By contrast, during was ineffective when applied during the delay or choice
memory retrieval, theta oscillations in the mPFC precede those in the hippocampus. The phase. An additional analysis of functional connectivity
bidirectional information flow carried in synchrony involves leads of approximately in the same study showed that gamma-locked spiking
30 ms, which is equivalent to the length of one gamma cycle.
activity in the vHPC preceded that in the mPFC dur-
ing the sample phase, whereas mPFC theta oscillations
the hippocampus to the mPFC. Conversely, when ani- preceded those in the vHPC during the choice phase.
mals began to sample an object before their decision, the Furthermore, vHPC-terminal inactivation disrupted
direction of information flow reversed, with mPFC theta the vHPC‑to‑mPFC connectivity (but not reciprocal
leading hippocampal theta by ~30 ms, consistent with connectivity), and vHPC‑to‑mPFC connectivity was
the flow of information from the mPFC to the hippo stronger during the sample phase and correlated with
campus. Furthermore, both directions of functional memory accuracy. These findings indicate that informa-
connectivity were observed only on trials in which the tion from the vHPC was crucial for encoding the sample
animal subsequently made the correct response, indicat- location but not for maintaining the memory during the
ing that the increase in functional connectivity predicted delay or for subsequent memory expression and that
memory accuracy. Importantly, the comparison between the functional connectivity during this sample phase
correct trials and errors was restricted to those trials in arose via the direct vHPC‑to‑mPFC pathway. An addi-
which the animals made the same behavioural response, tional confirmation of a role for hippocampus-to‑mPFC
either to the correct (rewarded) or to the incorrect projections was demonstrated in a study using a vari-
(non-rewarded) object, thus eliminating the possibility ant of contextual fear conditioning. In this experiment,
that the differences in connectivity were due to distinct chemogenetic inactivation of terminals in the prelim-
behaviours or different expectations of reward. bic area that arose from the dHPC blocked reminder-
Although the reason why these two studies92,98 differed induced fear memory, whereas inactivation of dHPC
in the maximal frequency band of functional connec- terminals in the infralimbic area blocked extinction101
tivity observed during the decision phase of their tasks (for a general review of the PFC in fear conditioning,
remains unclear, both studies indicated that communi- see REF. 37).
cation between the hippocampus and the mPFC is bidi-
rectional and suggest that distinct memory processes are The pathway via the nucleus reuniens. Other stud-
associated with opposing directions of the flow of infor- ies have focused on the indirect pathway between the
mation. Note also that the leads observed in both of mPFC and the hippocampus via the thalamic Re. A tet-
these studies, as well as in the earlier report of directional anus toxin molecular control system was used in mice to
reversibly inactivate specific projections from the mPFC Top-down control via other routes from the mPFC
that influenced the acquisition of the standard version to the hippocampus. Other pathways from the mPFC
of contextual fear conditioning (BOX 1) and subsequent to the hippocampus can mediate both a general modu-
generalization of fear to a different spatial context 102. lation and specific control of hippocampal representa-
Inactivation of the mPFC or the mPFC‑to‑Re pathway tions. One study reported discovery of a direct pathway
did not affect contextual fear acquisition but instead from the anterior cingulate cortex, which is considered
caused an overgeneralization from the training context to be a part of the mPFC area, to hippocampal areas CA1
to another context; furthermore, this inactivation was and CA3 (REF. 101) (see also REF. 104). Using a variant of
effective only if applied during the initial training and a contextual fear-conditioning paradigm, the authors
not if applied during fear expression. This finding sug- of this study found that optogenetic activation of anterior
gests that PFC–hippocampal interactions are important cingulate projections to CA3 modulated the engagement
in distinguishing a context during initial learning just as of memory-specific CA3 neuronal representations and
they are during memory retrieval. expression of fear memories. This finding suggests that an
In addition, optogenetic stimulation of the Re that anterior cingulate projection may have direct top-down
resulted in predominant excitation caused increased control over the hippocampal memory processing.
freezing in the new context, whereas stimulation that Early in training on a context-guided memory task
resulted in predominant inhibition reduced freezing 102. (BOX 1), many dorsal CA1 neurons initially fire at low
These results identified an essential role for the Re in rates during the sampling of an object in a particular
mPFC–hippocampal interactions in the specificity of place; then, associated with successful learning, some
memory encoding. However, because the manipulation of these neurons begin to fire selectively in response
of the Re involved artificial patterns of excitation and to one object in a particular place and context 12. One
inhibition, it is possible that, rather than directly com- study building on this research examined the influ-
municating specific information between areas, the Re ence of the mPFC and MEC on memory performance
may exert a general modulatory influence required for and on firing patterns of dorsal CA1 neurons in rats
specificity of memory coding. performing a context-guided memory task105 (see also
The role of the Re in the specificity of memories was REF. 106). The firing patterns of these CA1 neurons
also studied in rats performing a continuous spatial were characterized before and after either the mPFC
alternation task (as in ‘delayed spatial alternation’ shown or the MEC was inactivated by muscimol infusion. This
in BOX 1, but without delays between trials)103. Neurons in approach revealed that bilateral inactivation of either
the mPFC, Re and CA1 fired at different rates as animals the mPFC or the MEC strongly reduced memory per-
traversed the common segment of left-turn and right- formance (as does mPFC–hippocampal disconnec-
turn routes through the maze. In CA1, this ‘rate coding’ tion106), whereas unilateral inactivation of either area
of memories for specific trajectories was eliminated by had no effect 105. In addition, bilateral inactivation of
halorhodopsin-mediated optogenetic inactivation of the the mPFC, or unilateral mPFC inactivation ipsilat-
Re. Furthermore, memory-specific firing increased in eral (but not contralateral) to the recorded CA1 cells,
the Re and CA1 as the animal reached the end of the resulted in a specific loss of object selectivity of the
common segment of the maze, suggesting that the Re responses of these cells without affecting their spatial
coordinates mPFC–hippocampal communication as the specificity. That is, the CA1 neurons fired robustly in
critical choice is engaged. In a delayed spatial alternation response to multiple objects sampled in the same place
task (BOX 1), muscimol-mediated inactivation of the Re where, before treatment, they were activated for a sin-
during the memory delay or the choice phase decreased gle object. By contrast, MEC inactivation resulted in
phase-locking of mPFC spiking to dHPC theta and elim- a broad ‘remapping’ of both object and spatial coding
inated bidirectional functional connectivity between the in the dHPC, such that dHPC neurons stopped fir-
dHPC and the mPFC98. ing, developed firing in response to places or objects,
The combined findings of these studies indicate that or changed their firing pattern unpredictably. Thus,
the Re supports bidirectional synchronization and com- whereas the MEC determines the overall organization
munication important for the specificity of memory. In of CA1 firing patterns, the mPFC has a selective role
particular, the finding that artificial activation by opto in determining the specificity of object (though not
genetic stimulation can enhance memory 102 suggests that, spatial) memory representations and, consistent with
rather than bearing information about specific memories, the crossed-lesion studies (see above), this influence is
the Re has a modulatory role. Also, although Re firing mediated via an ipsilateral pathway.
rates differentiated maze routes, Re firing patterns did not
contain detailed information about spatial trajectories103, Towards a new model
suggesting that Re neuronal activity may instead reflect How might the findings described above inform our
a general biasing of mPFC and hippocampal ensem- understanding of the nature of mPFC–hippocampal
bles that do represent spatial trajectories. Moreover, the interactions that support memory? Here, I present
results of these studies differ on whether the Re is more a tentative model that focuses on context-guided mem-
important during encoding or retrieval periods, suggest- ory, a common situation in which a current contextual
ing that different memory processing demands in these cue or another recent experience guides the retrieval of
behavioural paradigms may differentially engage the flow specific memories (FIG. 4). When a subject is presented
of mPFC–hippocampal communication. with a specific contextual cue12, or is cued by a previous
Post-learning consolidation experience98,100, the Re coordinates the vHPC‑to‑mPFC evidence that the mPFC projects directly to the PRC
A prolonged period (hours to flow of information, and the vHPC sends information and LEC, which contain neurons that encode specific
months) after learning, over relating to the contextual cues or previous experi- objects and events59,77; evidence that the PRC and LEC
which memories that are ence to the mPFC via the direct pathway. Then, when gate information entering the hippocampus107; and
initially unstable become
stable. This process is thought
the animal must make a choice between alternative reports that the mPFC suppresses irrelevant memories
to involve the integration of memory-g uided responses 92,98, the Re reverses the in rats34,105. In addition, the model is consistent with
new episodic memories into flow of information by coordinating the mPFC‑to‑ findings indicating that the direction of communi-
a semantic memory network. hippocampus pathways, and the mPFC suppresses cation is from the hippocampus (and specifically the
context-inappropriate representations in the PRC vHPC) during a memory delay 98 or when cued by
and LEC to provide top-down control over retrieval of a context 92 or prior experience100, whereas communi-
specific memories in the dHPC. cation is directed from the mPFC to the hippocampus
This bidirectional dialogue is consistent with the during memory retrieval and choice making 91,92,98, and
experimental findings described above. Flow of con- with findings implicating the Re as being crucial for
textual cues from the vHPC to the mPFC is consist- directional synchronization98.
ent with the observation that the vHPC represents
the specific contexts in which particular events have Acquisition, consolidation and recall
occurred20 and with anatomical evidence on the direct Although this Review has focused on the role of mPFC–
pathway from the vHPC to the mPFC61. The flow of hippocampal interactions in memory retrieval, other
rule-based, top-down influences from the mPFC to the studies have focused on the contributions of this system
hippocampus is consistent with: observations that during the acquisition and post-learning consolidation
the PFC develops abstract rule-like representations49,56; 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
a Context presentation
Re synchrony 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
mPFC dHPC
an updated memory organization44. Such a function
Re 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
vHPC acquired memories. Immediately after the learning
Contextual cues 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
b Memory retrieval Bias memory retrieval
mPFC and other cortical areas become more acti-
vated during retrieval of remotely acquired memories,
A+ whereas the hippocampus becomes less activated; after
mPFC dHPC this point, mPFC damage selectively blocks remotely
acquired memories111–113. Further studies have observed
Re
markers of plasticity within the mPFC during initial
learning, even though the mPFC does not become cru-
B– cial for representing memories until several days after
initial encoding 114,115. One possibility consistent with the
vHPC role of the mPFC described above is that, in some tasks
PRC and LEC
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-
Nature Reviews | Neuroscience sion. Yet, over time, as the strength of the new mem-
Figure 4 | A model of prefrontal–hippocampal functional interactions. Here, a model ory fades somewhat, the mPFC becomes increasingly
of medial prefrontal cortex (mPFC)–hippocampal interactions in episodic memory is more important in integrating these remotely acquired
illustrated using the example of the context-guided memory task (BOX 1). a | When
memories with other stored information (for example,
contextual cues are presented, the nucleus reuniens (Re) engages synchrony directed
from the hippocampus to the mPFC to send contextual information from the ventral the initial exposure to a neutral context before shock)
hippocampus (vHPC) to the mPFC. b | Subsequently, during context-guided memory during retrieval49. This idea is very speculative, and
retrieval, the Re engages synchrony directed from the mPFC to the hippocampus such our understanding of the precise roles of the mPFC
that the mPFC biases retrieval of specific memories in the hippocampus. dHPC, dorsal and interactions with the hippocampus during learn-
hippocampus; LEC, entorhinal cortex; PRC, perirhinal cortex. ing and remote memory expression will be improved
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