Hippocampal Involvement in Contextual Modulation
of Fear Extinction
Jinzhao Ji1and Stephen Maren1,2*
model for the study of fear inhibition in humans. Substantial evidence
has shown that extinction is a new learning process that is highly con-
text-dependent. Several recovery effects (renewal, spontaneous re-
covery, and reinstatement) after extinction suggest that the contextual
modulation of extinction is a critical behavioral mechanism underlying
fear extinction. In addition, recent studies demonstrate a critical role
for hippocampus in the context control of extinction. A growing body
of evidence suggests that the hippocampus not only plays a role in con-
textual encoding and retrieval of fear extinction memories, but also
interacts with other brain structures to regulate context-specificity of
fear extinction. In this article, the authors will first discuss the funda-
mental behavioral features of the context effects of extinction and its
underlying behavioral mechanisms. In the second part, the review will
focus on the brain mechanisms for the contextual control of extinction.
C 2007 Wiley-Liss, Inc.
Extinction of fear conditioning in animals is an excellent
nisms; brain mechanisms; hippocampus; amygdale; prefrontal cortex
fear conditioning; extinction; context; behavioral mecha-
In the context of normal human life, fearful situations are regularly
encountered; characteristically, these are managed successfully and then
forgotten. However, in some individuals, the fearful situation is over-
whelming, such as military combat, motor vehicle accident, or sexual
assault. These fearful experiences persist and contribute to, such as, psy-
chological disturbances, post-traumatic stress disorders (PTSD), and
panic disorders (Friedman et al., 1994; Maren and Chang, 2006; Feld-
ner et al., 2007). Understanding the precise neural mechanisms of anxi-
ety is necessary for developing selective and effective treatments.
Pavlovian fear conditioning and its extinction are the most extensively
studied models that provide the laboratory tools to understand the neu-
ral mechanisms of fear and anxiety disorders in humans (Myers and
Davis, 2002; Kim and Jung, 2006). Pavlovian fear conditioning is a
form of associative learning, in which an animal (typi-
cally a rat) is exposed to pairings of a neutral condi-
tional stimulus (CS), such as a tone or light, with an
aversive unconditional stimulus (US), such as a foot-
shock; this procedure yields a conditioned fear
response to the CS. Extinction training, in which CSs
are repeatedly presented in the absence of USs, sup-
presses the amplitude and probability of the condi-
tional response (Pavlov, 1927). As a result, an animal
learns that a CS no longer predicts that aversive US.
Since Pavlov (1927) observed that extinguished condi-
tional response could recover with the passage of time,
extinction has been widely interpreted not to be a pro-
cess of erasing the original excitatory association (i.e.,
CS-US), but instead a process of learning a new inhibi-
tory association (i.e., CS-no US) (Myers and Davis,
2002; Bouton, 2004; Delamater, 2004). By the compe-
tition between an inhibitory CS-‘‘no-US’’ association
and excitatory CS-US association, the conditional fear
response is suppressed (Myers and Davis, 2002; Bou-
ton, 2004; Delamater, 2004).
During this competition, context appears to play an
important role to modulate the suppression of extinc-
tion memories (Bouton, 2002, 2004). For example,
one of the fundamental context effects is the renewal
effect, in which changing the context favors recall of
extinguished fear memory (Bouton, 1993, 1994).
Other context effects of extinction include spontane-
ous recovery and reinstatement, in which an ex-
tinguished response can be recovered following the
passage of time or re-exposure to an unsignaled US in
a relevant context (Myers and Davis, 2002; Bouton,
1993, 1994). These behavioral features of extinction
therefore indicate that extinction involves new learning
that is particularly dependent on context.
In this review, we will first summarize some funda-
mental behavioral features of context effects in extinc-
tion, and discuss behavioral mechanisms underlying
contextual modulation of fear extinction. Since there
is a growing body of research uncovering the neural
mechanisms enabling this modulation, in the second
part, we will discuss the data concerning the roles of
the brain structures that mediate the context-specific
expression of extinction, especially the involvement of
hippocampus, and hippocampal interactions with pre-
1Department of Psychology, University of Michigan, Ann Arbor, Michi-
*Correspondence to: Stephen Maren, Department of Psychology, Univer-
sity of Michigan, 530 Church Street, Ann Arbor, MI 48109–1043, USA.
Accepted for publication 2 May 2007
Published online 29 June 2007 in Wiley InterScience (www.interscience.
2Neuroscience Program, University of Michigan, Ann Arbor,
HIPPOCAMPUS 17:749–758 (2007)
C2007 WILEY-LISS, INC.
frontal cortex and amygdala network in the contextual regula-
tion of extinction.
BEHAVIORAL MECHANISMS OF EXTINCTION
New Learning Rather than Erasure Process
Considerable evidence has emerged to show that extinction
does not erase original learning but instead is an active learning
process. There are three impressive behavioral features of
extinction (including renewal, spontaneous recovery, and rein-
statement) that favor the view that extinction is a form of new
learning. In each case, the extinguished conditional response
returns after extinction. One property of extinction, known as
the renewal effect, has been extensively studied. In this phe-
nomenon, an extinguished conditional response returns if the
CS is presented outside of the extinction context in animals
(Bouton and Bolles, 1979a; Bouton and King, 1983) or
humans (Rodriguez et al., 1999). Another effect is spontaneous
recovery, in which the extinguished conditional response recov-
ers with a passage of time after extinction (for reviews, see Rob-
bins, 1990; Brooks and Bouton, 1993). The third phenomenon
is reinstatement, in which an extinguished conditional response
is partially restored if the subject is exposed to the US alone
following extinction (e.g., Rescorla and Heth, 1975; Bouton,
1993, 2002). Both renewal and spontaneous recovery indicate
that a CS retains its ability to drive conditional responding fol-
lowing extinction, and must therefore retain at least some of
the strength it acquired upon being paired with an US. In rein-
statement, contextual conditioning after extinction can reinstate
fear to the CS suggesting that extinction does not destroy the
CS-US association. Therefore, all these behavioral features indi-
cate that extinction does not erase the original CS-US associa-
tion. Meanwhile, all of these phenomena indicate that the
expression of extinction memories is also context-dependent
(Bouton 1993, 2002). Extinction involves new learning; there-
fore, it leaves the CS with two available ‘‘meanings’’ or associa-
tions with the US.
Context-Dependence of Fear Extinction Memory
The renewal effect is perhaps the most fundamental and im-
pressive context effect in extinction. There are several different
forms of renewal effects, including ABA, AAB and ABC
renewal (each letter denotes conditioning, extinction, or testing
context). Thus, in ABA renewal, conditioning (CS-US pairings)
occurs in context A, extinction (CS presentation in the absence
of US) in context B, and then CS is tested in original condi-
tioning context (context A). In AAB or ABC renewal, all re-
trieval testing is conducted outside of the conditioning context
as well as occurred in a context different from the extinction,
in that the CS is tested in a neutral context that has no history
of CS exposure. However, whether the animal is presented an
extinguished CS in the conditioning context (ABA) or in a
neutral context (AAB or ABC), renewal is demonstrated by
greater conditional response relative to the extinction context
(AAA or ABB). Hence, the expression of extinction is context-
dependent (Bouton, 2004; Bouton et al., 2006).
The renewal effect has been demonstrated in many condi-
tioning paradigms (Bouton, 1994, 2002; Bouton et al., 2006).
It has been demonstrated in appetitive conditioning (Brooks
and Bouton, 1994), taste aversion learning (e.g., Rosas and
Bouton, 1998; Chelonis et al., 1999), and operant conditioning
(for review, see Nakajajima et al., 2000; Bouton, 2002), as well
as fear conditioning (e.g., Bouton and Swartzentruber, 1989;
Wilson et al., 1995; Frohardt et al., 2000; Corcoran and
Maren, 2001, 2004; Ji and Maren, 2005). It has also been
demonstrated in a causal judgment task in humans (Rosas
et al., 2001). In addition, it appears that the renewal effect can
be induced by many kinds of contexts. In one experiment, for
example, alcohol was used as an intereroceptive drug ‘‘context’’
(Cunningham, 1979). In another experiment, Bouton et al.
(1990) obtained similar results that extinction under the influ-
ence of benzodiazepine tranquilizers renewed when rat was
tested in a drug-free state. Moreover, administration of adreno-
corticotropic hormone prior to testing yields renewal of fear in
the avoidance performance when rats are returned to the hor-
monal conditional context (Richardson et al., 1984; Ahlers and
Richardson, 1985). All of these observations suggest that the
renewal effect is fairly general.
The renewal effect is not only well studied in animals but
has also been studied in humans (Mineka et al., 1999; Rodri-
guez et al., 1999; Rosas et al., 2001; Kalisch et al., 2006). In
one study, a causal judgment task in humans was shown to be
modulated by context after retroactive interference (extinction)
(Rosas et al., 2001). In another experiment, Rodriguez et al.
(1999) examined the context-specificity of fear extinction
among the patients undergoing exposure treatment for spider
phobia. The results demonstrated a context-specific return of
fear after the exposure session. The renewal effect is also very
robust. In fear conditioning (bar suppression), Bouton and
Swartzentruber (1986) observed it after 84 extinction trials fol-
lowing eight conditioning trials. Corcoran and Maren (2001)
and others (Gunther et al., 1998; Rauhut et al., 2001) found it
occurred after as many as 180 extinction training trials,
although Denniston et al. (2003) have reported that ‘‘massive’’
extinction training with 800 trials eliminates renewal.
Some models have been proposed to illustrate the behav-
ioral mechanisms underlying contextual modulation of extinc-
tion. One model is that contextual stimuli can modulate the
performance of Pavlovian conditional response in extinction
(Bouton, 1993, 1994). According to Bouton (1994), an asso-
ciation between a CS and an US is formed during condition-
ing. In extinction, a new inhibitory CS-‘‘no US’’ association
that is formed blocks the activation of the original CS-US
association, thereby limiting the conditional responding to the
CS. The meaning of the CS is now ambiguous, and requires
the context to disambiguate the meaning of extinguished CS.
That is, the excitatory CS-US association established during
conditioning is not context-specific and generalizes in all test
JI AND MAREN
Hippocampus DOI 10.1002/hipo
contexts. In contrast, the inhibitory CS-‘‘no US’’ association
established during extinction is context-specific. Therefore,
the inhibitory association is ‘‘gated’’ so that its activation
requires the simultaneous presence of the CS and the extinc-
tion context. This ‘‘gated’’ activation allows the expression of
inhibitory association memory when the CS is presented in
the extinction context. In contrast, presenting the CS outside
of the extinction context would reduce activation of the inhib-
itory link, therefore causing a renewal of conditional response
to the CS (Bouton, 1994).
Similar to the ‘‘gating’’ model, context may be ‘‘on occasion
setter’’ for the current CS-US or CS-‘‘no US’’ associations
(Bouton and Swartzentruber, 1986; Holland, 1992). In nega-
tive occasion setting, a discrete cue stimulus (the feature) pre-
cedes a CS (a target) stimulus when the US does not follow
the target. Hence, the extinction context may act as a ‘‘nega-
tive occasion setter’’ by signaling the CS not followed by the
US (Bouton, 1993). In situations in which a CS acquires
multiple meanings (both an excitatory CS-US association and
an inhibitory CS-‘‘no-US’’ association after extinction train-
ing), retrieval context serves as the feature or occasion setter
for the selective retrieval of the appropriate meaning of the
target CS (Bouton, 1993).
Another view is that the context can serve as another CS, in
addition to participating in contextual encoding and retrieval.
That is, contexts themselves can signal US and enter into com-
(Rescorla and Wagener, 1972; Pearce and Hall, 1980; Wagner
and Brandon, 1989). It therefore enters into simple excitatory
or inhibitory associations with US during conditioning or
extinction. In the ABA renewal, for example, context B might
acquire inhibitory associations with US during extinction, and
context A might acquire excitatory associations. Either kind of
association would summate with the CS to produce extinction
and renewal performance in the extinction and conditioning
contexts, respectively. Nevertheless, a context does not need to
acquire excitatory or inhibitory associative strength itself to
modulate conditional response. That is, the context-specific
expression of Pavlovian memories is not simply because of exci-
tatory or inhibitory context-US associations, but rather can
occur in the absence of the demonstrable excitation in context
(A) or inhibition in context (B) (Bouton and King, 1983; Bou-
ton and Swartzentruber, 1986; Bouton et al., 2006). Nonethe-
less, the context specificity of memory might arise from the
configurative or conjunctive association of a context with a CS
(O’Reilly and Rudy, 2001).
One of Pavlov’s most famous discoveries was the return of
conditional responding with the passage of time (Pavlov,
1927). Pavlov noted that if time elapses after extinction, the
extinguished response could recover ‘‘spontaneously’’ when CS
was tested again. There are several basic empirical properties
of spontaneous recovery that are widely accepted. First, spon-
taneous recovery, similar to the renewal effect, has been dem-
onstrated in virtually every conditioning method (for review,
see Brooks et al., 2001). Moreover, spontaneous recovery has
been well documented to increase in a negatively accelerated
fashion over time (Rescorla, 2004). That is, the longer the
delay between extinction termination and testing, the greater
the recovery. This feature has been found in fear conditioning
in rats (Quirk, 2002), eyelid conditioning in rabbits (Haber-
landt et al., 1978), and sign-tracking in pigeons (Robbins,
1990). In addition, recovery declines with repeated extinction
Although there are several models available to explain spon-
taneous recovery, it can be viewed as a forum of context-
dependent inhibitory learning (Bouton, 1993, 1994). Accord-
ing to memory theorists (e.g., Spear, 1981), the passage of time
may provide a gradually changing context (also see Bouton,
2004). Given this possibility, Bouton (1993) has argued that
just as extinction is spatial context specific in renewal, it might
also be ‘‘temporal context’’ specific in the spontaneous recovery.
In the ‘‘gating’’ mechanism proposed by Bouton (1994), if the
CS is associated with the passage of time (temporal context),
the model also predicts spontaneous recovery. As time passes af-
ter extinction (temporal context gradually changes), shifts in
temporal context would reduce the activation of the inhibitory
association, leading to the occurrence of spontaneous recovery.
Therefore, spontaneous recovery is another ‘‘renewal effect’’,
that occurs when the CS is tested outside its ‘‘temporal extinc-
tion context’’, relative to the ‘‘physical context’’ (Bouton, 1993,
This idea suggests that both renewal and spontaneous effects
are controlled by a common mechanism: a failure to retrieve a
memory of extinction outside of the extinction context
(Bouton, 2004; Bouton et al., 2006). If this is true, either
effect should be attenuated if a retrieval cue that reminds the
subjects of extinction memories is presented just prior to the
recovery test. It appears that there have been several studies
supporting this view. For example, Brooks and Bouton (1993)
and Brooks (2000) presented a brief visual cue intermittently
during extinction and then presented the cue before the re-
trieval testing long after extinction. The results showed that the
cue presentation prior to testing attenuated spontaneous recov-
ery. Importantly, a reduced renewal effect was also found when
a similar retrieval cue was presented before testing outside of
the extinction context (Brooks and Bouton, 1994). These data
suggest that renewal and spontaneous recovery result from a
similar control mechanism, which is due to the failure to
retrieve a memory of extinction outside of the extinction con-
text (Bouton, 2004). In another experiment, animals with both
temporal and spatial context shifts after extinction showed a
stronger recovery of extinguished responding than after either
manipulation alone (Rosas and Bouton, 1998). This indicates
that the spatial and temporal contexts produce similar effects in
modulation of extinction, further supporting the view that
renewal and spontaneous recovery share a common mechanism
A recent study extends the idea of temporal context by
examining the interaction of temporal context and extinction
HIPPOCAMPUS AND CONTEXTUAL MODULATION OF EXTINCTION
Hippocampus DOI 10.1002/hipo
intertrial interval (ITI) (Bouton and Garcia-Gutierrez, 2006).
In this study, it was hypothesized that extinction ITI might be
encoded as the extinction context, and the interaction of the
ITI and retention interval (temporal context) could modulate
extinction memories. If the last extinction trial shifted the tem-
poral context, spontaneous recovery might occur. The results
confirmed this hypothesis in that rats receiving 4-min ITI
extinction trials showed spontaneous recovery when presented
with a 16-min ITI during the retention test. However, other
rats that received 16-min ITI extinction trial failed to show
recovery in this test. Therefore, ITI might also be encoded as
part of the context to modulate extinction memories. However,
further study demonstrated that spontaneous recovery did not
occur if a longer extinction ITI was followed by a shorter tem-
poral context (i.e., 16-min ITI followed by a 4-min ITI) de-
spite that the intervals are mismatched (for review, see Bouton
et al., 2006).
In addition to renewal and spontaneous recovery, the extin-
guished response returns after extinction if the animal is merely
re-exposed to the US alone (Pavlov, 1927; Rescorla and Heth,
1975; Bouton and Bolles, 1979b). In a typical fear reinstate-
ment task, animals first undergo conditioning and extinction.
Following extinction, an aversive US is presented a few times
in a distinct context. When fear to the CS is tested again, the
conditional response is reinstated (Bouton and Bolles, 1979b;
Bouton, 1993, 2002). In this case, evidence strongly suggests
that the reinstatement effect is due to context conditioning.
The context-US associations after extinction promote rein-
statement (Bouton, 1993, 2004). Similar to renewal and
spontaneous recovery, reinstatement also demonstrates the con-
text-dependence of extinction. That is, reinstatement only
occurs when the USs are presented in the context, in which the
extinguished CS is tested but not when reinstating USs are pre-
sented in a novel or irrelevant context (Bouton and Bolles,
1979b; Bouton and King, 1983; Bouton, 1984; Wilson et al.,
1995; Frohardt et al., 2000; Bouton, 2004).
Besides the context-specificity of extinction, there are several
other empirical properties in reinstatement. The first one is
that the strength of reinstatement is correlated with the
strength of contextual conditioning (Bouton and King, 1983;
Bouton, 1984, 2004). The second one is that reinstatement is
attenuated by exposure to the context, in which reinstatement
shock was delivered (Bouton and Bolles, 1979b; Baker et al.,
1991; Bouton, 1993). The third property is that the reinstate-
ment shock has a stronger effect on extinguished CSs compared
with nonextinguished CSs (Bouton, 1984, 1993). For example,
Bouton (1984) delivered reinstatement shock in the same or
different context under a comparable condition, in which the
fear of one group of rats was partially extinguished; whereas
the other group of rats reached the same level of fear by simple
CS-US conditioning but without extinction. The data showed
that contextual conditioning resulted in an impressive reinstate-
ment for the extinguished CS, but had no discernable effect on
performance to a nonextinguished CS (Bouton and King,
The results that extinguished CSs are particularly sensitive to
contextual control suggest that the reinstatement may be due to
a similar mechanism underlying other context effects of extinc-
tion (i.e., renewal and spontaneous recovery) (Bouton, 1993).
Bouton (1993) proposed that contextual conditioning may con-
stitute part of a background associated with conditioning and
thus may act as another feature of the conditioning ‘‘context’’.
When extinguished CS is returned to that conditioning con-
text, a feature of the conditioning ‘‘context’’ will activate the
original CS-US memory, leading to the reinstatement of extin-
guished conditional responding, just like another ABA renewal
(Bouton, 1993, 2004).
THE BRAIN MECHANISMS UNDERLYING
CONTEXT DEPENDENCE OF EXTINCTION
As theoretical studies in conjunction with recent empirical
discoveries reveal a role of context in regulating expression of
extinction, it has become important to understand the brain
mechanisms underlying the contextual control of extinction.
Considering the established role of the hippocampus in several
memory processes, including episodic memory (Squire and
Zola, 1996; Eichenbaum, 2000, 2001; Burgess et al., 2002),
researchers have began to explore how it mediates context
effects on learning.
Hirsh (1974) proposed one of the first theories to account
for context effects in memories. He suggested that the hippo-
campus was a critical substrate for contextual memory retrieval
(Hirsh, 1980; Ross et al., 1984; Good and Honey, 1991;
Honey and Good, 1993; Holt and Maren, 1999). Meanwhile,
an abundance of evidence reveals that the hippocampus is also
involved in encoding and consolidating representations of con-
texts, as well (e.g., Kim and Fanselow, 1992; Philips and
LeDoux, 1992; Antagnostaras et al., 1999). Therefore, it is
believed that the hippocampus is critical for using contextual
representations to guide behavior (Rudy and O’Reilly, 1999,
2001; Fanselow, 2000; Maren and Holt, 2000). Based on these
findings, the hippocampus has been explored for its role in
contextual modulation of extinction.
Hippocampal involvement in context-dependent
retrieval after extinction
As a first attempt to examine the role of the hippocampus in
contextual modulation of extinction, Wilson et al. (1995)
made permanent lesions of the fimbria/fornix prior to condi-
tioning and observed its influence on several context effects af-
ter extinction, including renewal, spontaneous recovery, and
reinstatement. The results showed that rats with hippocampal
lesions did not show reinstatement, but exhibited normal in
JI AND MAREN
Hippocampus DOI 10.1002/hipo
renewal and spontaneous recovery. This result was subsequently
replicated in another experiment (Frohardt et al., 2000), show-
ing that complete hippocampal lesions made before condition-
ing interfered with the reinstatement to fear to an extinguished
CS, but left renewal of fear to an extinguished CS intact. These
two studies suggest that the hippocampus is not necessary for
the context-specific expression of extinguished fear. However,
these conclusions are tempered by the fact that all these studies
used permanent pretraining lesions of the hippocampus, which
necessarily confound the hippocampal role in retrieval processes
with its possible role in encoding process (Maren et al., 1997;
Maren and Holt, 2000). To overcome these problems, Cor-
coran and Maren (2001) reversibly inactivated the dorsal
hippocampus (DH) with muscimol, a gamma-aminobutyric
acid receptor agonist prior to retention testing and examined
its effect on context-dependent expression of extinction. In this
experiment, intact rats exhibited context-specific retrieval after
multiple extinction training sessions, in that they displayed low
levels of freezing when presented in the extinction context but
showed high levels of freezing when tested outside of the
extinction context. The renewal of fear by the context shift was
so robust that the elevated fear reached a similar level to that
in nonextinguished rats. However, intrahippocampal muscimol
infusions prior to testing disrupted this context-specificity, elim-
inating the renewal of fear to an extinguished CS that occurred
outside of the extinction context. This experiment strongly sug-
gests, in contrast to the earlier work (Wilson et al., 1995; Fro-
hardt et al., 2000), that the hippocampus is involved in the
context-dependent expression of extinction.
One factor that might account for this discrepancy is that
Corcoran and Maren (2001) used an ABC renewal design
(Experiment 2), whereas Bouton and colleagues used an ABA
design (Wilson et al., 1995; Frohardt et al., 2000). It remains a
question, therefore, whether hippocampal lesions influence dif-
ferent types of contextual control in different ways. To address
this question, Corcoran and Maren (2004) examined the role
of the hippocampus in different renewal paradigms. Consistent
with their earlier findings, muscimol inactivation of DH prior
to testing resulted in impaired contextual memory retrieval af-
ter extinction, eliminating the renewal of conditional respond-
ing when animals were tested in a novel, neutral context (AAB
renewal). However, if animals were returned to the conditional
context during testing (ABA renewal), the context-specificity
was minimally affected by hippocampal inactivation, which is
consistent with the earlier lesion results (Wilson et al., 1995;
Frohardt et al., 2000). It is therefore interesting to understand
why the hippocampus plays a role in ABB or ABC renewal,
but not in ABA renewal. One possibility Corcoran and Maren
(2004) proposed is that the ambiguity in the relationship
between the test context and the CS in different renewal condi-
tions is not the same, and this may be differentially sensitive to
hippocampal manipulations. Therefore, ABA renewal is not
susceptible to hippocampal impairments because the testing
context reliably predicts the CS-US association and thus has an
unambiguous relationship with the CS. By contrast, in AAB
and ABC tests, the context has no history of CS exposure, and
therefore the meaning of the CS in testing contexts is ambigu-
ous. This may yield more interference between the retrieval of
CS-US and CS-‘‘no US’’ memories and thus results in more
susceptibility to hippocampal disruption.
In a subsequent study, Ji and Maren (2005) further com-
pared the nature and timing of the hippocampal lesions in
determining their influence on different renewal paradigms.
They made electrolytic lesions of the DH either before condi-
tioning or after extinction, and examined their effects on con-
text-specific expression of fear memory after extinction. The
results showed that DH lesions impaired the context-depend-
ence of extinction, independent on whether lesions were made
prior to conditioning or after extinction, and independent on
whether retrieval testing returned to the conditioning context
(ABA renewal) or occurred in a neutral context (AAB renewal).
These data are consistent with the inactivation reports (Cor-
coran and Maren, 2001, 2004), indicating a critical role for the
hippocampus in contextual fear memory retrieval. On the other
hand, these results are in contrast to lesion studies (Wilson
et al., 1995; Frohardt et al., 2000), which demonstrate unaf-
fected ABA renewal by pretraining fornix or hippocampus
lesions. One possible interpretation for the disparities, for
example, may be that Bouton and colleague used bar-suppres-
sion (Wilson et al., 1995; Frohardt et al., 2000), whereas Ji
and Maren (2005) used freezing to index fear. These responses
have been demonstrated to be neuroanotomically dissociated,
and rats can continue to suppress bar pressing in the absence
of freezing under some conditions (Amorapanth et al., 1999).
Interestingly, ABA renewal is not affected by hippocampal
inactivation, which is inconsistent with the results showed by Ji
and Maren (2005). One possibility to account for this discrep-
ancy may be that the electrolytic lesions clearly disrupt more
neurochemical systems than muscimol alone (Ji and Maren,
2005). Another possibility may be the difference in the effects
between pretraining and pretesting hippocampal manipulations
on the contextual memory retrieval as suggested by Maren et al.
(1997). This possibility has been supported by a recent study
showing that hippocampal inactivation impaired renewal of fear
regardless of testing context occurred when the inactivation was
conducted before extinction training (Corcoran et al., 2005).
Nonetheless, the findings from permanent lesions (Ji and
Maren, 2005) are consistent with the studies with pharmacologi-
cal inactivation of DH (Corcoran and Maren, 2001, 2004), sug-
gesting the critical requirement of DH in using contextual stim-
uli to regulate the expression of fear to a Pavlovian CS after
extinction. Based on Bouton’s extinction model (Bouton, 1994),
Maren and Holt (2000) have posited a model to illustrate hip-
pocampus engagement in latent inhibition (LI). According to
Maren and Holt (2000), the DH is necessary for the contextual
‘‘gating’’ of inhibitory CS-‘‘no event’’ associations in LI. Extinc-
tion and LI are similar phenomena in that contextual retrieval
cues disambiguate conflicting CS memories and guide behavior.
Therefore, this model is also suitable to reveal a role for the DH
in contextual ‘‘gating’’ of inhibitory CS-‘‘no US’’ association in
extinction. In this model, the functional hippocampus allows
contextual gating of the inhibitory association, leading to the
HIPPOCAMPUS AND CONTEXTUAL MODULATION OF EXTINCTION
Hippocampus DOI 10.1002/hipo
expression of CS-‘‘no US’’ association memory in the extinction
context. This contextual gating of the CS-‘‘no US’’ association,
however, is mitigated by the absence of a functional hippocam-
pus. Hence, the expression of the CS-‘‘no US’’ memory becomes
context-independent, and conditional responding to the CS is
reduced in all test contexts.
Hippocampal involvement in encoding
context-specificity of extinction
Collectively, it seems that one function of the hippocampus
is to control the context-specific expression of extinction. But it
still remains unclear whether the hippocampus is also required
to encode extinction or the context-specificity of extinction. To
address this question, recent work has investigated the impact
of pre-extinction inactivation of the DH by muscimol on
encoding the context specificity of extinction (Corcoran et al.,
2005). DH inactivation prior to extinction training attenuated
extinction learning and disrupted contextual encoding of
extinction memory. Rats that underwent extinction training
after hippocampal inactivation showed renewal of fear irrespec-
tive of the context, in which testing context occurred. There-
fore, it appears that the hippocampus plays a role in acquiring
extinction, and is required in encoding the CS-context relation-
ship to guide behavior after extinction. Similarly, the context-
dependency of extinction was abolished by hippocampal inacti-
vation when muscimol was administered before testing. Inter-
estingly, it did so by diminishing renewal of fear when retrieval
occurred outside of extinction context. This contrasted with
those rats treated with muscimol before extinction, which
exhibited renewal of fear, independent of the context, in which
retrieval testing took place (Corcoran et al., 2005). The reasons
for the differential effects between pre- and post-extinction hip-
pocampal inactivation on context-specificity of extinction might
be due to different hippocampal mechanisms. Corcoran et al.
(2005) argued that when hippocampus is engaged in encoding
context-specificity of extinction, it plays a role in mediating
negative occasion setting, which signals the CS-‘‘no US’’ associ-
ations in extinction as suggested by Holland et al. (1999). A
deficit in an occasion-setting process produced by hippocampal
inactivation prior to extinction would engender the rats’ inabil-
ity to retrieve extinction memories in the contexts, in which
they were learned. However, this model does not account for
the effects of pretesting hippocampal inactivation on context-
specific expression of extinction. Instead, it is because hippo-
campal inactivation removes the contextual gating and thus
cause the extinction memory to prevail during retrieval (Holt
and Maren, 1999; Maren and Holt, 2000), leading to condi-
tional responding reduced in all contexts.
This study, along with previous data, further elaborates an
important role for the hippocampus in mediating contextual
control of extinction. In addition to animal research, there is
emerging evidence indicating hippocampal involvement in
(Charney et al., 1993; Mineka and Zinbarg, 1996; LaBar and
Phelps, 2005; Kalisch et al., 2006). For example, many patients
human extinction memory
with anxiety disorders, including phobias and PTSD, are char-
acterized by hippocampal dysfunction and inappropriate con-
text control of the expression of acquired fear response.
Recently, Kalisch et al. (2006) examined context-dependent re-
trieval of human extinction memory with the use of fMRI.
They showed that CS-evoked brain activity is context-de-
pendent, and this context-dependent brain activity specifically
exhibited in ventromedial prefrontal cortex (vmPFC) and the
hippocampus. Also, this activity positively correlated between
vmPFC and hippocampus. The role of the hippocampus as
supporting context-dependent retrieval of extinction memory
has also been strengthened by the finding of impaired con-
text-specific reinstatement in two patients (LaBar and Phelps,
2005). In this report, LaBar and Phelps (2005) used environ-
mental cues as context to investigate how it regulates recovery of
conditional fear following extinction. The results showed the
context-specificity in the recovery of extinguished fear response
after reinstating shock in normal participants. However, two
amnesic patients with bilateral ischemic hippocampal damage
failed to exhibit recovery following reinstatement in the same
context after extinction, despite performing intact fear acquisi-
tion and extinction. These results suggest that human hippocam-
pus not only provides for context-dependent retrieval of extinc-
tion memory, but also is essential in this memory retrieval.
Although the earlier data suggest an important role for the
hippocampus in mediating the contextual modulation of
extinction, extinction memory is not stored in the hippocam-
pus. Instead, evidence from animal and human studies indi-
cates that the amygdala is involved in the acquisition and
extinction of fear memory (Maren et al., 1996; Rogan and
LeDoux, 1996; Goosens et al., 2003; for review, see Davis
et al., 1994; Maren, 2001; Sotres-Bayon et al., 2004), and
seems to have a pivotal role in the extinction of learned fear
(Falls et al., 1992; Lu et al., 2001; for review, see Walker and
Davis, 2002; Sotres-Bayon et al., 2004). The mediation of
extinction by the amygdala is manifested in the firing of lat-
eral amygdala (LA) neurons. The neuronal activity of LA enc-
odes conditional fear memories and is correlated with the be-
havioral responses to a fearful CS (Maren, 2000; for review
see, Maren and Quirk, 2004). Therefore, it is reasonable to
hypothesize that amygdala neuronal activity would be contex-
tually modulated after extinction training, as well as that a
renewal of fear occurs in the animal’s behavioral performance.
In addition, the hippocampus would contribute to the context
regulated effects for the CS-evoked neuronal activity.
To test this idea, Hobin et al. (2003) trained rats using a
fear extinction procedure that yields context-specific memories
for two different CSs, in which they could record CS-elicited
firing in LA neurons in two different contexts. The results of
this experiment showed that LA neuronal activity exhibited
context-dependent spike firing, in that CS-evoked LA firing
responded more to the CS when presented outside of extinc-
JI AND MAREN
Hippocampus DOI 10.1002/hipo
tion context, compared with CS-evoked firing observed when
the same CS was tested in its own extinction context. Similarly,
conditional freezing was context-dependent, in which rats dem-
onstrated renewal of fear to an extinguished CS when tested in
a context different from extinction (Hobin et al., 2003). In
addition, rats with hippocampal inactivation prior to testing
were incapable of being recorded the context-dependent spike
firing, in that they lost the ability to get the renewal of CS-
evoked LA responses that normally observed in intact rats
(Maren and Hobin, 2007). In this case, CS-evoked LA neuro-
nal activity diminished in all contexts, which matches the
pattern of behavioral performance modulated by context after
hippocampal inactivation that was previously reported (Cor-
coran and Maren, 2001, 2004).
Collectively, these data suggest that context-dependent neu-
ronal activity in the LA may be an important mechanism for
disambiguating the meaning of fear signals, thereby enabling
appropriate behavioral responses to such stimuli. This contex-
tual modulation of amygdala neuronal activity requires a func-
tional hippocampus to implement. However, it is not clear
what the mechanisms are, by which the hippocampus interacts
with the amygdale, to regulate CS-evoked firing and context-
specific behavioral response. Because there are reciprocal con-
nections between amygdala and hippocampus (Maren and Fan-
selow, 1995; Pitkanen et al., 2000), one model suggests that a
direct projection from hippocampus to LA subserves contextual
modulation of neuronal activity (Maren and Quirk, 2004).
Alternatively, the medial prefrontal cortex (mPFC) has been
anatomically identified to receive strong hippocampal projec-
tion, and exerts strong inhibitory control over the amygdala
(Jay and Witter, 1991; Conde et al., 1995; Rosenkranz and
Grace, 1999, 2001, 2002; Ishikawa and Nakamura, 2003; for
review, see Tamminga, 2006), substantial evidence suggests that
mPFC plays a critical role in the representation of fear extinc-
tion (Quirk et al., 2000; Milad and Quirk, 2002; for review,
see Stotres-Bayon et al., 2004; Quirk et al., 2006), and hippo-
campal modulation of mPFC may control LA projections to
the central amygdala (Thierry et al., 2000; Hobin et al., 2003;
Sotres-Bayon et al., 2004). This model proposes that the hip-
pocampus performs an executive role in the balance of excita-
tion and inhibition in the fear circuits, in which mPFC may
come to inhibit LA neuronal activity during fear extinction
that otherwise excite fear response (Hobin et al., 2003; Sotres-
Bayon et al., 2004; Maren, 2005). Also, the regulation of this
fear is dependent on the context, in which fear stimuli are
encountered (Hobin et al., 2003; Maren, 2005). When animals
are tested in the extinction context, the hippocampus drives
mPFC inhibition of LA. However, if animals are presented
with an extinguished CS outside the extinction context, the
hippocampus may inhibit mPFC activation and thus promote
excitation in the LA to renew extinguished fear under these
conditions (Hobin et al., 2003; Maren, 2005). This point of
view is supported by a recent study in humans demonstrating
that CS-evoked brain activity is context-dependent after extinc-
tion, and this activity is particularly observed in vmPFC and
the hippocampus (Kalisch et al., 2006). In addition, CS-evoked
in the hippocampus and the vmPFC is positively correlated,
which is consistent with the view that the hippocampus may
confer contextual information to vmPFC during the expression
of extinction (Hobin et al., 2003; Kalisch et al., 2006).
Although the network of the hippocampus, prefrontal cortex,
and amygdala is involved in regulating conditional response
performance after extinction (Hobin et al., 2003; Maren and
Quirk, 2004; Maren, 2005), it is not clear what causes the hip-
pocampus to be activated when the CS is presented outside the
extinction context. It is also unclear whether the prefrontal cor-
tex itself is engaged in the context-dependency of extinction,
and if so, how prefrontal cortex uses the contextual information
to regulate extinction memories. Thus, there is considerable
work to do to uncover the brain mechanisms that underlie the
contextual control of extinction.
In summary, a variety of research indicates that responding
to an extinguished CS is susceptible to many recovery effects,
suggesting that extinction involves new learning, and this new
learning is especially sensitive to manipulations of context. Sub-
stantial evidence supports a critical role for the hippocampus in
mediating contextual control of extinction. These data reveal
that the DH is involved in the acquisition, contextual encod-
ing, and context-dependent retrieval of fear extinction (Cor-
coran et al., 2005; Ji and Maren, 2004). Moreover, emerging
evidence suggests that the context-dependence of extinguished
fear involves the interactions between the hippocampus, amyg-
dala, and prefrontal cortex (Hobin et al., 2003). Although the
hippocampus plays an important role in the contextual modu-
lation of extinction, it is not required for storing extinction
memories. Instead, the amygdala appears to be a critical site for
storing and expressing of fear extinction, and mPFC may play
a critical role in regulating the expression of fear extinction by
inhibiting the amygdala. The hypothesis that LA neurons
encode fear memories and CS-elicited LA firing is contextually
modulated after extinction has been demonstrated to require
the functional hippocampus. According to this result, it has
been proposed that contextual modulation of CS-evoked spike
firing could be implemented by hippocampal modulation of
mPFC to exert control over the amygdala (Hobin et al., 2003;
Maren and Quirk, 2004; Sotres-Bayon et al., 2004). Alterna-
tively, direct projections from the hippocampus to the amyg-
dala may regulate fear expression after extinction (Maren and
Quirk, 2004). Because the hippocampus has strong reciprocal
connections with mPFC and the amygdala, it is yet unclear,
which of these connections is important for the contextual
modulation of extinction. Nevertheless, it is without doubt that
the hippocampus plays a central role in contextual control of
HIPPOCAMPUS AND CONTEXTUAL MODULATION OF EXTINCTION
Hippocampus DOI 10.1002/hipo
The authors would like to thank Ewelina Knapska and April
Qian for editing on an earlier draft of the manuscript.
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