Brain Research Bulletin 195 (2023) 141–144

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Brain Research Bulletin

journal homepage: www.elsevier.com/locate/brainresbull

Interaction between reconsolidation and extinction of fear memory

Satoshi Kida
Department of Applied Biological Chemistry, Graduate School of Agriculture and Life Sciences, The University of Tokyo, Tokyo 113-8657, Japan

A R T I C L E I N F O A B S T R A C T

Keywords: Memory retrieval is not a passive process. When a memory is retrieved, it returns to a labile state and undergoes
Reconsolidation reconsolidation to be re-stored. The discovery of this memory reconsolidation has had a major impact on memory
Extinction consolidation theory. In other words, it suggested that memory is more dynamic than expected and can be
Fear memory
modified through reconsolidation. Conversely, a conditioned fear memory undergoes memory extinction after
Consolidation
Retrieval
retrieval, and it is thought that extinction does not reflect its erasure, but rather new inhibitory learning of the
original conditioned memory. We have investigated the relationship between memory reconsolidation and
extinction by comparing their behavioral, cellular, and molecular mechanisms. Memory reconsolidation and
extinction have opposite functions on contextual fear and inhibitory avoidance memories; reconsolidation
maintains or strengthens fear memory, whereas extinction weakens it. Importantly, reconsolidation and
extinction are contrasting memory processes not only at the behavioral level but also at cellular and molecular
levels. Furthermore, our analysis revealed that reconsolidation and extinction are not independent processes, but
interact with each other. Interestingly, we also found a "memory transition process" that switches the fear
memory process from reconsolidation to extinction after retrieval. Investigating the mechanisms of reconsoli­
dation and extinction will contribute to our understanding of the dynamic nature of memory.

Short-term memory is labile. A labile memory is stabilized through
“memory consolidation” to generate a stable long-term memory (Silva
et al., 1998; Kida and Serita, 2014). However, Nader, Ledoux, and col­
leagues have shown that even a consolidated memory, following
memory retrieval, returns to the labile state (destabilization) and is
restabilized through “memory reconsolidation” for re-storage (Nader
et al., 2000a, 2000b; Kida, 2029, 2020). The discovery of memory
reconsolidation indicated that memories are more flexible than expected
and had a big impact on our understanding of memory consolidation.
1. Mechanisms and function of memory reconsolidation
Behavioral evidence showing that a retrieved memory is disrupted
by the inhibition of protein synthesis suggests that it becomes labile
(destabilized) and restabilized through memory reconsolidation (Nader
et al., 2000a, 2000b; Kida, 2019, 2020). This observation also indicates
that the molecular mechanism of memory reconsolidation is similar to
that of consolidation. Importantly, a common molecular signature of
memory consolidation and reconsolidation is the essential requirement
for gene expression activated by the transcription factor CREB (Kida,
2020; Kida et al., 2002; Tronson and Taylor, 2007). However, memory
reconsolidation involves specific molecules, such as the transcription
factor Zif268 (Lee et al., 2004), and specific brain regions (Taubenfeld
et al., 2001), indicating that the mechanisms of consolidation and
reconsolidation are similar, but not identical.
Importantly, a memory is not always destabilized following retrieval,
and there are boundary conditions to induce the destabilization of a
retrieved memory, e.g., the duration of memory retrieval, the strength of
the memory, and the age of the memory (Kida, 2020; Suzuki et al.,
2004). For example, a memory is less destabilized if the retrieval
duration is short, or if the memory is strong, or old (Suzuki et al., 2004).
The functional roles of memory reconsolidation have been suggested to
update, strengthen, and/or modify a retrieved memory (Kida, 2019,
2020). In the contextual fear conditioning task, rodents receive elec­
trical footshocks in a conditioning chamber to form a contextual fear
memory and retrieve this memory when they are re-exposed to the
chamber. Importantly, this re-exposure to the chamber initiates either
memory reconsolidation or extinction; a short or long duration of the
re-exposure induces memory reconsolidation or extinction, respectively
(Mamiya et al., 2009; Suzuki et al., 2004) (Fig. 1). Therefore, in the
contextual fear conditioning test, it is difficult to investigate the func­
tional roles of reconsolidation under conditions in which the interaction
between reconsolidation and extinction does not occur and only
reconsolidation is induced.

E-mail address: akida@g.ecc.u-tokyo.ac.jp.

https://doi.org/10.1016/j.brainresbull.2023.02.009
Received 27 September 2022; Received in revised form 11 February 2023; Accepted 15 February 2023
Available online 16 February 2023
0361-9230/© 2023 The Author. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-
nc-nd/4.0/).
S. Kida
Fig. 1. Reconsolidation and extinction of contextual fear memory. Retrieval of
a contextual fear memory by the short (e.g., 3 min) or long (e.g., 30 min) re-
exposure to the conditioning chamber induces memory reconsolidation or
extinction, respectively. Activation of gene expression is observed in the
amygdala/hippocampus or the medial prefrontal cortex (mPFC)/amygdala
when the retrieved memory is reconsolidated or extinguished, respectively.
We have focused on the inhibitory avoidance (IA) task to understand
the function of reconsolidation (Fukushima et al., 2014, 2021) (Fig. 2).
In this task, mice are first placed in a light compartment and then given
an electrical footshock immediately after entering a dark compartment
from the light compartment. This experience generates an IA memory to
avoid the dark compartment, even though mice prefer dark places.
When the mouse is re-exposed to the light compartment, the IA memory
is retrieved, but it is not extinguished unless the mouse learns that the
electrical footshock is not given once it re-enters the dark compartment;
therefore, re-exposure to the light compartment induces only IA memory
reconsolidation without extinguishing this memory. Interestingly, the
time spent in the light compartment (test session) after re-exposure to
the light compartment only (re-exposure session) is significantly
increased compared to that duration during re-exposure despite the
absence of an electrical footshock, indicating that the IA memory is
enhanced after memory retrieval (Fukushima et al., 2014). In contrast,
blocking gene expression during re-exposure to the light compartment
by protein synthesis inhibition or genetic inhibition of CREB-mediated
transcription disrupts the retrieved IA memory (Fukushima et a,
2014). These observations suggest that IA memory is enhanced through
memory reconsolidation following memory retrieval. Therefore, our
findings suggest that one of the functions of memory reconsolidation is
to reinforce memories and that destabilization opens a window to
Fig. 2. Reconsolidation, transition, and extinction of IA memory. Retrieval of
an IA memory by the re-exposure to the light compartment (0 min re-exposure
to the dark compartment) induces memory reconsolidation that strengthens the
retrieved memory, whereas retrieval of this memory by the re-exposure to the
dark compartment (e.g., 3–10 min) after the entry from the light compartment
induces memory extinction. Brief re-exposure to the dark compartment (e.g.,
1 min) cancels the induction of reconsolidation but is insufficient for memory
extinction. Activation of gene expression is observed in the medial prefrontal
cortex (mPFC)/amygdala/hippocampus or mPFC/amygdala when the retrieved
memory is reconsolidated or extinguished, respectively. This activation of gene
expression when memory is reconsolidated is not induced by brief re-exposure
to the dark compartment.
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strengthen them.
2. Function and mechanisms of fear memory extinction
A conditioned fear memory is retrieved by re-exposure to the
conditioned stimulus (CS) such as a conditioned context and tone. Fear
memory retrieval induces fear responses in rodents such as freezing.
However, fear responses are attenuated under conditions in which the
unconditioned stimulus (US), e.g., an electrical shock, is not given for a
long period during re-exposure to the CS. This behavioral change is
termed "memory extinction" (Myers and Davis, 2002) (Figs. 1 and 2).
Importantly, memory extinction is thought not to reflect erasure or
forgetting of the original conditioned fear memory since behavioral
evidence showed that fear responses to the CS can be recovered after a
long period (spontaneous recovery) or even when a weak CS is given,
even after extinction learning (Myers and Davis, 2002). Memory
extinction is thought to represent new inhibitory learning that generates
inhibitory circuits suppressing fear responses. Similar to memory
consolidation and reconsolidation, long-term extinction memory is sta­
bilized through gene expression activated by CREB (Fukushima et al.,
2014, 2021; Mamiya et al., 2009; Suzuki et al., 2004).
3. Interaction between reconsolidation and extinction
Reconsolidation and extinction play opposite roles in states of fear
memory; memory reconsolidation maintains or strengthens fear mem­
ory, whereas memory extinction weakens it. The reconsolidation and
extinction processes of contextual fear memory have been compared at
the behavioral and molecular levels. A short duration of contextual fear
memory retrieval, e.g., 3 min re-exposure to the conditioning chamber,
induces reconsolidation, whereas a long duration, e.g., 30 min re-
exposure, induces extinction (Mamiya et al., 2009; Suzuki et al., 2004)
(Fig. 1). Expectedly, inhibition of gene expression after short
re-exposure to the conditioning chamber disrupts the retrieved memory
by blocking memory reconsolidation. In contrast, inhibition of gene
expression after long re-exposure blocks long-term extinction without
affecting the original contextual fear memory. These observations are
not surprising since reconsolidation and extinction both depend on new
gene expression. However, the observation that inhibition of gene
expression blocks long-term extinction indicates that the retrieved
contextual fear memory is not disrupted, even though gene expression is
inhibited when the memory is retrieved by prolonged re-exposure.
Therefore, these behavioral observations suggest that the reconsolida­
tion and extinction of contextual fear memory are not independent
processes and interact with each other (Kida, 2019, 2020; Suzuki et al.,
2004). It is important to note that this interaction may not be observed
in other types of memory such as amygdala-dependent cued fear
memory (Duvarci et al., 2006).
Phosphorylation of CREB is a crucial step for the activation of CREB-
mediated transcription (Kida and Serita, 2014). Increases in CREB
phosphorylation are observed in the hippocampus/amygdala and
amygdala/medial prefrontal cortex when contextual fear memory is
reconsolidated by a short reminder or extinguished by a long one,
respectively (Mamiya et al., 2009) (Fig. 1). Interestingly, these obser­
vations indicate that CREB phosphorylation in the hippocampus to
induce reconsolidation with a short reminder is no longer observed
because extinction learning (within-session extinction) progresses with
a long reminder (Mamiya et al., 2009). In other words, the hippocampal
CREB phosphorylation that is observed following short re-exposure is
abrogated by extinction learning. Furthermore, reconsolidation and
extinction of contextual fear memory differ in the time course of the
increase in CREB phosphorylation in the amygdala; although increased
CREB phosphorylation is observed at 30 min after a short re-exposure
inducing reconsolidation, this time point is the same as that for the
end of the extended re-exposure that induces extinction, but no increase
in CREB phosphorylation is observed (Mamiya et al., 2009). These
S. Kida
differences in the molecular signatures of reconsolidation and extinction
suggest an interaction between them at the molecular level.
4. Mechanisms of fear memory transition from reconsolidation
to extinction
Since the reconsolidation and extinction of contextual fear memory
are induced by re-exposure to the same conditioning chamber, the time
point at which memory processes are shifted from reconsolidation to
extinction is unclear (Fig. 1). In contrast, the IA task allows discrimi­
nation of the reconsolidation and extinction processes at the time point
at which mice enter the dark compartment from the light compartment,
as described above (Fig. 2). In this task, reconsolidation is induced when
the mice stay only in the light compartment, whereas extinction is
induced when the mice stay in the dark compartment for 3–10 min after
entry from the light compartment without receiving an electrical shock
(Fig. 2) (Fukushima et al., 2014, 2021). Importantly, similar to the ob­
servations in contextual fear conditioning, inhibition of gene expression
blocks only long-term extinction without disrupting the retrieved IA
memory when it is extinguished, even though the mouse is re-exposed to
the light compartment before entering the dark compartment and the IA
memory is retrieved (Fukushima et al., 2014, 2021). This observation
confirms the interaction between reconsolidation and extinction at the
behavioral level in the IA task.
More interestingly, neither reconsolidation nor extinction is
observed when mice are re-exposed to the dark compartment for only
1 min after entry from the light compartment; extinguishing or weak­
ening of the IA memory is not observed, whereas the retrieved IA
memory is not disrupted by protein synthesis inhibition (Fukushima
et al., 2021) (Fig. 2). Most importantly, although re-exposure only to the
light compartment induces memory reconsolidation and activates gene
expression, as measured by c-fos induction, and proteasome-dependent
protein degradation in the hippocampus, amygdala, and medial pre­
frontal cortex, this activation of gene expression and protein degrada­
tion is not observed after re-exposure to the dark compartment for 1 min
following re-exposure to the light compartment (Fukushima et al.,
2021). In contrast, extended exposure to the dark compartment that is
sufficient for extinction learning, i.e., 3–10 min, re-activates those
changes in gene expression (Fukushima et al., 2021). These observations
indicate that this brief re-exposure to the dark compartment for 1 min
cancels the changes in gene expression that are observed after
re-exposure to the light compartment (Fig. 2). These findings suggest
that a "transition" process of the retrieved IA memory from reconsoli­
dation to extinction inhibits the induction of destabilization/reconsoli­
dation and puts the retrieved memory in a state that enables the
initiation of memory extinction. It is important to note that a similar
transition of retrieved memory was suggested by measuring extracel­
lular signal-regulated kinase (ERK) phosphorylation following memory
retrieval in contextual fear conditioning (Merlo et al., 2014, 2018).
Phosphorylation of ERK increases in the hippocampus, amygdala,
and medial prefrontal cortex during memory transition from reconsoli­
dation to extinction by brief, i.e., 1 min, re-exposure to the dark
compartment (Fukushima et al., 2021). This observation suggests that
this transition process shows specific molecular signatures, although
there is no activation of gene expression and protein degradation. More
interestingly, pharmacological inhibition of ERK activation in any of
those brain regions disinhibits the cancellation of reconsolidation; the
retrieved IA memory is enhanced even though the animals are
re-exposed to the dark compartment for 1 min (Fukushima et al., 2021).
This observation suggests that the memory transition process actively
inhibits the induction of memory reconsolidation. In this transition
process, ERK may act as a molecular switch to abrogate reconsolidation
and enables the initiation of extinction learning.
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4.1. Interaction of fear and extinction neurons
The above findings suggest that the transition of memory phases
from reconsolidation to extinction is regulated by a specific process. In
contrast, there is evidence that competition between “fear” neurons and
“extinction” neurons determines the states of fear in the amygdala. Fear
neurons in the basolateral amygdala (BLA) are activated during the fear
response to a CS following cued fear conditioning, whereas extinction
neurons in this brain region are activated in response to the same cue
after extinction learning (Herry et al., 2008). Interestingly, fear and
extinction neurons in the medial intercalated neurons clusters between
the BLA and central amygdala have also been identified that are located
upstream of the fear and extinction neurons in the BLA and determine
the states of the fear response through mutual inhibition (Hagiwara
et al., 2021). These observations suggest that the fear response is regu­
lated by the competition between the two neural circuits for fear and
extinction. This supports the hypothesis that a new inhibitory circuit is
formed by extinction learning and suppresses the fear responses.
Interestingly, cell ensembles responding to the CS in the basolateral
regions of the amygdala are transformed after fear conditioning as if
they were responding to a US and do not return to their original en­
sembles even after extinction learning (Grewe et al., 2017). This in­
dicates that cell ensembles are qualitatively different before and after
extinction learning, suggesting that they are also shifted from the state of
reconsolidation to extinction. This may reflect the competition in which
new inhibitory circuits suppress the activity of the fear circuits inducing
the fear responses.
In summary, the reconsolidation and extinction of contextual fear
and IA memories are not independent and interact with each other since
the induction of reconsolidation can be canceled at the behavioral,
cellular, and molecular levels once fear memory is extinguished.
Importantly, this transition of memory phases from reconsolidation to
extinction of fear memory is actively controlled in an ERK-dependent
manner. It is important to understand further the molecular and
cellular mechanisms underlying this memory transition process. Since
the amygdala shows distinct populations of fear and extinction neurons
and regulation of fear memory states through competition between
these neurons, it is also important to identify reconsolidation and
extinction memory engram neurons in the amygdala and other brain
regions and understand the mechanisms underlying the transition of
memory phases through their interactions.
Declaration of Competing Interest
The authors declare no conflict of interest.
Data Availability
No data was used for the research described in the article.
Acknowledgment
S.K. was supported by Grant-in-Aids for Scientific Research (A)
(15H02488, 18H03944, 19H01047, 22H00358), Scientific Research (B)
(23300120 and 20380078), and Challenging Exploratory Research
(24650172, 26640014, 17K19464, 20K21265, 22K19142); Grant-in-
Aids for Scientific Research on Priority Areas—Molecular Brain Sci­
ence (18022038 and 22022039); Grant-in-Aid for Scientific Research on
Innovative Areas (Research in a proposed research area) (24116008,
24116001, 23115716, 17H06084, 17H05961, 17H05581, 18H05428,
18H05434, 19H04917, 22H05486); JST [Moonshot R&D]
[JPMJMS2298]; MEXT-Supported Program for the Strategic Research
Foundation at Private Universities (S1311017); Core Research for Evo­
lutional Science and Technology (CREST), Japan; The Sumitomo
Foundation, Japan; the Takeda Science Foundation, Japan; The Naito
Foundation, The Uehara Memorial Foundation, Daiichi Sankyo
S. Kida
Foundation of Life Science, The Food Science Institute Foundation
(Ryoushoku-kenkyukai), Danone Research Grant from Danone Institute
of Japan Foundation, and The Science Research Promotion Fund; and
The Promotion and Mutual Aid Corporation for Private Schools of
Japan.
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