Implications of memory modulation for post-traumatic stress and fear disorders

Article (PDF Available)inNature Neuroscience 16(2):146-53 · January 2013with181 Reads
DOI: 10.1038/nn.3296 · Source: PubMed
Abstract
Post-traumatic stress disorder, panic disorder and phobia manifest in ways that are consistent with an uncontrollable state of fear. Their development involves heredity, previous sensitizing experiences, association of aversive events with previous neutral stimuli, and inability to inhibit or extinguish fear after it is chronic and disabling. We highlight recent progress in fear learning and memory, differential susceptibility to disorders of fear, and how these findings are being applied to the understanding, treatment and possible prevention of fear disorders. Promising advances are being translated from basic science to the clinic, including approaches to distinguish risk versus resilience before trauma exposure, methods to interfere with fear development during memory consolidation after a trauma, and techniques to inhibit fear reconsolidation and to enhance extinction of chronic fear. It is hoped that this new knowledge will translate to more successful, neuroscientifically informed and rationally designed approaches to disorders of fear regulation.
1 4 6 VOLUME 16 | NUMBER 2 | FEBRUARY 2013 nature neuroscience
r e v i e w f o c u s o n m e m o r y
The laboratory study of fear learning and memory continues to yield
knowledge that holds promise for the understanding and treatment of
post-traumatic stress disorder (PTSD) and other fear-related disorders.
Here we discuss how these new and exciting observations are being
translated from the basic science fields to the clinic. Furthermore, we
point areas where basic research using animal models can be improved
to better account for the dysregulation of fear seen in many disorders.
Experiencing an extremely traumatic event, such as combat or
violent assault, can lead to PTSD. Estimates are that up to 90% of
all people will be exposed to a severe traumatic event during their
lifetime
1
. Given the high rates of trauma exposure, the prevalence
of PTSD is relatively low, affecting approximately only 5–10% of the
general population, with women being twice as likely to develop
PTSD as men
2
. However, the rates of lifetime PTSD are closer to
20–30% in highly exposed trauma populations, such as low-income
urban populations
1
and repeatedly traumatized soldiers. Recent
studies have demonstrated a steep dose-response curve between
trauma frequency and PTSD symptom severity, such that the more
traumatic events a person experiences, the greater the intensity of
PTSD symptoms
3,4
. PTSD is the fourth most common psychiatric
diagnosis
1
and is defined by three primary symptom clusters after
an event that elicited fear, helplessness or horror
5
. The first cluster
of symptoms includes re-experiencing the traumatic event through
intrusive thoughts, nightmares, flashbacks and related phenom-
ena that are often produced by reminders of the traumatic event.
The second cluster is characterized by avoidance symptoms, including
loss of interest in social situations and emotional detachment. The
third cluster includes psychophysiological reactivity in response to
trauma-related stimuli, including exaggerated startle, hypervigilance,
elevated perspiration and shortness of breath.
Several other anxiety disorders are also characterized primarily
by a dysregulated fear response. These include simple phobia; social
phobia (also called social anxiety disorder), which involves fear and
avoidance of social situations; and panic disorder. What is particularly
interesting about this collection of disorders is that they all share a
similar set of fear or panic symptoms that now have a clearly under-
stood neurological basis (Fig. 1). Anxiety disorders affect around
18% percent of adults in the United States in a given year. Moreover,
in 64% of suicide attempts, at least one anxiety disorder is present.
Therefore, from a clinical perspective, improving treatment and iden-
tifying prevention measures is of critical importance. Furthermore,
from a scientific perspective, we would argue that the fear-related
anxiety disorders provide among the ‘lowest-hanging fruit’ for under-
standing the neural circuitry and pathophysiology of psychiatric dis-
orders. This is because (i) the neural substrates of fear have been well
worked out through over 50 years of neurobiological studies, (ii) the
basic behavioral mechanisms underlying fear have been studied for
over 100 years since the time of Pavlov, (iii) these neural and behav-
ioral mechanisms are remarkably well conserved across mammalian
species, including humans, and (iv) in many cases of fear-related
disorders, particularly PTSD, the traumatic incident that initiates
the dysregulated fear response can be identified. As a result of this
last component, not only may we improve our understanding of the
biological and psychological processes leading to a transformation
from a normal’ fear reaction to a pathologically dysregulated fear
response, but we also may be able in some cases to prevent the develop-
ment of inappropriate fear responses through early intervention.
An important observation in recent years is that there are sev-
eral different learning components that distinguish normal fear or
trauma exposure and recovery from the pathological responses to
trauma exposure associated with lack of recovery and/or worsen-
ing of symptoms (Fig. 2). Evidence suggests that exposure to trauma
in the past, before the index trauma associated with the PTSD
1
Department of Psychiatry and Behavioral Sciences, Yerkes National Primate
Research Center, Emory University, Atlanta, Georgia, USA.
2
Howard Hughes
Medical Institute, Chevy Chase, Maryland, USA. Correspondence should be
addressed to K.J.R. (kressle@emory.edu).
Received 11 October 2012; accepted 3 December 2012; published online
28 January 2013; doi:10.1038/nn.3296
Implications of memory modulation for
post-traumatic stress and fear disorders
Ryan G Parsons
1
& Kerry J Ressler
1,2
Post-traumatic stress disorder, panic disorder and phobia manifest in ways that are consistent with an uncontrollable state of
fear. Their development involves heredity, previous sensitizing experiences, association of aversive events with previous neutral
stimuli, and inability to inhibit or extinguish fear after it is chronic and disabling. We highlight recent progress in fear learning
and memory, differential susceptibility to disorders of fear, and how these findings are being applied to the understanding,
treatment and possible prevention of fear disorders. Promising advances are being translated from basic science to the clinic,
including approaches to distinguish risk versus resilience before trauma exposure, methods to interfere with fear development
during memory consolidation after a trauma, and techniques to inhibit fear reconsolidation and to enhance extinction of chronic
fear. It is hoped that this new knowledge will translate to more successful, neuroscientifically informed and rationally designed
approaches to disorders of fear regulation.
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particularly childhood trauma exposure—is of substantial impor-
tance. Furthermore, it appears that some gene pathways (for example,
FKBP5; ref. 3) interact with childhood trauma, but not adult trauma,
to predict adult PTSD. One possible reason for this is that devel-
opmental critical periods of amygdala function are glucocorticoid
dependent
6
, and FKBP5 regulates glucocorticoid receptor sensitivity.
Also, it is known that the level of trauma exposure is of critical import
in the later development of post-traumatic symptoms. During the
minutes to hours, and possibly days, after trauma exposure, the mem-
ory remains in a labile state, called the consolidation period. Some
updates on the neurobiology of consolidation are outlined below, and
there are exciting areas of inquiry suggesting that new pharmaco-
therapeutic and psychotherapeutic approaches may be initiated that
may inhibit the emotional component of fear memory consolidation,
without markedly affecting the explicit memory formation. Such an
approach may not cause amnesia per se but could prevent the severe
emotional reactions that underlie later development of PTSD. Another
aspect of memory modulation that will be addressed below is the idea
of reconsolidation, in which reactivation of a memory may cause it
to re-enter a labile state after it has become permanent. The extent to
which reconsolidation occurs with chronic, long-term memories in
humans remains under some debate, but, if robust, it is an extremely
exciting potential area of modulation. Finally, there are several fur-
ther cognitive mechanisms that are associated with pathological rea-
ctions, such as generalization and sensitization of reminders of fear or
trauma. In contrast, the mechanisms of discrimination and extinction
of memory serve to counter these processes. In summary, as outlined
below, understanding the different components of fear memory for-
mation and modulation may enable powerful and targeted treatment
and intervention approaches.
Although there are several existing pharmacological and psycho-
therapeutic treatments for fear-related disorders
7,8
, all of these rely on
empirically derived approaches. The first-line medication approach
for all anxiety disorders includes the antidepressant and anxiolytic
classes of selective and nonselective serotonin and other monoamine
reuptake inhibitors (for example, fluoxetine, sertraline or venlafax-
ine). Although our understanding of the monoaminergic regulation
of fear circuitry is improving, it is clear that these are not specific in
their actions, they can have difficult side effects and they are only
effective in some cases. The second-most-common class of agents
used to treat these disorders are the benzodiazepines (for example,
clonazepam, alprazolam or lorazepam), which act through enhance-
ment of GABA
A
activity. Enhancing inhibitory transmission in the
amygdala and bed nucleus of the stria terminalis (BNST) has been
shown to diminish fear responses, but these agents have all of the same
limitations as the monoaminergic anxiolytics, in addition to having
abuse and tolerance potential.
A particularly promising area of inquiry arises from the burgeoning
understanding of the neurobiological mechanisms of learning and
memory. Although there are many ways to model the disorders of
fear regulation, among the most robust approaches results from func-
tionally dissecting the differential cognitive, learning and memory
components that regulate fear learning, consolidation, modulation,
generalization, sensitization, discrimination and extinction. Below
we will review some of the differential learning and memory aspects
underlying fear processing and illustrate how breakthroughs in these
areas are leading to new approaches to the modulation of memory,
Fear learning Output targets Fear or panic symptoms
Thalamus
(CS, US)
Cortex
(CS, US)
LA
BLA
CEI
ITC
CEm
Amygdala
Lateral hypothalamus
Dorsal vagal nucleus
Parabrachial nucleus
Basal forebrain
Nucleus reticularis
pontis caudalis
Central gray area
Paraventricular nucleus
Corticosteroid release
Freezing, diminished social
interaction
Increased startle response
Increased arousal, vigilance,
attention
Panting, respiratory distress
Bradycardia, ulcers
Increased heart rate, blood
pressure, perspiration
Figure 1 Schematic depicting the amygdala, the
brain site most critical for fear learning. Information
regarding the conditioned stimulus (CS) and
unconditioned stimulus (US) is transmitted to
the amygdala by way of sensory areas in the
thalamus and cortex. Within the amygdala, the
critical plasticity underlying the acquisition of
fear conditioning is thought to occur in the lateral
amygdala and the lateral portion of the central
nucleus (CEl). The medial division of the central
nucleus of the amygdala (CEm) projects to various
brain areas that produce fear and panic symptoms
seen in people with fear-related disorders.
LA, lateral nucleus; BLA, basolateral nucleus;
ITC, intercalated cells (see also ref. 99).
Pre-existing sensitivity
(gene + environment)
Learning of fear
(index traumatic event)
Consolidation of fear
(hours to days following event)
Expression of fear
(memories,nightmares, flashbacks,
avoidance, sympathetic response, startle)
Pathology
Generalization
Recruitment of
non-associated
cues
Limiting of fear to
specific trauma cue
Diminished response
to cues over time
Increased fear
with repeated
exposure
Sensitization Discrimination Extinction
+
Recovery
Reconsolidation
Figure 2 A model for the development of fear-related disorders. Certain
individuals are predisposed to the development of fear-related disorders on
the basis of early life experience and genetic background, among other risk
factors. When a traumatic event occurs, people learn to fear the cues that
are associated with the traumatic event, and this memory consolidates over
the course of the subsequent hours and days. The expression of fear comes
in several different forms, including flashbacks of the traumatic event,
nightmares, avoidance of situations that trigger memory for the traumatic
event and altered sympathetic responses such as increased startle. The
expression of the fear triggered by memory for the traumatic event may serve
to sensitize those who develop psychopathology, resulting in increased fear.
Additionally, fear may generalize to cues not associated with the traumatic
event in those people who go on to develop a fear-related disorder.
In contrast, with resilience, fear responses to cues related to the traumatic
event extinguish over time, and discrimination occurs between cues that are
associated with the traumatic event and those that are not.
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and thus new treatment and intervention approaches targeting
disorders of fear regulation.
The essential neural circuit supporting fear conditioning
The progress made in developing strategies to treat fear-related dis-
orders has been greatly aided by the knowledge gained in the past
several decades regarding the brain circuitry involved in Pavlovian
fear conditioning and the cellular and molecular mechanisms in this
network that support this form of learning. Fear conditioning involves
learning an association between a neutral conditioned stimulus, such
as a light or tone, and an aversive unconditioned stimulus, typically a
foot shock (Fig. 3a). Memory for fear conditioning is inferred by pre-
senting the cue that signaled the shock (Fig. 3b), and several condi-
tioned responses consistent with a state of fear can be assessed. Some
commonly measured fear responses in rats and mice include freezing
behavior and potentiated startle; in humans, potentiated startle and
skin conductance responses are often measured.
At the heart of the brain circuitry mediating fear learning and fear
responses is a group of subcortical nuclei referred to collectively as
the amygdala (Fig. 1). The lateral nucleus of the amygdala receives
multimodal sensory information regarding the conditioned stimu-
lus from thalamic and sensory cortical areas
9,10
. This converges with
input regarding the unconditioned stimulus, believed to arrive from
somatosensory thalamic and cortical areas
11,12
and the periaqueductal
gray
13
. This convergence of the conditioned stimulus and uncondi-
tioned stimulus, along with other types of data, indicates that the lateral
nucleus is a critical site for plasticity underlying fear learning
14
. Because
the central nucleus of the amygdala sends projections to several brain
areas responsible for generating fear responses
15
, it typically has been
thought of as an output structure. However, the central nucleus also
receives direct thalamic and cortical inputs, and work has shown that
preventing the activity of NMDA-type glutamate receptors and pre-
venting the synthesis of protein in the central nucleus blocks the acqui-
sition and consolidation of fear conditioning, respectively
16,17
. Recent
studies
18,19
showed that the lateral (CEl) and medial (CEm) divisions
of the central nucleus make distinct contributions to fear conditioning,
with the CEl being necessary for the acquisition of fear and the CEm
responsible for the production of fear responses.
Learning of environmental contextual cues also occurs during
standard fear conditioning. Although contextual fear conditioning
also depends on the amygdala
20
, it requires the dorsal hippocampus,
which is not normally involved in fear conditioning to discrete cues.
Lesions of the dorsal hippocampus shortly after fear conditioning were
found to block the formation of contextual fear
21
, and subsequent
work showed that pharmacological disruptions in the hippocampus
around the time of learning have similar effects
22
. The neural inter-
actions of the fear circuit external to and within the amygdala are
more complex than is being presented here, and we direct the reader
to a recent review for a more detailed description
14
.
Data from studies of fear conditioning in humans largely mirror
findings from rodents with respect to the brain areas engaged dur-
ing acquisition. People with damage to the amygdala show a disrup-
tion in fear learning, as measured by changes in skin conductance
responses
23
. Functional brain imaging studies have shown increased
amygdala activation during acquisition of fear conditioning
24
and
during the production of fear responses
25
. Human brain imaging
studies have also demonstrated that the hippocampus and related
areas are active during contextual fear learning
26
, which parallels
findings from rodent research.
Many studies spanning the preclinical to clinical in humans have
demonstrated that the brain areas implicated in rodent models are
also robustly involved in human fear learning and modulation.
Furthermore, these areas appear to be notably dysregulated in fear-
related disorders such as panic disorder, specific and social phobia, and
PTSD. Perhaps the most replicated and robust finding is the activation
of amygdala nuclei in the presence of fearful cues, most notably fear-
ful faces
27
(Fig. 4a). Several studies have demonstrated hyperactive
amygdala response in people with PTSD and other fear disorders rela-
tive to healthy subjects
28
. In addition to the action of the amygdala in
directly mediating the fear response reflex, many areas are involved in
the inhibition and modulation of amygdala activity, most notably the
hippocampus
29–31
and medial prefrontal cortex
32–37
. These areas have
also been demonstrated to have abnormal responses to fearful cues
and fear inhibition in human functional magnetic resonance imaging
studies
38–41
(Fig. 4bf ). These data provide face and construct validity
for the power of understanding the learning and modulation mecha-
nisms of fear memories in rodent models to provide new therapeutic
approaches to amygdala, hippocampal and ventromedial prefrontal
cortex (vmPFC) regulation of fear in human disorders.
Blocking fear memory formation to prevent fear disorders
To appreciate how the study of fear conditioning can help develop
strategies to treat fear disorders, it is critical to understand the differ-
ent phases of learning and how they are typically studied in the labora-
tory. Acquisition of fear conditioning (Fig. 5a) refers to the process by
which the organism learns that the conditioned stimulus predicts the
unconditioned stimulus. Treatments that block the acquisition of fear
conditioning are applied before conditioned-unconditioned stimulus
pairings and prevent the development of short-term memory (STM)
memory, tested within a few hours, and consequently the formation
of long-term memory (LTM), tested many hours or days later. There
are several cellular and molecular processes known to underlie the
acquisition of fear conditioning. For example, NMDA antagonists
applied just before training prevent the acquisition of fear condition-
ing, resulting in disrupted STM and LTM
42
.
The consolidation of fear conditioning refers to the transforma-
tion of memory from a labile state immediately after acquisition to
a more permanent state with the passage of time. Treatments that
disrupt the consolidation of memory are usually applied a few min-
utes to a few hours after conditioned-unconditioned pairings, leaving
STM intact but resulting in disrupted LTM (Fig. 5b). The time
window for memory consolidation is defined by the period of
time after acquisition during which memory can be disrupted by
amnesic treatments. For example, protein synthesis inhibitors applied
after acquisition of fear conditioning do not affect STM and are only
effective in disrupting LTM if they are delivered within a few hours
US
CS
CS
a b
Figure 3 Basic fear conditioning and testing procedures. (a) Fear
conditioning involves training an animal to fear a neutral conditioned
stimulus (CS) such as an auditory cue by having it signal an aversive
unconditioned stimulus (US) such as an electrical shock. (b) Memory for
fear conditioning is tested by presenting the conditioned stimulus alone and
measuring fear responses.
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after conditioned–unconditioned stimulus pairings
43
. The acquisi-
tion and consolidation of fear conditioning require many cellular
and molecular changes in addition to the two examples given here, a
full explanation of which is beyond the scope of this review. We
point the reader to some excellent recent reviews that describe
these in depth
44,45
.
The point at which a traumatic event occurs represents the first
opportunity to use treatments designed to disrupt the acquisi-
tion and/or consolidation of the memory. There are several recent
studies that suggest that molecular mediators of fear consolidation
may be impaired by specific treatments targeting this memory proc-
ess. Among the most robust are data suggesting that modulation
of the endogenous opioid system may inhibit fear consolidation.
Rodent studies have suggested that µ-opioid pathway activation
opposes fear consolidation and enhances extinction
46,47
. Moreover,
κ-opioid antagonists have similar effects on fear learning
48
and
mediate stress effects on attention
49
. Morphine treatment after
the experience of traumatic burns may decrease later PTSD symp-
toms in children
50
. More recent studies in civilians and soldiers
suggest that acute morphine administration during the immedi-
ate aftermath of traumatic injury may prevent the subsequent
development of PTSD
51
. It has not been fully clarified, however,
whether opioid treatment is acting at the level of pain control and, by
thus decreasing the pain—the unconditioned stimulus—decreasing
the initial fear learning. Alternatively, given the animal results, the
opioid pathways may be directly acting in amygdala and brainstem
areas involved in fear consolidation and thus may have a direct
neural mechanism for decreasing the fear memory, independent
of pain regulation.
Another pathway that has been associated with fear memory con-
solidation is activation of β-adrenergic receptors in amygdala
52
.
As propranolol has been used in humans safely for decades for block-
ade of cardiovascular sympathetic activity, as well as for inhibiting
social anxiety responses, it is a safe medication to use potentially
to intervene in fear and trauma memory consolidation. Although
preliminary studies were promising
53
and propranolol appears to
decrease amygdala activation in humans
54
, more recent, larger stud-
ies have not found a significant effect of propranolol administration
after trauma
55–57
.
There have also been exciting recent approaches focused on non-
medication-based psychotherapeutic approaches. Specifically, it
has previously been shown in animal models that re-exposure to a
a
d e
Fearful faces
Amygdala
Prefrontal cortex
Impaired fear inhibition
PTSD
Hippocampus
b c
PTSDPTSD Non-PTSD
Figure 4 Human neural circuitry involved in fear-related disorders and
PTSD. (a) Viewing of fearful or angry faces (compared to shapes) robustly
activates human amygdala across protocols and cohorts (reproduced with
permission from ref. 27). Often this amygdala activation is increased in
fear-related disorders. (b) Right hippocampal activity is lower in youths
with post-traumatic stress symptoms than in healthy controls (reproduced
with permission from ref. 38). (c) Reduced hippocampal volume in
a patient with PTSD (right) compared to that in a subject without
PTSD (left). Hippocampus outlined in red (adapted with permission
from ref. 39). (d) Reduced neural activation of vmPFC during an
inhibition task is associated with impaired fear inhibition (reproduced
with permission from ref. 41). (e) Subjects with PTSD show lower regional
cerebral blood flow activity in the rostral anterior cingulate during
exposure to traumatic or stressful script-driven imagery (reproduced
with permission from ref. 40).
d
Reconsolidation
CS CS
c
Consolidation
CS-US CS-US
Acquisition
a b
CS-US
Acquisition
training
Acquisition
training
Acquisition
training
Extinction
training
Extinction
testing
CS-US CS-US CS-US CSCS
STM
test
LTM
test
Acquisition
training
STM
test
STM
test
LTM
test
LTM
test
CS CS CS CS CS CS
Extinction
CS-US CS-US CS CSCS
Retrieval
Control treatment Drug treatment Timing of treatment
Figure 5 Different components of fear learning and modulation as they
are studied in the laboratory. (a) Acquisition training involves pairings of a
conditioned stimulus (CS) with an aversive unconditioned stimulus (US).
A treatment is said to prevent acquisition of fear if it is applied before
training and blocks both STM and LTM from forming. (b) Fear memories
can also undergo extinction by repeated presentation of the CS without
the US during extinction training. Treatments that block the formation of
extinction memory are typically given before extinction training and result
in more fear during extinction testing in comparison to control treatments.
(c) The consolidation of fear memory refers to time-dependent stabilization
of memory after acquisition. Treatments that block memory consolidation
are usually given shortly after training and result in disrupted LTM but
intact STM. (d) When a memory is retrieved it may undergo reconsolidation,
which results in a period of time during which the memory is labile.
Reconsolidation of memory is considered to be disrupted when a drug is
applied shortly after retrieval and leaves STM intact yet disrupts LTM. Green
arrows indicates the timing of a given treatment or manipulation for each of
the different learning phases; x axes represent time; y axes, fear behavior.
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conditioned cue in the absence of reinforcement can impair the ini-
tial consolidation of that fear memory process
58
(but see ref. 59).
Translating this to humans, Rothbaum and colleagues recently per-
formed a proof-of-concept trial with 137 traumatized civilians, with
full exposure-based psychotherapy in the emergency department in
the hours after the trauma
60
. Exposure therapy is thought to rely on
extinction mechanisms (see below) and to be well modeled by extinc-
tion in rodents. It was found that this early intervention may have a
significant protective effect on development of PTSD and depression
symptoms assessed 4 and 12 weeks later. Larger, randomized trials are
needed, but this suggests the possibility that exposure to appropriate
therapy after trauma may lead to more rapid recovery or even preven-
tion of PTSD formation.
There are many questions that have been raised regarding the
wisdom and ethics of potential prevention of memory formation in
the aftermath of trauma exposure. In particular are issues related to
the ethics of induced amnesia and the potential complexity of com-
plete forgetting of an event that may be important to remember for
reasons related to future safety or possible legal ramifications. One
potential solution to this issue is the recognition of multiple memory
systems—that a given traumatic experience is encoded in parallel
across declarative, emotional and motor pathways, which all have
different underlying neurocircuitry. If the field of neuroscience is
able to identify ways to target the overlearning of the emotional com-
ponent of the memory while leaving the declarative trace intact, it
may be possible to convert an overly strong, indelible, overwhelming
emotional experience—one that becomes a ‘black hole’ of memo-
ries for many with PTSD—to simply a bad memory, which can then
be managed, modulated and overcome in appropriate ways, leading
to recovery.
Enhancing fear extinction to treat fear–related disorders
The extinction of fear conditioning refers to the decrease in fear
responses during repeated presentations of the conditioned stimu-
lus without unconditioned stimulus reinforcement. Extinction can
refer to the within-session decrement in fear responses while animals
are receiving presentations of the conditioned stimulus alone during
extinction training. It can also refer to the retention of extinction
learning when animals are presented with the conditioned stimulus at
later time points (Fig. 5c). Extinction is thought to involve new learn-
ing rather than erasure or unlearning of the association. Evidence for
this assertion comes from the observation that fear responses spon-
taneously recover with passage of time
61
, that fear responses show
renewed responding when the conditioned stimulus is presented in a
different environmental context from that in which extinction train-
ing occurred
62
, and that presentation of the unconditioned stimulus
alone reinstates fear to a cue that has undergone extinction training
63
.
The extinction of fear conditioning relies on some of the same brain
circuitry necessary for acquiring fear memories, including the amyg-
dala
64
and hippocampus
29
. There is good evidence that extinction
also requires activity of the vmPFC, which is not normally involved
in the acquisition of fear conditioning. In rats, the infralimbic por-
tion of the vmPFC appears to be critical for the extinction of fear
conditioning. Lesions of this area have been shown to disrupt the
retention of extinction
32
, and neurons in the infralimbic cortex show
increased firing during the recall of extinction memory
33
. Neurons in
the infralimbic cortex are thought to decrease fear responses by means
of projections to GABAergic intercalated neurons positioned between
the lateral or basal and the central nuclei of the amygdala, which
inhibit the output of the central nucleus. Studies of extinction learn-
ing in humans largely parallel studies rats, demonstrating that the
vmPFC
36,38
, amygdala
24
and hippocampus
31
are all engaged during
extinction learning or the recall of extinction.
Pharmacological approaches that enhance fear extinction are being
evaluated for treatment efficacy in PTSD. The use of -cycloserine
(DCS), a partial NMDA receptor agonist, as a potential treatment
for PTSD arose as a result of many preclinical studies implicating
NMDA receptor activity in learning and memory processes
65,66
.
DCS was first tried in humans for anxiety disorders in combination
with virtual reality exposure (VRE) therapy for the fear of heights
67
.
After treatment, those patients that received DCS in combination
with VRE showed greater improvement than those who received
placebo and VRE. Since that study, DCS has been shown to be an
effective therapeutic compound for increasing the rate of recovery
with exposure-based psychotherapy several fear- and anxiety-related
disorders, including panic disorder
68
, social anxiety disorder
69
,
obsessive-compulsive disorder
70
and PTSD
71
. Although there have
been some negative trials, most of these can be explained retrospec-
tively as the mechanism of DCS is further understood, and two recent
meta-analyses support the conclusion that it is an effective augmen-
tation strategy to enhance the rate of emotional learning underlying
exposure-based psychotherapy
72,73
. Other methods of augmenting
NMDA receptor activity in conjunction with extinction are also now
being explored.
More recent work has identified brain-derived neurotrophic factor
(BDNF) as a molecular target for facilitating extinction learning and
a potential treatment for fear disorders
74
. Studies have shown that
blocking the activity of BDNF in the amygdala
75
or hippocampus
30
disrupts the retention of extinction. Other studies indicate that
memory for extinction can be facilitated by infusion of recombinant
BDNF in the infralimbic cortex or dorsal hippocampus
35
or by systemic
injection of an agonist for its receptor TrkB
76
. Further very interest-
ing work involves the Val66Met variant of BDNF in humans. Carriers
of the methionine-encoding allele release less BDNF peptide
77
.
Recently humans with this allele have been shown to have been found
to have diminished extinction of conditioned fear
78
, which may
serve as a partial explanation for the increased prevalence of anxiety-
related disorders in people with this genotype
79
. Most intriguingly,
in the same study
78
, it was shown in ‘humanized’ mouse models
using knock-ins of each of the human alleles to the mouse Bdnf gene
locus that these alleles lead to phenotypes in mice similar to those in
human: decreased extinction of fear in the methionine allele carriers
relative to that in the valine allele carriers. Some meta-analyses have
failed to find increased incidence of anxiety disorders in methionine
allele carriers
80
; however, this might be the result of low samples sizes.
Together these data extend our understanding and appreciation of the
role of BDNF in extinction and recovery from fear and fear-related
disorders. They also provide further evidence for the face validity of
the usefulness of the extinction-of-fear model in mice for extinction
of fear in humans.
Disrupting traumatic memories after retrieval
Recently there has been renewed interest in the notion that LTM
becomes susceptible to disruption after a consolidated memory is
retrieved. In fear conditioning studies, memory is retrieved by pre-
senting the animal with a single presentation of the conditioned
stimulus used to signal shock during acquisition (Fig. 5d). The
seminal finding was that when a protein synthesis inhibitor is given
after retrieval, LTM is impaired on subsequent tests
81
. This result
generated wide interest, and this phenomenon, termed reconsolida-
tion, has now been observed in organisms ranging from invertebrates
to humans
82
. Somewhat less is known about memory reconsolidation
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than about initial consolidation, but the available evidence suggests
that the molecular and cellular mechanisms supporting reconsolida-
tion are similar to those necessary for consolidation, although they
do not overlap completely
83
.
The observation that fear memories can be disrupted by combin-
ing retrieval of memory with drug treatment opens up the possibility
of using this strategy to treat fear-related disorders. Theoretically,
patients could be brought into a clinical setting, presented with a
stimulus that retrieves the fearful memory and given a drug, and
the fear memory would be weakened. Recent laboratory studies have
used this basic approach to determine whether fear memories can be
disrupted by combining retrieval with a memory-impairing drug. In
one study
84
, human subjects were fear conditioned, given a retrieval
trial the next day in conjunction with oral administration of the
β-adrenergic blocker propranolol, and tested the day after. The results
showed that those given the drug while the memory was reactivated
showed significantly less fear-potentiated startle during testing the
next day than those given placebo. At least one study
85
has shown
that a similar approach can be taken to disrupt traumatic memories
in humans. In this study, PTSD patients were asked to describe a
traumatic experience and were given a single dose of propranolol or
a placebo. Patients given propranolol showed reduced physiological
signs of fear when they were asked to once again describe the trau-
matic experience a week later.
Although there are some differences, there is also evidence that
disruption of reconsolidation and extinction may share some inter-
esting properties
86
. Of note, in vivo and ex vivo physiological studies
have suggested that fear learning leads to LTP-like potentiation of
synapses with fear learning. Extinction of fear then appears to be
associated with depotentiation and LTD-like mechanisms in some
models
87,88
. Thus, diminished representation of synaptic strength
may be achieved, in part, both through strengthened extinction and
through inhibited reconsolidation.
Although this strategy is promising, laboratory studies of reconsoli-
dation indicate that there may be limitations to using a reconsolidation-
disruption approach as a way to treat fear-related disorders. Several
studies have indicated that retrieval does not always trigger recon-
solidation, including the observation that both older and stronger
memories are less susceptible to disruption after retrieval
89,90
. If this
pattern of data extends to humans with fear-related disorders, it may
prove difficult to disrupt traumatic memories after retrieval because
these memories are most certainly strong and in many cases have
persisted for some time. In fact, many PTSD patients may take years
to seek treatment, and chronic PTSD is often the most difficult to
treat. Another consideration is that memory retrieval happens outside
of the clinical context, often in the form of re-experiencing of the
traumatic event. Replaying the traumatic event over and over again
can sensitize patients with fear-related disorders and lead to worsen-
ing of the disorder. As in sensitization in humans with fear-related
disorders, animal studies have also shown that repeated retrieval can
strengthen fear memory and make it impervious to disruption with
treatments that normally disrupt memory reconsolidation
91
. Thus,
even if a drug is given each time a patient re-experiences a traumatic
event, it may not be sensitive to disruption.
Future directions
Further areas of interest that are less well developed include studies
of generalization versus discrimination, avoidance behavior and com-
bined extinction-reconsolidation processes. The use of more sophis-
ticated behavioral techniques in the laboratory to understand how
fear generalizes to stimuli not originally associated with the traumatic
event, which is a hallmark of PTSD and panic disorder, may pro-
vide powerful insight. An approach to studying generalization is to
use differential fear conditioning whereby, in addition to a cue that
signals shock, there is also a cue that is not followed by shock. Studies
have shown that in rats
92
some animals show good discrimination,
whereas others generalize fear to the safe cue, similarly to what is
seen in patients with fear-related disorders. Another approach is to
use conditioned inhibition training to identify animals that do not
inhibit fear in the presence of a safety signal
93
. Both of these strategies
can address a potential limitation of animal studies: that the variability
of responses is often not factored into the analyses, even though in
people who experience a traumatic event there is great variability in
responses, with some developing a pathological disorder and others
being resilient
94
. In a similar vein, early life stress and previous trauma
experience factor into the development PTSD (Fig. 2), yet there are
relatively few laboratory studies determining the effects of previous
trauma and early life stress on fear learning and fear extinction. More
refined protocols are needed to model this important aspect of sus-
ceptibility to developing PTSD.
Another line of research that could potentially be relevant for the
treatment of fear-related disorders is based on recent behavioral stud-
ies
95–97
demonstrating that, if extinction training occurs shortly after
a single retrieval trial, fear memories are diminished and show no
evidence of recovery. Although this finding is not always consistent
98
,
the ability to diminish fear memories in this manner opens another
potential avenue by which traumatic memories can be targeted in
patients with fear-related disorders.
Conclusions
Our goal is to describe how knowledge of basic learning and mem-
ory processes has translated into potential treatments for PTSD and
other fear-related disorders. We wish to point to recent areas that
have potential to drive clinical treatments in the future. If animal
models are modified to better account for fear dysregulation in these
disorders, we may improve the impact of preclinical research on pre-
vention and treatment. Recent advances in molecular and cellular
approaches to cognitive function are rapidly advancing our under-
standing of fear-related disorders. Progress in this area is exciting, not
only in its potential to affect and improve treatment but also in the
hope that it provides to biological psychiatry in general. Success in
this arena suggests that if the neural circuitry underlying functional
pathophysiology can be defined, then powerful behavioral neuro-
science approaches can be effectively translated to the clinic, even in
debilitating and previously mysterious psychiatric disorders.
ACKNOWLEDGMENTS
Support was provided by the US National Institutes of Health (F32MH090700,
R01MH071537, R01MH094757 and R01MH096764), the Burroughs Wellcome
Fund and a US National Institutes of Health National Center for Research
Resources base grant (P51RR000165) to Yerkes National Primate Research Center.
COMPETING FINANCIAL INTERESTS
The authors declare competing financial interests: details accompany the online
version of the paper.
Published online at http://www.nature.com/doifinder/10.1038/nn.3296.
Reprints and permissions information is available online at http://www.nature.com/
reprints/index.html.
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    • "Furthermore, individuals with lower platelet MAO activity were found to exhibit stronger fear conditioning (Garpenstrand et al., 2001), while stress and glucocorticoids were reported to decrease MAOA activity and binding pervasively in the human brain (Soliman et al., 2012). In the present study, MAOA enzymatic activity was evaluated after a long-term conditioned fear test in the amygdala, hippocampus, infralimbic, prelimbic, and anterior cingulate cortex, as these are some of the major brain regions implicated in the expression and extinction of fear (McNally et al., 2011; Sierra-Mercado et al., 2011; Fani et al., 2012; Maroun, 2012; Parsons and Ressler, 2013; Hitora-Imamura et al., 2015), in addition to their recruitment in responding to ambiguity conferred by unpredictability and uncertainty (e.g. Huettel et al., 2005; Herry et al., 2007; Tsetsenis et al., 2007; Rushworth and Behrens, 2008; Sarinopoulos et al., 2010). "
    [Show abstract] [Hide abstract] ABSTRACT: There is a great deal of individual variability in the emotional outcomes of potentially traumatic events, and the underlying mechanisms are only beginning to be understood. In order to further our understanding of individual trajectories to trauma, its vulnerability and resilience, we adapted a model of fear expression to ambiguous vs certain cues in adult male rats, and examined long-term fear extinction, 2, 3, and 50 days from acquisition. After the final conditioned fear test, mitochondrial enzyme monoamine oxidase A (MAOA) function was examined. In order to identify associations between this function and behavioral expression, an a posteri median segregation approach was adopted, and animals were classified as high or low responding according to level of freezing to the ambiguous cue at remote testing, long after the initial extinction. Those individuals characterized by their higher response showed a freezing pattern that persisted from their previous extinction sessions, in spite of their acquisition levels being equivalent to the low-freezing group. Furthermore, unlike more adaptive individuals, freezing levels of high-freezing animals even increased at initial extinction, to almost double their acquisition session levels. Controlling for perfect cue response at remote extinction, greater ambiguous threat cue response was associated with enhanced prelimbic cortex MAOA functional activity. These findings underscore MAOA as a potential target for the development of interventions to mitigate the impact of traumatic experiences.
    Full-text · Article · Aug 2016
    • "Advancing the current understanding about the latter aspect is of a potential translational value for the post-traumatic stress disorder (PTSD) treatment because it may highlight a target for intervention during, and even beyond, the theoretical time-window ($ 6 h; Nader et al., 2000) in which aversive memory reconsolidation takes place. Pharmacological interventions after memory retrieval have shown to be able to attenuate abnormal memories present in psychiatric conditions such as PTSD (Parsons and Ressler, 2013). PTSD symptoms are often associated with breast cancer and its treatment (Hermelink, 2015 ). "
    [Show abstract] [Hide abstract] ABSTRACT: The mechanisms underpinning the persistence of emotional memories are inaccurately understood. Advancing the current level of understanding with regards to this aspect is of potential translational value for the treatment of post-traumatic stress disorder (PTSD), which stems from an abnormal aversive memory formation. Tamoxifen (TMX) is a drug used in chemotherapy for breast cancer and associated with poor cognitive performances. The present study investigated whether the systemic administration of TMX (1.0-50mg/kg) during and/or beyond the reconsolidation time-window could attenuate a reactivated contextual fear memory in laboratory animals. When administered 0, 6 or 9h (but not 12h) post-memory retrieval and reactivation, TMX (50mg/kg) reduced the freezing behavior in male rats re-exposed to the paired context on day 7, but not on day 1, suggesting a specific impairing effect on memory persistence. Importantly, this effect lasts up to 21 days, but it is prevented by omitting the memory retrieval or memory reactivation. When female rats in the diestrous or proestrous phase were used, the administration of TMX 6h after retrieving and reactivating the fear memory also impaired its persistence. Altogether, regardless of the gender, the present results indicate that the TMX is able to disrupt the persistence of reactivated fear memories in an expanded time-window, which could shed light on a new promising therapeutic strategy for PTSD.
    Full-text · Article · Aug 2016
    • "However, if this does not happen, a person can develop a condition, possibly diagnosed as Post Traumatic Stress Disorder (PTSD), that strongly affects one's life. During the past decades, post-trauma and PTSD patients have been extensively studied, leading to a better understanding of their symptoms; e.g., (Masten & Narayan, 2012; Parsons & Ressler, 2013; Duvarci & Pare, 2014). A traumatized person can suffer from different symptoms, such as repeated and unwanted re-experiencing of the event (flashbacks), hyperarousal, avoidance of stimuli or thoughts that could remind to the event, and emotional numbing involving loss of body perception (dissociation); all of these lead to unwanted emotional responses. "
    [Show abstract] [Hide abstract] ABSTRACT: In this paper, a computational model is presented to simulate traumas, including their development, recovery, and the effect of group support. The model is built upon mechanisms known from cognitive and social neuroscience. Using the model, several scenarios were explored, considering both individual and multiple persons. The simulation results of the model were compared to a data-set on symptoms and recovery of traumatized patients. The obtained model enables simulation and analysis of group therapy and its effects on traumatized patients.
    Full-text · Conference Paper · Jul 2016 · European neuropsychopharmacology: the journal of the European College of Neuropsychopharmacology
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