Reconsolidation of Amygdala-Based Fear Memories: A Newly
Discovered Mechanism and its Implications for Exposure Stefan G.
Hofmann, Ph.D. Michael W. Otto, Ph.D. Elizabeth A. Phelps, Ph.D.
Bradford C. Richards, Ph.D.
Slide 2
Bradford C. Richards, Ph.D., ABPP Director and Supervising
Psychologist, Cognitive Behavioral Institute of Albuquerque Editor,
IACP journal Cognitive Behavioral Therapy Book Reviews Former
faculty member, Seton Hall Taught courses in Cognitive Science,
Behavioral Learning Theory Research interests: Cognition and
Emotion
Slide 3
Elizabeth A. Phelps, Ph.D. Laboratory Director, Phelps Lab, NYU
Silver Professor; Professor of Psychology and Neural Science;
Associate, Center for Neural Science, NYU Fellow, American Academy
of Arts and Sciences Former Editor, APA journal Emotion Research
interests: Cognitive neuroscience of emotion, learning and
memory
Slide 4
Michael W. Otto, Ph.D. Professor of Psychology, Boston
University Director, Translational Research Program, Center for
Anxiety and Related Disorders Past President, ABCT Over 270
articles, chapters, and books on CBT and translational research
Fellow, American Psychological Association Scientific Advisory
Board, Anxiety Disorders Association of America
Slide 5
Stefan G. Hofmann, Ph.D. Professor of Psychology, Boston
University Director, Social Anxiety Program, Center for Anxiety and
Related Disorders Editor-in-Chief, Cognitive Therapy and Research
Associate Editor, Journal of Clinical and Consulting Psychology
President-Elect, ABCT President, International Association for
Cognitive Psychotherapy
Slide 6
Images and animation by Greg J. Siegle, Ph.D., Program in
Cognitive Affective Neuroscience, U. Pittsburgh
Slide 7
Review principles and mechanisms of classical conditioning and
extinction
Slide 8
Introduce a newly discovered mechanism of reduction in
conditioned fear: reconsolidation in the amygdala
Slide 9
Review principles and mechanisms of classical conditioning and
extinction Introduce a newly discovered mechanism of reduction in
conditioned fear: reconsolidation in the amygdala Present evidence
that it works in humans without drugs
Slide 10
Review principles and mechanisms of classical conditioning and
extinction Introduce a newly discovered mechanism of reduction in
conditioned fear: reconsolidation in the amygdala Present evidence
that it works in humans without drugs Present evidence that it can
be manipulated with propranolol
Slide 11
Slide 12
NS UCS
Slide 13
CS CR
Slide 14
NS UCS CS CR NS must provide Incremental Predictive Information
about the UCS for conditioning to occur (Rescorla, 1988)
Slide 15
Slide 16
Repeatedly present CS without UCS
Slide 17
CR eventually diminishes
Slide 18
Repeatedly present CS without UCS CR eventually diminishes But
the CR does not disappear forever
Slide 19
Repeatedly present CS without UCS CR eventually diminishes But
the CR does not disappear forever CR reappears spontaneous
recovery
Slide 20
Repeatedly present CS without UCS CR eventually diminishes But
the CR does not disappear forever CR reappears spontaneous recovery
CR reappears renewal of learning context
Slide 21
Repeatedly present CS without UCS CR eventually diminishes But
the CR does not disappear forever CR reappears spontaneous recovery
CR reappears renewal of learning context CR reappears reinstatement
of UCS
Slide 22
Repeatedly present CS without UCS CR eventually diminishes But
the CR does not disappear forever CR reappears spontaneous recovery
CR reappears renewal of learning context CR reappears reinstatement
of UCS CR reappears faster relearning of CS
Slide 23
Repeatedly present CS without UCS CR eventually diminishes But
the CR does not disappear forever CR reappears spontaneous recovery
CR reappears renewal of learning context CR reappears reinstatement
of UCS CR reappears faster relearning of CS Memory of CS UCS never
goes away
Slide 24
Slide 25
New memories are added
Slide 26
New memories (of CS ) compete with the old ones (of CS UCS) for
activation and behavioral expression
Slide 27
New memories are added New memories (of CS ) compete with the
old ones (of CS UCS) for activation and behavioral expression Often
termed inhibitory learning
Slide 28
New memories are added New memories (of CS ) compete with the
old ones (of CS UCS) for activation and behavioral expression Often
termed inhibitory learning Craske et al. (2008) BRAT paper great
review
Slide 29
New memories are added New memories (of CS ) compete with the
old ones (of CS UCS) for activation and behavioral expression Often
termed inhibitory learning Craske et al. (2008) BRAT paper great
review Pharmacological Augmentation
Slide 30
New memories are added New memories (of CS ) compete with the
old ones (of CS UCS) for activation and behavioral expression Often
termed inhibitory learning Craske et al. (2008) BRAT paper great
review Pharmacological Augmentation D-Cycloserine, NMDA glutamate
agonist
Slide 31
New memories are added New memories (of CS ) compete with the
old ones (of CS UCS) for activation and behavioral expression Often
termed inhibitory learning Craske et al. (2008) BRAT paper great
review Pharmacological Augmentation D-Cycloserine, NMDA glutamate
agonist Infused into rat amygdalas, or given systemically
Slide 32
New memories are added New memories (of CS ) compete with the
old ones (of CS UCS) for activation and behavioral expression Often
termed inhibitory learning Craske et al. (2008) BRAT paper great
review Pharmacological Augmentation D-Cycloserine, NMDA glutamate
agonist Infused into rat amygdalas, or given systemically Hofmann,
Pollack, & Otto (2006) found efficacy in Social Anxiety
exposures
Slide 33
Clear jar is held up A fear memory (chocolate covered almond)
is dropped into jar Extinction adds safety memories (yogurt covered
almonds are added to jar) Retrieval is similar to sampling from the
pool of memories (jar is shaken) Extinction with D-cycloserine adds
even more safety memories (more yogurt covered almonds are added to
jar)
Slide 34
Original memories remain unaltered
Slide 35
New memories are added in exposure
Slide 36
Original memories remain unaltered New memories are added in
exposure Old memories can always resurface
Slide 37
Original memories remain unaltered New memories are added in
exposure Old memories can always resurface This was the best we
could hope for
Slide 38
Original memories remain unaltered New memories are added in
exposure Old memories can always resurface This was the best we
could hope for Then a new mechanism was seen
Slide 39
Center for Neural Science, NYU, 1999
Slide 40
Studying protein synthesis in the formation of fear memories in
the amygdala
Slide 41
Center for Neural Science, NYU, 1999 Studying protein synthesis
in the formation of fear memories in the amygdala blocking protein
synthesis prevents consolidation
Slide 42
Center for Neural Science, NYU, 1999 Studying protein synthesis
in the formation of fear memories in the amygdala blocking protein
synthesis prevents consolidation Nader hypothesized that blocking
protein synthesis during memory retrieval would prevent the
re-storage of the fear memory
Slide 43
Center for Neural Science, NYU, 1999 Studying protein synthesis
in the formation of fear memories in the amygdala blocking protein
synthesis prevents consolidation Nader hypothesized that blocking
protein synthesis during memory retrieval would prevent the
re-storage of the fear memory Nader predicted subsequent amnesia
for the fear component of the memory
Slide 44
Center for Neural Science, NYU, 1999 Studying protein synthesis
in the formation of fear memories in the amygdala blocking protein
synthesis prevents consolidation Nader hypothesized that blocking
protein synthesis during memory retrieval would prevent the
re-storage of the fear memory Nader predicted subsequent amnesia
for the fear component of the memory LeDoux bet a bottle of tequila
against it
Slide 45
Center for Neural Science, NYU, 1999 Studying protein synthesis
in the formation of fear memories in the amygdala blocking protein
synthesis prevents consolidation Nader hypothesized that blocking
protein synthesis during memory retrieval would prevent the
re-storage of the fear memory Nader predicted subsequent amnesia
for the fear component of the memory LeDoux bet a bottle of tequila
against it Nader won
Slide 46
Nader, Schafe, & LeDoux reported: The protein synthesis
inhibitor anisomycin, infused directly into the LBA of rats after
reactivation of a fear memory, prevented subsequent reconsolidation
of the fear memory and produced amnesia for the fear
Slide 47
Nader, Schafe, & LeDoux reported: The protein synthesis
inhibitor anisomycin, infused directly into the LBA of rats after
reactivation of a fear memory, prevented subsequent reconsolidation
of the fear memory and produced amnesia for the fear Delaying the
infusion for six hours after the presentation of the reminder cue
did not produce amnesia for the fear memory
Slide 48
Nader, Schafe, & LeDoux theorized: Consolidated fear
memories, when reactivated during retrieval, return to a labile
state
Slide 49
Nader, Schafe, & LeDoux theorized: Consolidated fear
memories, when reactivated during retrieval, return to a labile
state Once rendered labile by retrieval, these fear memories must
undergo reconsolidation in order to persist
Slide 50
Nader, Schafe, & LeDoux theorized: Consolidated fear
memories, when reactivated during retrieval, return to a labile
state Once rendered labile by retrieval, these fear memories must
undergo reconsolidation in order to persist Reconsolidation has a
limited temporal window during which the memory is labile and
subject to disruption
Slide 51
Debiec & LeDoux reported: -Adrenaline blockade
(propronalol) disrupts reconsolidation, but not initial 24 hours of
consolidation, of fear memory in rats
Slide 52
Debiec & LeDoux reported: -Adrenaline blockade
(propronalol) disrupts reconsolidation, but not initial 24 hours of
consolidation, of fear memory in rats Dissociation of propranolol
effects was shown with both direct LBA infusion and with systemic
administration
Slide 53
Debiec & LeDoux reported: -Adrenaline blockade
(propronalol) disrupts reconsolidation, but not initial 24 hours of
consolidation, of fear memory in rats Dissociation of propranolol
effects was shown with both direct LBA infusion and with systemic
administration Direct infusion of propranolol 2mm dorsal to the LBA
had no effect
Slide 54
Debiec & LeDoux reported: -Adrenaline blockade
(propronalol) disrupts reconsolidation, but not initial 24 hours of
consolidation, of fear memory in rats Dissociation of propranolol
effects was shown with both direct LBA infusion and with systemic
administration Direct infusion of propranolol 2mm dorsal to the LBA
had no effect Speculation: might help after PTSD exposures
Slide 55
Monfils, Cowansage, Klann, & LeDoux
Slide 56
Extinction-Reconsolidation Boundaries: Key to persistent
Attenuation of Fear Memories
Slide 57
Monfils, Cowansage, Klann, & LeDoux
Extinction-Reconsolidation Boundaries: Key to persistent
Attenuation of Fear Memories Drug-free reconsolidation
paradigm
Slide 58
Monfils, Cowansage, Klann, & LeDoux
Extinction-Reconsolidation Boundaries: Key to persistent
Attenuation of Fear Memories Drug-free reconsolidation paradigm
Manipulated only the timing of extinction trials in rats
Slide 59
On day 1 all rats received 3 tone-shock pairings, with 24 hours
to consolidate the fear memory
Slide 60
On day 2, the time delay between retrieval and extinction
trials was varied between groups: NoRet, 10m, 1h, 6h, and 24h.
Slide 61
On day 1 all rats received 3 tone-shock pairings, with 24 hours
to consolidate the fear memory On day 2, the time delay between
retrieval and extinction trials was varied between groups: NoRet,
10m, 1h, 6h, and 24h. One month later, rats were tested for
spontaneous recovery of freezing in response to the CS
Slide 62
Rats given 10m and 1h delays between retrieval and extinction
showed no spontaneous recovery at one month, whereas rats given
delays of 0m, 6h, and 24h showed marked spontaneous recovery at one
month
Slide 63
Interpretation: The window of lability for memory
reconsolidation is open at 10m and 1 hour but closed by 6h. Outside
of that window, classical extinction occurs.
Slide 64
A second experiment showed that context renewal of the fear
response did not occur when extinction trials were administered
within the reconsolidation window (1h), but did occur with
classical extinction (NoRet)
Slide 65
A third experiment showed that the classically extinguished
(NoRet) CR returned with reinstatement of 5 unsignaled footshocks,
but the reconsolidated (1h) CS-CR memory was not reinstated by the
footshocks.
Slide 66
A fourth experiment investigated a neural mechanism of memory
destabilization
Slide 67
Glutamate R1 receptors in the Lateral Amygdala were found to be
phosphorylated immediately after the first memory retrieval
(Western Blot, Ser 845 )
Slide 68
A fourth experiment investigated a neural mechanism of memory
destabilization Glutamate R1 receptors in the Lateral Amygdala were
found to be phosphorylated immediately after the first memory
retrieval (Western Blot, Ser 845 ) These GluR1 receptors were found
to be de- phosphorylated immediately after the second memory
retrieval, but only if the second retrieval occurred 1 hour later.
If the second retrieval occurred only 3 minutes later, GluR1
remained phosphorylated. Without a 2 nd retrieval, GluR1 remained
phosphorylated for more than 1hour
Slide 69
A fifth experiment showed that extinction trials within the
reconsolidation window (1h) led to slower relearning of the fear
contingency than did classical extinction (NoRet)
Slide 70
The sixth experiment showed that extinction trials within the
reconsolidation window (1h) led to slower relearning of the fear
contingency than nave rats
Slide 71
The authors theorized: The initial valence conferred by the
first conditioning session no longer seems to exist in its original
fear-inducing form.
Slide 72
an adaptive purpose of reconsolidation is to incorporate new
information at the time of retrieval, and to update a memory in the
present case leading to a destabilization of the initial trace in
the lateral amygdala, and the reencoding of the once fear-inducing
CS as safe.
Slide 73
Clear jar is populated with many yogurt covered almonds and one
chocolate covered almond The authors are asserting that the
mechanism they manipulated is very different from simply adding
more safety memories The authors assert that they have accomplished
this: (chocolate covered almond is removed from jar and replaced by
a yogurt covered almond) They are not asserting that a retrieval
process has changed They are asserting that they have changed the
valence of the memory itself When you sample, all youll get is
safety memories
Slide 74
The authors noted that it would be important to understand the
retardation of reacquisition induced by our behavioral procedure
because it could, in principle, result in maladaptive behavior in
some cases.
Slide 75
At CBIA, we considered and discussed some possible
misapplications and their ethical implications
Slide 76
Slide 77
Overall, this paper showed how to overcome all four limitations
of classical extinction: Spontaneous recovery, context renewal,
reinstatement, and rapid relearning
Slide 78
These violations of the century-old principles of classical
extinction were accomplished very simply: by inserting a delay of
10m 1h between the first extinction trial and subsequent
trials
Slide 79
Slide 80
Preventing the return of fear in humans using reconsolidation
update mechanisms
Slide 81
Schiller, Monfils, Raio, Johnson, LeDoux, & Phelps in the
Phelps Lab using SCR
Slide 82
Preventing the return of fear in humans using reconsolidation
update mechanisms Schiller, Monfils, Raio, Johnson, LeDoux, &
Phelps in the Phelps Lab using SCR Showed 3 very important
things
Slide 83
Preventing the return of fear in humans using reconsolidation
update mechanisms Schiller, Monfils, Raio, Johnson, LeDoux, &
Phelps in the Phelps Lab using SCR Showed 3 very important things
The timed reconsolidation effect works in humans (n=65)
Slide 84
Preventing the return of fear in humans using reconsolidation
update mechanisms Schiller, Monfils, Raio, Johnson, LeDoux, &
Phelps in the Phelps Lab using SCR Showed 3 very important things
The timed reconsolidation effect works in humans (n=65) It doesnt
show spontaneous recovery, even with reinstatement, at 1 year
follow up
Slide 85
Preventing the return of fear in humans using reconsolidation
update mechanisms Schiller, Monfils, Raio, Johnson, LeDoux, &
Phelps in the Phelps Lab using SCR Showed 3 very important things
The timed reconsolidation effect works in humans (n=65) It doesnt
show spontaneous recovery, even with reinstatement, at 1 year
follow up It does not generalize to stimuli not retrieved at the
start of of the reconsolidation procedure
Slide 86
Experiment 1 Day 1 Day 2Day3 Group1: Acquisition
Reminder/10m/ExtinctionRe-extinction Group2: Acquisition
Reminder/6h/ExtinctionRe-extinction Group3: Acquisition No
reminder/ExtinctionRe-extinction
Slide 87
Copyright 2010 Macmillan Publishers Limited.
Slide 88
Authors interpretation of experiment 1: These results indicate
that the spontaneous recovery of fear after extinction can be
prevented if extinction training is conducted during the time
window in which the fear memory is proposed to be undergoing
reconsolidation.
Slide 89
Experiment 2 Participants from Experiment 1 were brought back 1
year later They were exposed only to a reinstatement test
consisting of four unsignalled UCSs (shocks), followed by
non-reinforced presentations of the conditioned stimuli Result:
Subjects who had received the reminder within the proposed
reconsolidation time window did not show reinstatement. The other
subjects showed significant reinstatement of the CR
Slide 90
Experiment 3: Non-generalization
Slide 91
Used two different colored squares as CS+ for shock (CSa+ &
CSb+), another colored square for CS-
Slide 92
Experiment 3: Non-generalization Used two different colored
squares as CS+ for shock (CSa+ & CSb+), another colored square
for CS- Day 1 Day 2 Day3 Acquisition Reminder/10m/Extinction
Reinstatement (4 shocks) CSa+, CSb+, CS-(CSa+, CS-/10m/all 3 CSs)
Re-extinction, all 3 CSs
Slide 93
Experiment 3: Non-generalization Used two different colored
squares as CS+ for shock (CSa+ & CSb+), another colored square
for CS- Day 1 Day 2 Day3 Acquisition Reminder/10m/Extinction
Reinstatement (4 shocks) CSa+, CSb+, CS-(CSa+, CS-/10m/all 3 CSs)
Re-extinction, all 3 CSs Result: The conventionally extinguished
CSb+ was reinstated by the shocks on day 3, but the reconsolidated
CSa+ was not
Slide 94
Copyright 2010 Macmillan Publishers Limited.
Slide 95
The authors interpreted: In conclusion, the present study
showed that updating fear memories with non- fearful information
provided through extinction training led to the blockade of
previously learned fear responses and a lasting change in the
original fear memory. These results have significant implications
for the treatment of anxiety disorders.
Slide 96
Within the last year, there have been at least two additional
replications of the same effect of timing alone on reconsolidation
in humans
Slide 97
Agren, Furmark, Eriksson, & Fredrikson (2012) showed
resistance to reinstatement and slower relearning after
reconsolidation (10m window as compared to 6h window) Genetic
testing of the participants showed that allelic differences in
particular genes modulated fear memory reconsolidation
Slide 98
Oyarzun et al. (2012) paired colored squares with loud aversive
sounds, and measured SCR during acquisition, reconsolidation, and
re-extinction Reinstatement occurred for stimuli extinguished
without a reminder trial before extinction, but reconsolidated
stimuli (10m) were not susceptible to reinstatement
Slide 99
Slide 100
Kindt, Soeter, & Vervliet (2009) Nature Neuroscience Double
blind, placebo controlled test of 40mg propranolol administered 90m
prior to a single retrieval Used pictures of spiders as CS,
electric shock as UCS Measured fear-potentiated startle
response
Slide 101
24h after the single-trial reminder, the group reminded on
propranolol was the only group that showed no startle response,
even after 3 reinstatement shocks The propranolol group still
indicated high declarative expectations that they would be shocked,
but their differential startle response had disappeared
Slide 102
Slide 103
The authors interpreted: Notably, the propranolol manipulation
left the declarative memory for the acquired contingency between
the conditioned and unconditioned stimulus intact, but this
knowledge no longer produced emotional effects. Our findingis
consistent with the observed double dissociation of fear
conditioning and declarative knowledge relative to the amygdala and
hippocampus in humans (Phelps, 2004).
Slide 104
Brunet, Orr, Tremblay, Robertson, Nader, & Pitman (2008) J.
Psychiat. Res. Randomized, double-blind, placebo controlled trial
Gave propranolol to chronic PTSD patients after they described
their traumatic events One week later, patients listened to a
narrative of their traumas while HR, SC, and corrugator EMG were
monitored HR and SC were significantly lower in the post-retrieval
propranolol group
Slide 105
Slide 106
The theory of the reconsolidation window after retrieval of an
amygdala-based fear memory is well- supported and accepted now
Capitalizing on this window of memory lability has been
accomplished numerous times, with and without drugs It is likely to
yield new treatment options, including timed exposures