TICS 2407 No.

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Review

Face your fears: attenuating remote fear

memories by reconsolidation-updating
1,2 3,
Bianca A. Silva and Johannes Gräff *

Traumatic events generate some of the most enduring memories, yet little is known Highlights
about how long-lasting fear memories can be attenuated. In this review, we collect Despite an inherent resistance to be
the surprisingly sparse evidence on remote fear memory attenuation from both changed, remote fear memories can be
attenuated by reconsolidation-updating
animal and human research. What is becoming apparent is twofold: although
approaches.
remote fear memories are more resistant to change compared with recent ones,
they can nevertheless be attenuated when interventions are targeted toward Reconsolidation-updating capitalizes on
the period of memory malleability instigated by memory recall, the reconsolidation an etiologically relevant period of memory
malleability induced by recall, which is
window. We describe the physiological mechanisms underlying remote characterized by elevated levels of neu-
reconsolidation-updating approaches and highlight how they can be enhanced ronal plasticity.
through interventions promoting synaptic plasticity. By capitalizing on an intrinsi-
cally relevant phase of memory, reconsolidation-updating harbors the potential to Such neuronal plasticity helps fearful
memories to be updated toward safety,
permanently alter remote fear memories. which has been evidenced at the level
of fear circuits, engrams, and molecular
changes.
The fate of long-lasting fear memories
Therefore, treatments aimed at fos-
Long-lasting memories lie at the core of an individual’s identity. Unfortunately, this is also true tering this plasticity constitute a promis-
for fear and trauma-related remembrances. Every person with traumatic memories can testify ing approach to support
that such memories can be extremely long-lasting and difficult to change. Yet, surprisingly little reconsolidation-updating for perma-
nently changing remote fear memo-
is known about the neural mechanisms at the basis of the attenuation of remote fear memories.
ries.
This is showcased by a recent PubMed search using the terms ‘fear memory’ versus ‘remote fear
memory’, and ‘fear memory extinction’ versus ‘remote fear memory extinction’, both of which
yielded a meager 3% of studies dealing with the remote form. Indeed, it is only over the past de-
cade that we have started to gain a more comprehensive picture of the brain areas implicated in
remote fear memory storage [1] and its attenuation [2]. This dearth of knowledge is inexplicable
for several reasons: first, in light of the elevated lifetime prevalence of fear and stress-related disor-
ders, such as post-traumatic stress disorder (PTSD) [3]; second, with respect to a core criterion for
PTSD diagnosis, namely that its symptoms have to last for more than 1 month [4]; and finally, be-
cause the available knowledge of remote memories from basic studies shows that remote memo-
ries are not only stored differently than recent ones [1,5], but also more difficult to attenuate [6,7].
Thus, there is a strong need to advance the study of remote fear memories, from their storage
1
mechanisms to means to modify them. National Research Council of Italy,
Institute of Neuroscience, Milan, Italy
2
IRCCS Humanitas Research Hospital,
Once recalled, memories enter a period of malleability, the so-called ‘reconsolidation window’, Rozzano, Milan, Italy
3
during which they can be either strengthened, left unchanged, or updated according to current Laboratory of Neuroepigenetics, Brain
Mind Institute, School of Life Sciences,
environmental contingencies [8–10] (Figure 1A). Similar to learning-induced plasticity during con-
Ecole Polytechnique Fédérale Lausanne
solidation [11], the reconsolidation window is accompanied by heightened neuronal plasticity (EPFL), Switzerland
[10,12]. Therefore, to attenuate an acquired memory, two options are available. On the one
hand, a memory can be impaired by blocking its reconsolidation; on the other hand, a memory
can be modified, or updated, by facilitating neuronal plasticity mechanisms that promote the
incorporation of new information. From an etiological viewpoint, the former approach appears *Correspondence:
somewhat more artificial, while the latter (reconsolidation-updating) represents a more natural johannes.graeff@epfl.ch (J. Gräff).

Trends in Cognitive Sciences, Month 2023, Vol. xx, No. xx https://doi.org/10.1016/j.tics.2023.01.004 1

© 2023 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
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Figure 1. Harnessing memory reconsolidation to update fearful memories toward safety. (A) The concept of
memory reconsolidation. After learning, memories are stored in the brain by a protein synthesis-dependent process called
memory consolidation. When recalled, memories enter another round of protein synthesisdependency, during which they
thereby become modifiable. This period of memory malleability is time-limited and often referred to as the ‘reconsolidation
window’. Memory malleability allows the memory to be either strengthened (when a higher valence is encountered at
recall), maintained (when similar situations are encountered at learning and recall), or weakened (when a lower valence is
encountered at recall). Pharmacological agents blocking reconsolidation, such as propranolol or glucocorticoids, are
destined to block the first two scenarios. By contrast, the third scenario is ideally suited to incorporate safe or non fear-
eliciting information into a fearful memory so that its fear component is updated toward one of safety and no longer
persists in its original form. Behavioral interventions or pharmacological agents aimed at increasing plasticity are destined
to target this scenario. (B) Theoretical mode of action of reconsolidation-updating paradigms to attenuate fearful
memories. During memory formation of a fearful association, fear increases. Upon memory recall, the reconsolidation
(Figure legend continued at the bottom of the next page.)

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way for memory change. Therefore, the appeal of reconsolidation-updating lies in capitalizing on
inherently occurring mnemonic mechanisms with the potential for a robust and lasting change of
the memory trace.

In recent years, it has become apparent that, although memories become more generalized, stable,
and dependent on widely distributed circuits with age [13], they nevertheless enter a period of mem-
ory malleability when recalled and, therefore, can be attenuated by reconsolidating updating (Box 1).
In this review, we summarize the state-of-the-art in reconsolidation-updating research targeted to
remote forms of memory in both animal models and humans, and identify important areas for further
investigation. We note that this review focuses solely on reconsolidation-updating procedures, while
other approaches to alter remote fear memories with a translational potential, such as
reconsolidation blockade, are not covered here, but have been extensively described elsewhere
[14].

The premise of reconsolidation-updating

Reconsolidation-updating was shown for the first time to be capable of attenuating aversive
memories in a groundbreaking study by Monfils and colleagues in 2009. For this, the authors
applied extinction training to previously fear conditioned rats during the period of memory malleability
instigated after memory recall 1 day after conditioning. In Pavlovian conditioning, extinction relies on
the repeated presentation of the conditioned stimulus (CS) that has been associated during
memory encoding with an unconditioned stimulus (US), such as an electrical foot shock, which
gradually reduces the CS-associated fear response [15,16]. When fear-conditioned rats underwent
extinction training between 10 min and 6 h post recall, fear memory was efficiently and persistently
updated toward safety [17] (Figure 1B); by contrast, when extinction was performed outside the
reconsolidation window, fear resurfaced with time, which indicates that the original fear memory
had only been temporarily suppressed (Figure 1C) [18]. Subsequently, a large body of studies has
confirmed that recent fearful memories are readily amenable to updating using extinction paradigms
applied during the reconsolidation window [19,20]. Notwithstanding, several studies have failed to
replicate these findings despite using similar procedures, which highlights not only the need to care-
fully control for experimental factors such as stress levels, housing conditions, or experimenter, but
also the fragile nature of such reconsolidation-updating interventions [21,22].

Remote fear memories are more difficult to change

When hen applied to a remote (i.e., a 28-day-old) memory , retrieval-extinction paradigms initially
failed to permanently update fearful memories. For example, although a reconsolidation-updating
protocol nearly identical to that in the 2009 study led to reduced remote fear memory expression
immediately after the extinction procedure, fear expression resurfaced with time, evidencing a
memory change that was merely transient [23]. Similarly, another study attempting to change re-
mote memories with a spaced extinction paradigm, in which re-exposure sessions were set 2 h
apart and that had yielded promising results for recent fear memories [24], reported similarly resilient
remote memories [25], despite being compatible with conditions that trigger reconsolidation-
updating. The failure of these behavioral intervention strategies to attenuate remote memories is

window of memory malleability opens. If extinction learning occurs during this time-limited period, it is thought to become
linked to the recalled memory trace, which thereby becomes updated toward safety. Immediately after the extinction
paradigm, fear expression is decreased and, importantly, stays low even when retested at delayed times thereafter.
(C) Theoretical mode of action of conventional extinction to attenuate fearful memories. During memory formation of a
fearful association, fear increases. Since no isolated recall is given and, thus, the original memory is not rendered labile,
extinction training is thought to lead to a new memory trace of safety (green), which competes with, and suppresses, the
original memory trace of fear. Immediately after the extinction paradigm, fear expression is decreased. However, since the
original memory trace was only suppressed, it continues to exist (red dashed line) and, thus, is prone to resurface when
tested at delayed times thereafter.

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Box 1. The history of (remote) memory reconsolidation

Memory reconsolidation was discovered almost twice. First, when Misanin et al. in 1968 observed that electroconvulsive
shocks (ECS) administered to rats led to retrograde amnesia after the animals had recalled a fear conditioned memory, but
not without the recall [111]; and, second, around 30 years later, when the laboratories of Sara and Le Doux found that the
administration of NMDA and beta-adrenergic blockers, as well as the infusion of protein synthesis inhibitors in rats, had the
same memory-reducing effect, but again only in the presence of memory recall [112,113].

Almost simultaneously, but often overlooked, the same principles of memory reconsolidation were also shown to account for
remote forms of memories; for example, in 1975, the application of post-retrieval ECS was found to be capable of changing
episodic memories in humans up to several months after learning [114,115] (although such effect was not always permanent),
while, in 2002, protein synthesis inhibitor administration to rats significantly reduced memory expression after the animals had
recalled a conditioned fear memory several weeks post-training [27]. Nevertheless, unlike recent memories, remote memories
are not always as readily amenable to change by reconsolidation-updating.

reminiscent of earlier unsuccessful attempts aimed at blocking reconsolidation for remote fear mem-
ory attenuation. For example, postrecall inhibition of protein synthesis in rodents, although effective for
reducing recent fear memories, has failed, in several instances, to reduce remote fear memories
[6,7,26] (but see also [27]).

Why such resistance occurs is not clear, but is most likely due to a spatiotemporal change in the
brain areas subserving memory storage, to different molecular memory storage mechanisms
implied, or to a combination of both [5,28]. Importantly, both are hallmarks of fear generalization
[29], a typical feature of remote memories. Fear memory generalization refers to the process by
which memories become more imprecise with time, which has adaptive value for an organism
to survive in the face of changing environmental contingencies. However, precisely because of
such generalization, it may be more difficult to fully recall remote traumatic memories with the
CS of the original event and, thus, to use reconsolidation-updating paradigms to attenuate
remote fear memories. In support of this view, it has long been known that the recall of a traumatic
memory is a sine qua non for it to be changed by interventional therapies, to the point that, when
recall is incomplete, traumatic memories can be inadvertently strengthened, rather than weakened
[30,31]. Together with the age and strength of a memory, these parameters form the so-called
‘boundary conditions’ [32,33], which define, or at least influence, under which circumstances
memories undergo reconsolidation, but are themselves not thoroughly defined for remote memo-
ries (see ‘Face your fears: moving forward’ section).

Nevertheless, changing the parameters of the boundary conditions, such as duration, timing, or
context of memory recall and/or type of extinction paradigm (such as its length, intertrial interval,
or pharmacological support), has rendered even remote memories amenable to reconsolidation-
induced attenuation [25,32,34]. Thus, exposure to novelty with an open field paradigm 1 day be-
fore a retrieval extinction session successfully attenuated remote fear memories [35]. Similarly, an
isolated US exposure 10 min or 1 day before extinction was also found to lead to persistent
remote fear memory attenuation in reconsolidation-updating settings [2,36–38]. To better under-
stand under which conditions even remote fear memories can be changed, it is important to
investigate the physiological and molecular mechanisms underlying their attenuation, and how
they compare to the attenuation of recent ones.

Brain mechanisms of reconsolidation-updating of remote fear memories in

rodents
Neuronal circuits
Recent and remote memories are profoundly different in nature, with remote memories being less
precise, more resistant to attenuation, and stored in distinct brain networks. In particular, several
studies indicate that, as time goes by, sites for memory storage shift from areas typically involved

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in memory encoding, such as the amygdala and hippocampus, to more widely distributed cortical
and thalamic circuits [1,5,39,40]. Thus, remote fear memory attenuation may rely on brain circuits
fundamentally different to those implicated for recent fear memory, but only a handful of studies
have investigated this question so far.

The first study to allude to this point used a spaced fear extinction paradigm over 4 days, which is
compatible with reconsolidation-updating paradigms for recent fear memories, and assessed
brain activity patterns by the immediate early gene marker cFos, an indicator of neuronal activity
[2]. Surprisingly, connections between the infralimbic cortex (IL) and the basolateral amygdala
(BLA), the canonical pathway for the extinction of recent fear memories [41–43], were not
recruited during the attenuation of remote fear memories [38]. Conversely, remote fear attenua-
tion was accompanied by the activation of a circuit centered on the nucleus reuniens of the thal-
amus (NRe), a structure previously associated with fear memory reconsolidation [44–46] and
generalization [47] (Figure 2A). Of note, all brain areas recruited at the end of the extinction proce-
dure, when fear responses were reduced, had already been active upon remote fear memory re-
call, when fear expression was still high, which speaks in favor of a valence updating from fear to
safety within the original fear memory trace rather than having extinction-specific areas emerge
over time (Box 2). In addition, although the same set of areas remained active, their functional
connectivity partially changed [2], suggesting that remote fear memory attenuation is accompa-
nied by a reorganization within the original memory storage network.

A functional follow-up study subsequently found that the NRe, and its monosynaptic outputs to
the BLA, bidirectionally mediate the attenuation of remote, but not recent, fear memories [38].
Importantly, several findings of this study confirmed that reconsolidation-updating mechanisms
are implicated in this process. First, NRe manipulation decoupled from memory recall left the
memory intact, which indicates that remote fear memory attenuation was bound to memory

(A) (B)
Hippocampus
PFC
PFC Thalamus
Hippocampus
Thalamus

Amygdala Amygdala

[2,38,48,51] [2,38,51] [79] [70, 144]

[37,48] [2,38,44] n.a. [70]
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Figure 2. Brain areas underlying reconsolidation-updating of remote fear memory. Schematic indicating brain
regions found to be implicated in reconsolidation-updating of remote fear memories in both rodent (A) and human
(B) studies. The modulation of prefrontal cortico-amygdalar networks as well as thalamic structures has been identified as
crucial for the persistent attenuation of remote fear memories by reconsolidation-updating mechanisms in both rodent and
human studies. By contrast, the contribution of hippocampal and thalamic structures, although important for the
attenuation of remote fear memoires in rodents and recent fear memories in rodents and humans, has not been
investigated in the human brain. For details of these studies, please refer to the main text [2,37,38,44,48,51,70,79,144].
Abbreviations: PFC prefrontal cortex; n.a., not assessed.

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Box 2. Are reconsolidation-updating and extinction mutually exclusive?

In theory, two scenarios can explain how fear attenuation is brought about: behavioral extinction and reconsolidation-
updating. The first dates back to Ivan Pavlov’s (1849–1936) original studies, which led him ‘to conclude that experimental
extinction is based on inhibition’ [15] or, in other words, that, during behavioral extinction, a new memory trace of safety is
formed, which coexists, competes with, and inhibits the original memory trace of fear. The second scenario, named
reconsolidation-updating, postulates instead that behavioral fear attenuation is mediated by an unlearning or updating
of the original fearful association toward a nonfearful one [8,80,116]. A key difference between the two concerns the
long-term fate of the attenuated fear memory, which can be measured by spontaneous recovery (fear resurfacing with
the passage of time), renewal (fear resurfacing when the CS is presented in a different context), or reinstatement (fear
resurfacing when the CS is presented unexpectedly). While extinction as a mere competition mechanism is prone to
any of the three, reconsolidation-updating mechanisms, by virtue of having permanently updated the original memory
trace of fear, should not lead to any sign of fear resurfacing.

In addition to this behavioral distinction between reconsolidation-updating and extinction, the same dichotomy has also
been observed on other levels: on a circuit/brain area level, where both the prefrontal cortex and amygdala are reportedly
implicated in reconsolidation-updating and extinction [117]; on a cell population/engram level, where evidence exists that
behavioral attenuation is mediated by the same memory trace having changed toward safety [37,56,59] or by a new mem-
ory trace of safety having formed [118,119]; on a cellular level, where both reconsolidation-updating and extinction have
been shown to alter spine formation and density in the same brain area [120,121] and even on the same neuron
[122,123]; on a molecular level, where distinct protein and gene expression signatures have been reported for either
reconsolidation-updating or extinction [19,26,80,124,125]; and on a computational level, where both new learning and
unlearning models can account for behavioral attenuation [126,127].

This has led several groups to conclude that reconsolidation updating and extinction are mutually exclusive
[14,26,128,129], but, given the limited modalities assessed in these studies in often different brain areas with usually
different experimental paradigms, it is somewhat premature for such statements. Rather, it appears likely that
reconsolidation-updating (i.e., relearning of the original fearful association) and extinction (i.e., inhibition of the original fear-
ful association) coexist [80]. Ultimately, the occurrence of the two processes heavily hinges on the experimental paradigm
that is used to induce and/or study them. For example, reconsolidation-updating paradigms are triggered only when the
behavioral extinction paradigm is temporarily separated from recall [17,23,63,130]. Likewise, if the extinction paradigm is
applied outside the time-limited reconsolidation window of approximately 6 h, both recent and remote fear memories have
been observed to spontaneously resurface [17,25], highlighting the limited period during which extinction paradigms can
be applied to update the original memory trace.

reactivation, a typical feature of reconsolidation-updating. Second, NRe-mediated fear memory

attenuation was not followed by spontaneous fear recovery, suggesting that the memory was
permanently updated. Third, using in vivo fiber photometry, activity in the NRe was found to be
present as early as the first recall session and remained stable throughout the entire behavioral
extinction, excluding the participation of inhibitory mechanisms. Fourth, synaptic strength in the
NRe–BLA pathway increased with attenuation, which is not expected were a different extinction
network at play. Along the same line, an earlier study showed that optogenetic activation of an
anterior cingulate cortex–hippocampal area CA1 pathway, which is sufficient to drive fear recall
after fear conditioning, was insufficient to reactivate the memory after a remote fear extinction
procedure [48].

Together, these findings corroborate the idea that, during remote fear memory attenuation, func-
tional updating adaptations occur within the original fear memory networks instead of having
dedicated extinction networks emerging over time. Nevertheless, these data do not exclude
the possibility that reconsolidation-updating and extinction mechanisms coexist during remote
fear memory attenuation (Box 2), and they did not examine whether, and the extent to which,
reconsolidation-updating also occurs at the cellular level.

Cells and engrams

The first study to investigate which memory trace(s) contribute to remote fear memory attenuation
used a recently developed cellular tagging technique, by which neurons active at any given
moment of a fear memory can be visualized and functionally manipulated later on. This approach,

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the engram tagging technique [49,50], relies on either a reporter gene, or a chemo- or optoge-
netic effector gene coupled to an inducible, neuronal activity-dependent promoter, the expres-
sion of which can be temporally controlled. This way, fear, recall, or extinction engrams can be
captured (i.e., visualized), and their co-activation at later time points studied. Thus, when neurons
active at remote fear memory recall were tagged with a specific fluorophore, and subsequently
analyzed for their reactivation after a spaced fear extinction paradigm (i.e., by using cFos), the
degree of reactivation positively correlated with fear attenuation efficacy: The more pronounced
fear attenuation was, the more cells active at remote memory recall were also activated after
fear attenuation [37]. Importantly, such reactivation of recall-induced neurons was observed
across different extinction paradigms, across different brain areas (namely the dentate gyrus
(DG), IL, and BLA), using different tagging techniques [37,51], and was found to be functionally
relevant for fear memory attenuation: When remote fear recall-induced neurons were chemogenet-
ically activated, fear memory attenuation was improved; conversely, when remote fear recall-
induced neurons were chemogenetically silenced, fear memory attenuation was worsened [37].

This seemingly paradoxical finding can be readily explained by reconsolidation-updating mecha-

nisms. The key to successful attenuation of remote fear memories lies in the same cells that were
used to store the memory in the first place (i.e., in an updating of the original memory trace of fear
toward safety). Indeed, the fact that recall-induced neurons contain mnemonic information has
been documented in many studies, which showed that recall-induced engram cells are capable
of transmitting learned information from one context to another [52,53] or of changing valence de-
pending on environmental circumstances [54]. Thus, this finding lends experimental support to a
long-standing empirical tenet in psychotherapy, which is the prime importance of successfully
recalling a traumatic memory for it to be changed [31]. Albeit not for remote memories, the evi-
dence of reconsolidation-updating mechanisms at the engram level has since been confirmed
in several other studies, insofar as optogenetic and chemogenetic stimulation of the original hip-
pocampal fear engram were found to facilitate recent fear attenuation [55–59].

Molecular mechanisms
What are the molecular mechanisms that would facilitate such updating of the original fear memory
trace? Converging evidence suggests the involvement of epitranscriptional mechanisms that
promote synaptic plasticity. The first study indicating so found that increasing histone
acetylation, a transcription-permissive epigenetic modification [60], by means of small-molecule
inhibitors of histone deacetylases (HDACis) facilitated the reconsolidation-updating of remote fear
memories [25], which was accompanied by an enhanced transcription of several key plasticity-
related genes. These findings were later replicated in other studies of remote fear memories
using different behavioral paradigms, for both histone acetylation [35], and other members of the
enzymatic histone acetylation machinery [61].

Importantly, where assayed, these epitranscriptional changes were accompanied by enhanced

functional and structural synaptic plasticity, such as long-term potentiation (LTP) and an increased
number of dendritic spines. Thus, this observation not only advocates for means to promote plas-
ticity to facilitate fear attenuation, but is also reminiscent of the notion that plasticity-promoting
treatments induce a state of metaplasticity [62], which could thus be harnessed to improve fear
attenuation during reconsolidation-updating (Box 3).

Reconsolidation-updating of remote memories: studies in humans

Behavioral strategies
That reconsolidation-updating is also at play for fear attenuation in humans was shown for the
first time in a seminal study by Schiller and colleagues in 2010, who applied a post-retrieval

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Box 3. Metaplasticity to promote reconsolidation-updating?

Cellular and molecular changes that accompany the reconsolidation updating of remote fear memories predominantly fall
in the category of promoting synaptic plasticity. As such, these observations are in line with the concept of metaplasticity
[62], which refers to the prospective change in plasticity of a neuron following a prior experience [131]. Accordingly, recall-
induced metaplasticity of the fear memory engram would be further enhanced by plasticity-promoting treatments. For
example, a recent study highlighted that engram cells increase their intrinsic excitability upon memory recall, which
coincides with a facilitation to adopt to new environments [132,133]. Although no study to date has investigated the mo-
lecular underpinnings of engram cells underlying remote fear memory attenuation, synaptic plasticity-related changes have
already been observed at the whole-tissue level. Thus, HDACi-mediated reconsolidation updating of remote fear memo-
ries was paralleled by an increase in cFos, Npas4, and Arc [25], immediate early genes (IEGs) that are known to orchestrate
transcriptional cascades important for synaptic plasticity as well as for learning and memory [134–136]. By contrast, in an-
imals with impaired fear attenuation, the same IEGs were found to be significantly downregulated [137]. In similar fashion,
Zif268, another IEG promoting synaptic plasticity [138], was found to be upregulated following reconsolidation-updating of
recent fear memories [124,139]. Importantly, these transcriptional changes were also paralleled by facilitated LTP, a synaptic
correlate of learning [140], and by an increased number of dendritic spines and synapses, which are structural correlates of
learning [141]. Of note, this interpretation applies not only to HDACi-based treatments, but also to the NMDA receptor ago-
nist D-cycloserine (DCS), which is known to increase synaptic plasticity [142] and to promote fear attenuation [143].

extinction paradigm to fear-conditioned subjects 1 day after conditioning, and showed that
those exposed to behavioral extinction within 10 min to 6 h after the reminder cue presented
no resurfacing of fear [63]. This experimental approach was extensively repeated in other condi-
tions and replicated by most follow-up work [19]. However, similarly to rodent studies, several
studies failed to efficiently attenuate fear memory despite using similar paradigms, again highlight-
ing that reconsolidation-updating approaches may be particularly susceptible to differences in
experimental conditions [64–68].

What about remote forms of human fear memories? Only one study has thus far used the original
Schiller et al. paradigm to attenuate older fear memories, but was able to replicate its findings
for 7-day-old fear memories [69]. Subsequently, another study applied a modified version of
post-retrieval extinction, in which memory reactivation was induced by exposure to the US, to
2-week-old memories [36]: The presentation of a reminder shock 10 min before behavioral
extinction prevented spontaneous recovery and reinstatement, suggesting that a reconsolidation-
updating mechanism was at play. Interestingly, the application of a similar protocol to life-long
arachnophobia also yielded encouraging results [70,71]. Recently, the implementation of exposure
therapy triggering reconsolidation-updating has also shown promise in patients with PTSD (for
whom the trauma was mostly remote), for whom beneficial effects of a brief memory reactivation
session before exposure therapy were observed [72–75]. Taken together, these studies indicate
that behavioral strategies based on reconsolidation-updating can also effectively modulate remote
fear memories in humans and, thus, represent valuable therapeutic avenues for trauma-related
disorders.

Brain areas involved in human reconsolidation-updating

As for behavioral studies, investigations of the brain substrates of reconsolidation-updating have
mostly focused on recent memories. Similar to animal findings, these studies converge on the
notion that reconsolidation-updating directly modulates brain responses in sites storing the
original fear memory trace, such as amygdala–cortical networks [76–78]. This substantially differs
from extinction, which relies on a distinct neural circuitry involving interactions between the amygdala,
ventromedial prefrontal cortex (vmPFC), and hippocampus [77].

Whether similar networks are involved in the reconsolidation-updating of remote forms offear
memories remains unclear. One study investigated the brain activity of life-long arachnophobia
and observed a neutralization of associated amygdala activity following reconsolidation-updating

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but not standard extinction paradigms [70]. Furthermore, continuous theta-burst stimulation, a
brain stimulation technique that can induce long-lasting changes in synaptic plasticity, over the
right dorsolateral (dl)PFC was able to attenuate remote fear memories if delivered 10 min, but
not 6 h, following memory reactivation by a reminder cue [79]. Together, these findings suggest
that modulation at the level of the PFC–amygdala network is also critical for the reconsolidation-
updating of remote fear memories (Figure 2B). But whether reconsolidation-updating is
accompanied by a permanent modification of the distributed remote fear memory trace in
other parts of the human brain remains to be addressed.

Face your fears: moving forward

From the evidence available to date and summarized above, two conclusions can be drawn. First,
remote fear memories are more resistant to change compared with recent ones, which calls for
finding ways to facilitate such change (see Outstanding questions). Second, despite this resis-
tance, reconsolidation-updating mechanisms have proven effective to attenuate remote forms
of fear memories in several animal and human studies. Based on that, we propose that memory
updating is a promising mechanism to be capitalized upon for changing remote fearful memories
to nonfearful ones.

A central means to do so is to increase neuronal plasticity during the period of memory updating
(Box 3). Since memory updating per se is already accompanied by increased synaptic, structural,
and epitranscriptomic plasticity [19,80,81], it follows that any intervention aimed at furthering
this increase is likely to be beneficial for behavioral updating. Examples include the administration
of HDACis to increase epigenetic plasticity, which coordinates gene expression programs under-
lying synaptic plasticity [25], the NMDA agonist D-cycloserine (DCS) [82], or transcranial stimula-
tion [83], which showed beneficial effects when applied concomitantly to reconsolidation-
updating interventions in preclinical studies. Similarly, promising results were obtained for HDACis
[84], DCS [85], and transcranial magnetic stimulation [86] in clinical settings, and advanced-stage
clinical trials are underway.

However, the beneficial effects of these plasticity-promoting treatments were not always
observed [87,88], and sometimes even opposite results obtained. Therefore, the biggest chal-
lenge in the field lies in better understanding the boundary conditions of remote fear memory
reconsolidation, or what makes memories enter the period of malleability during which they can
be updated. Among the most important boundary conditions for memory reconsolidation
are the age and strength of the memory, as well as the parameters of the recall itself [89]. Thus,
the older a memory or the more intense the learning episode, the more resilient a memory is to
change by reconsolidation-updating [32,33], which is particularly relevant for long-lasting traumata.

In addition to memory age and strength, the level of prediction error (PE) during recall strongly
affects updating efficacy. By definition, PE is the failure of an expected event to occur. Thus,
PE is a central tenet to memory reconsolidation-updating insofar as the likelihood to update
positively correlates with the degree of PE [68,90]. PE was found to be paramount for memory
reconsolidation in multiple lines of evidence, in both rodents and humans. For example, only
when a mismatch between the presentation of US during encoding and memory recall occurred
was the memory susceptible to drug-induced amnesia in rats [90]. In like manner for humans,
when no new information could be learned following memory recall, reconsolidation did not
occur, as evidenced by a complete unsusceptibility to drug-induced amnesia [91]. However,
despite the importance of PE, the objective evaluation of the degree of PE experienced by an
individual is particularly challenging because no clear definition or a reliable physiological readout
of PE exists to date.

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Another factor influencing the capacity of memory updating during reconsolidation is the internal Outstanding questions
state (IS) of the test subject at the time of memory recall. IS can be influenced by basic needs, How do fear memory storage and
such as hunger, thirst, and sleep, by basic external sensory systems, such as vision, audition, attenuation evolve over time? Studying
storage and attenuation of recent to
olfaction, gustation, and mechanosensation, by basic internal sensory systems, such as the
remote fear memories in side-by-side
vestibular systems and proprioception, as well as by more complex feelings, such as motivation comparisons from a circuit, cellular,
and arousal [92]. How precisely IS can influence reconsolidation-updating of aversive memories and molecular perspective at regular
in general, and in particular for long-lasting forms thereof, is not well understood, but there are intervals postencoding is likely to yield
important answers to this question.
several studies showing that it does. One study used lithium chloride (LiCl), a compound
known to induce gastric malaise, and found that its administration after encoding induced an What are boundary conditions that
amnesia of conditioned taste aversion that was reversible with another exposure to LiCl 2 days dictate whether a remote memory
later [93]. Thus, the second LiCl injection served as a reminder cue to the first bolus, and thereby enters a period of malleability
following recall? A systematic investi-
to the IS of the animal at the first memory recall (when the memory was still present). Similar findings gation thereof is warranted to better
were obtained in another study of transient acidosis [94]. In addition to an individual’s multimodal understand reconsolidation-updating
IS, experiments assessing how hormonal state [95], exercise [96], metabolism [97], or microbiota mechanisms of long-lasting fear memo-
composition [98] contribute to remote reconsolidation-updating are also warranted. ries.

If reconsolidation-updating and pure

Moreover, as exemplified by an individual’s IS, memory formation and recall do not happen on a extinction mechanisms coexist, whether
clean slate, (i.e., irrespective of an individual’s past). However, life-history events that might and to what extent do they interact?
influence memory expression and storage are often either ignored in preclinical studies (although
What is the role of sleep in
they would be relatively easy to control for), or not fully assessable in clinical studies, given the attenuating remote fear memories
complexity of human memory. For example, early life stress has been shown to impinge on using reconsolidation-updating ap-
memory reconsolidation in rodents [99,100]. Furthermore, depending on the timing of the stress- proaches? This question arises from
studies showing that remote memo-
ful period during development (prenatal, early postnatal, or in adulthood), such stress can have ries become amenable to
different outcomes, and even affect neurodevelopment itself [101], providing a hard-wired obsta- reconsolidation-updating when the
cle to memory change as seen, for example, for developmentally controlled perineuronal net extinction training is preceded by a
formation preventing memory extinction [102]. Likewise for humans, in whom it is known that social recall session 24 h earlier.

stress is associated with several mental health disorders [103,104] as well as with memory forma-
tion per se [105], it is likely that stress also has a predominant role in memory reconsolidation. Given
that the probability of experiencing stress or any life history-related event increases with time, such
considerations are particularly relevant for memories with a longer incubation period.

Lastly, stress susceptibility and resilience are partly genetically encoded [106,107], from which
follows that interventions aimed at reducing stress or fearful memories are also dependent
on an individual’s genetic makeup. In rodents, C3H/HeNTac mice, a strain characterized by
increased stress susceptibility, display elevated freezing levels compared with the stress-
resilient 129S6/SvEvTac strain [108]. Accordingly, C3H/HeNTac mice are more resilient to fear
memory extinction. Likewise, in humans, reconsolidation is known to be influenced by genetic
polymorphisms in several genes involved in dopamine or serotonin signaling, or in promoting
synaptic plasticity [109,110]. Therefore, it would be interesting to study genetic polymorphisms
underlying particularly long-lasting and resilient forms of trauma in humans.

Concluding remarks
Given such high interindividual variability in trauma processing, which includes internal and external
circumstances at the moment of memory recall, the path to translation for reconsolidation-
updating is unlikely to be straightforward, and a one-size-fits-all strategy is not what is required.
Rather, akin to personalized healthcare approaches for other diseases, genetics, life history, and
IS should be taken into consideration when attempting to change fearful memories in the clinic.
This is not as far-fetched a scenario as it may seem, because genetic biomarkers of stress suscep-
tibility and resilience, detailed questionnaires, or stress hormone measurements are already, or will
soon become, available to account for these factors. Furthermore, both behavioral and functional

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human studies are needed to complement studies in rodents to unravel the neural networks re-
sponsible for attenuating remote fear memories. This could be achieved by human fMRI studies
conducted during memory reconsolidation, which compare recent and remote signatures of mem-
ory attenuation, for both healthy participants and patients with PTSD. Obtaining such neural signa-
tures will in turn allow for the design of a reference atlas of successful fear attenuation that can be
matched to interindividual variability. In extension, these neural signatures could be harnessed in
future studies to investigate whether and how plasticity enhancing measurements improve remote
fear memory attenuation. In light of the premise of reconsolidation-updating to permanently alter
even remote fear memories, the need to shed further light onto its underlying processes is
undeniable.

Declaration of interests
None declared by authors.

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