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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.

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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

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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

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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

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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

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Images and animation by Greg J. Siegle, Ph.D., Program in Cognitive Affective Neuroscience, U. Pittsburgh

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Review principles and mechanisms of classical conditioning and extinction

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Introduce a newly discovered mechanism of reduction in conditioned fear: reconsolidation in the amygdala

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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

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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

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NS UCS

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CS CR

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NS UCS CS CR NS must provide Incremental Predictive Information about the UCS for conditioning to occur (Rescorla, 1988)

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Repeatedly present CS without UCS

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CR eventually diminishes

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Repeatedly present CS without UCS CR eventually diminishes But the CR does not disappear forever

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Repeatedly present CS without UCS CR eventually diminishes But the CR does not disappear forever CR reappears spontaneous recovery

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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

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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

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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

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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

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New memories are added

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New memories (of CS ) compete with the old ones (of CS UCS) for activation and behavioral expression

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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

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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

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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

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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

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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

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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

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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)

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Original memories remain unaltered

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New memories are added in exposure

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Original memories remain unaltered New memories are added in exposure Old memories can always resurface

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Original memories remain unaltered New memories are added in exposure Old memories can always resurface This was the best we could hope for

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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

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Center for Neural Science, NYU, 1999

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Studying protein synthesis in the formation of fear memories in the amygdala

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Center for Neural Science, NYU, 1999 Studying protein synthesis in the formation of fear memories in the amygdala blocking protein synthesis prevents consolidation

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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

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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

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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

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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

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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

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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

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Nader, Schafe, & LeDoux theorized: Consolidated fear memories, when reactivated during retrieval, return to a labile state

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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

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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

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Debiec & LeDoux reported: -Adrenaline blockade (propronalol) disrupts reconsolidation, but not initial 24 hours of consolidation, of fear memory in rats

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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

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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

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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

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Monfils, Cowansage, Klann, & LeDoux

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Extinction-Reconsolidation Boundaries: Key to persistent Attenuation of Fear Memories

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Monfils, Cowansage, Klann, & LeDoux Extinction-Reconsolidation Boundaries: Key to persistent Attenuation of Fear Memories Drug-free reconsolidation paradigm

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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

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On day 1 all rats received 3 tone-shock pairings, with 24 hours to consolidate the fear memory

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On day 2, the time delay between retrieval and extinction trials was varied between groups: NoRet, 10m, 1h, 6h, and 24h.

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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

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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

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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.

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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)

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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.

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A fourth experiment investigated a neural mechanism of memory destabilization

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Glutamate R1 receptors in the Lateral Amygdala were found to be phosphorylated immediately after the first memory retrieval (Western Blot, Ser 845 )

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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

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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)

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The sixth experiment showed that extinction trials within the reconsolidation window (1h) led to slower relearning of the fear contingency than nave rats

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The authors theorized: The initial valence conferred by the first conditioning session no longer seems to exist in its original fear-inducing form.

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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.

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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

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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.

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At CBIA, we considered and discussed some possible misapplications and their ethical implications

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Overall, this paper showed how to overcome all four limitations of classical extinction: Spontaneous recovery, context renewal, reinstatement, and rapid relearning

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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

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Preventing the return of fear in humans using reconsolidation update mechanisms

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Schiller, Monfils, Raio, Johnson, LeDoux, & Phelps in the Phelps Lab using SCR

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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

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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)

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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

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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

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Experiment 1 Day 1 Day 2Day3 Group1: Acquisition Reminder/10m/ExtinctionRe-extinction Group2: Acquisition Reminder/6h/ExtinctionRe-extinction Group3: Acquisition No reminder/ExtinctionRe-extinction

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Copyright 2010 Macmillan Publishers Limited.

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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.

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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

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Experiment 3: Non-generalization

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Used two different colored squares as CS+ for shock (CSa+ & CSb+), another colored square for CS-

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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

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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

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Copyright 2010 Macmillan Publishers Limited.

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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.

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Within the last year, there have been at least two additional replications of the same effect of timing alone on reconsolidation in humans

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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

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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

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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

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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

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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).

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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

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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