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The Amygdala, Fear and Reconsolidation: Neural and Behavioral Effects of Retrieval-Extinction in Fear Conditioning and Spider Phobia
Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
2017 (English)Doctoral thesis, comprehensive summary (Other academic)
Description
Abstract [en]

The amygdala is crucially involved in the acquisition and retention of fear memories. Experimental research on fear conditioning has shown that memory retrieval shortly followed by pharmacological manipulations or extinction, thereby interfering with memory reconsolidation, decreases later fear expression. Fear memory reconsolidation depends on synaptic plasticity in the amygdala, which has been demonstrated in rodents using both pharmacological manipulations and retrieval-extinction procedures. The retrieval-extinction procedure decreases fear expression also in humans, but the underlying neural mechanism have not been studied. Interfering with reconsolidation is held to alter the original fear memory representation, resulting in long-term reductions in fear responses, and might therefore be used in the treatment of anxiety disorders, but few studies have directly investigated this question.

The aim of this thesis was to examine the effects of the retrieval-extinction procedure on amygdala activity and behavioral fear expression in humans. The work presented here also investigated whether findings from studies on recent fear memories, established through fear conditioning, extends to naturally occurring long-term phobic fears.

Study I, combining fear conditioning and a retrieval-extinction procedure with functional magnetic resonance imaging (fMRI), demonstrated that memory retrieval shortly followed by extinction reduces later amygdala activity and fear expression in healthy subjects. In Study II, these subjects were re-tested 18 months later. The results showed that the effects on fear expression were still present and that initial amygdala activity predicted long-term fear expression. Using an adapted version of the retrieval-extinction procedure, Study III showed that memory retrieval shortly followed by exposure to spider pictures, attenuates subsequent amygdala activity and increases approach behavior in subjects with life-long fear of spiders. In Study IV, these subjects were re-tested 6 months later, and the results showed that effects on amygdala activity as well as approach behavior were maintained.

In summation, retrieval-extinction leads to long-lasting reductions in amygdala activity and fear expression. These findings are consistent with the hypothesis that retrieval-extinction alters an amygdala dependent fear memory. Retrieval-extinction can also attenuate long-term phobic fears, indicating that this manipulation could be used to enhance exposure-based treatments for anxiety disorders. 

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2017. , 72 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Social Sciences, ISSN 1652-9030 ; 140
Keyword [en]
Fear conditioning, phobia, memory reconsolidation, retrieval-extinction, exposure therapy, amygdala, fMRI
National Category
Psychology
Research subject
Psychology
Identifiers
URN: urn:nbn:se:uu:diva-317866ISBN: 978-91-554-9863-4 (print)OAI: oai:DiVA.org:uu-317866DiVA: diva2:1083292
Public defence
2017-05-12, Gunnar Johansson salen, Blåsenhus, von Kraemers allé 1A, Uppsala, 13:00 (English)
Opponent
Supervisors
Available from: 2017-04-20 Created: 2017-03-20 Last updated: 2017-04-20
List of papers
1. Disruption of reconsolidation erases a fear memory trace in the human amygdala
Open this publication in new window or tab >>Disruption of reconsolidation erases a fear memory trace in the human amygdala
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2012 (English)In: Science, ISSN 0036-8075, E-ISSN 1095-9203, Vol. 337, no 6101, 1550-1552 p.Article in journal (Refereed) Published
Abstract [en]

Memories become labile when recalled. In humans and rodents alike, reactivated fear memories can be attenuated by disrupting reconsolidation with extinction training. Using functional brain imaging, we found that, after a conditioned fear memory was formed, reactivation and reconsolidation left a memory trace in the basolateral amygdala that predicted subsequent fear expression and was tightly coupled to activity in the fear circuit of the brain. In contrast, reactivation followed by disrupted reconsolidation suppressed fear, abolished the memory trace, and attenuated fear-circuit connectivity. Thus, as previously demonstrated in rodents, fear memory suppression resulting from behavioral disruption of reconsolidation is amygdala-dependent also in humans, which supports an evolutionarily conserved memory-update mechanism.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-181451 (URN)10.1126/science.1223006 (DOI)000308912900054 ()22997340 (PubMedID)
Available from: 2012-09-24 Created: 2012-09-24 Last updated: 2017-03-20Bibliographically approved
2. Disruption of Memory Reconsolidation Erases a Fear Memory Trace in the Human Amygdala: An 18-Month Follow-Up.
Open this publication in new window or tab >>Disruption of Memory Reconsolidation Erases a Fear Memory Trace in the Human Amygdala: An 18-Month Follow-Up.
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2015 (English)In: PLoS ONE, ISSN 1932-6203, Vol. 10, no 7, e0129393- p.Article in journal (Refereed) Published
Abstract [en]

Fear memories can be attenuated by reactivation followed by disrupted reconsolidation. Using functional magnetic resonance imaging we recently showed that reactivation and reconsolidation of a conditioned fear memory trace in the basolateral amygdala predicts subsequent fear expression over two days, while reactivation followed by disrupted reconsolidation abolishes the memory trace and suppresses fear. In this follow-up study we demonstrate that the behavioral effect persists over 18 months reflected in superior reacquisition after undisrupted, as compared to disrupted reconsolidation, and that neural activity in the basolateral amygdala representing the initial fear memory predicts return of fear. We conclude that disrupting reconsolidation have long lasting behavioral effects and may permanently erase the fear component of an amygdala-dependent memory.

National Category
Psychology
Identifiers
urn:nbn:se:uu:diva-259785 (URN)10.1371/journal.pone.0129393 (DOI)000358153000028 ()26132145 (PubMedID)
Funder
Swedish Research Council, 521-2010-3284, 421-2009-2343The Swedish Brain Foundation, FO2014-0151
Note

Boethius stiftelse  PSYK2010/143, Swedish Council for Working Life and Social Research, Heumanska stiftelsen

Available from: 2015-08-11 Created: 2015-08-11 Last updated: 2017-03-20Bibliographically approved
3. Disrupting Reconsolidation Attenuates Long-Term Fear Memory in the Human Amygdala and Facilitates Approach Behavior
Open this publication in new window or tab >>Disrupting Reconsolidation Attenuates Long-Term Fear Memory in the Human Amygdala and Facilitates Approach Behavior
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2016 (English)In: Current Biology, ISSN 0960-9822, E-ISSN 1879-0445, Vol. 26, no 19, 2690-95 p.Article in journal (Refereed) Published
Abstract [en]

Memories become labile and malleable to modification when recalled [1]. Fear-conditioning experiments in both rodents and humans indicate that amygdala-localized short-term fear memories can be attenuated by disruption of their reconsolidation with extinction training soon after memory activation [2-7]. However, this may not be true for natural long-term fears. Studies in rodents indicate that although it is possible to disrupt the reconsolidation of older memories [8-11], they appear to be more resistant [1, 3, 9, 12, 13]. In humans, 1-week-old conditioned fear memories have been attenuated by behaviorally induced disruption of reconsolidation [14], but it remains to be seen whether this is possible for naturally occurring long-term fears and whether the underlying neural mechanisms are similar to those found in experimental fear-conditioning paradigms. Using functional brain imaging in individuals with a lifelong fear of spiders, we show that fear memory activation followed by repeated exposure to feared cues after 10 min, which disrupts reconsolidation, attenuates activity in the basolateral amygdala at re-exposure 24 hr later. In contrast, repeated exposure 6 hr after fear memory activation, which allows for reconsolidation, did not attenuate amygdala activity. Disrupted, but not undisrupted, reconsolidation facilitated approach behavior to feared cues, and approach behavior was inversely related to amygdala activity during re-exposure. We conclude that memory activation immediately preceding exposure attenuates the neural and behavioral expression of decades-old fear memories and that, similar to experimentally induced fear memories, the basolateral amygdala is crucially involved in this process.

National Category
Psychology Radiology, Nuclear Medicine and Medical Imaging
Identifiers
urn:nbn:se:uu:diva-302737 (URN)10.1016/j.cub.2016.08.022 (DOI)000385690800032 ()27568591 (PubMedID)
Funder
Swedish Research CouncilThe Swedish Brain Foundation
Available from: 2016-09-08 Created: 2016-09-08 Last updated: 2017-03-20Bibliographically approved
4. Think twice, it's all right: Long lasting effects of disrupted reconsolidation on brain and behavior in human long-term fear
Open this publication in new window or tab >>Think twice, it's all right: Long lasting effects of disrupted reconsolidation on brain and behavior in human long-term fear
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2017 (English)In: Behavioural Brain Research, ISSN 0166-4328, E-ISSN 1872-7549, Vol. 324, 125-129 p.Article in journal (Refereed) Published
Abstract [en]

Memories can be modified when recalled. Experimental fear conditioning studies support that amygdala-localized fear memories are attenuated when reconsolidation is disrupted through extinction training immediately following memory activation. Recently, using functional brain imaging in individuals with lifelong spider fears, we demonstrated that fear memory activation followed by repeated exposure to feared cues after 10 min, thereby disrupting reconsolidation, attenuated activity in the amygdala during later re-exposure, and also facilitated approach behavior to feared cues. In contrast, repeated exposure 6 h after fear memory activation, allowing for reconsolidation, did not attenuate amygdala activity and resulted in less approach behavior as compared to the group that received disrupted reconsolidation. We here evaluated if these effects are stable after 6 months and found that amygdala activity was further reduced in both groups, with a tendency towards greater reductions in the 10 min than the 6 h group. Hence, disrupted reconsolidation results in long lasting attenuation of amygdala activity. The behavioral effect, with more approach towards previously feared cues, in the 10 min than the 6 h group also persisted. Thus, the brain effect of disrupted reconsolidation is stable over 6 months and the behavioral effect also remained. We therefore conclude that disrupted reconsolidation result in a long-lasting diminished fear memory representation in the amygdala which may have clinical importance.

Keyword
Reconsolidation disruption, Extinction, Exposure therapy, Amygdala, Approach behavior, Spider fear
National Category
Neurology
Identifiers
urn:nbn:se:uu:diva-315854 (URN)10.1016/j.bbr.2017.02.016 (DOI)000397691100016 ()28214541 (PubMedID)
Funder
Swedish Research Council, 2013-2825, 2012-00804The Swedish Brain Foundation, F02014-0151
Available from: 2017-02-21 Created: 2017-02-21 Last updated: 2017-05-16Bibliographically approved

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