How the Brain Learns to Forget - The Neural Signature of Fear Memory Erasure

Projektinformationen

WipeOutFear

ID Finanzhilfevereinbarung: 648176

DOI

10.3030/648176

Projekt abgeschlossen

EK-Unterschriftsdatum 17 August 2015

Startdatum 1 September 2015

Enddatum 31 August 2021

Finanziert unter

• EXCELLENT SCIENCE - European Research Council (ERC)

Gesamtkosten

€ 2 000 000,00

EU-Beitrag

€ 2 000 000,00

Koordiniert durch

KATHOLIEKE UNIVERSITEIT LEUVEN
Belgium

Periodic Reporting for period 4 - WipeOutFear (How the Brain Learns to Forget - The Neural Signature of Fear Memory Erasure)

Berichtszeitraum: 2020-03-01 bis 2021-08-31

Zusammenfassung vom Kontext und den Gesamtzielen des Projekts

Targeted pharmacological or behavioural interventions applied at the time of retrieval of an emotional memory can persistently block its later expression, perhaps due to memory erasure. The possibility to block the expression of targeted emotional memories carries enormous potential for the treatment of emotional memory disorders such as anxiety, depression, PTSD and addiction. In the current project, we explored the nature of such post-reminder amnesia and the conditions under which it occurs. In particular, we wanted to uncover whether post-reminder amnesia reflects memory erasure (a storage or retention deficit) or an impairment to retrieve an otherwise intact memory trace (an expression or retrieval deficit), develop new techniques to block the expression of emotional meories, and reveal under which circumstances memories become sensitive to such amnestic interventions.
While we obtained evidence that the brain mechanisms underlying post-reminder amnesia may be partly different than those underlying other forms of memory suppression, we also found that post-reminder amnesia can be reversed if the reminder cues used for retrieval prior to the amnestic intervention are slightly dissimilar from cues present at the time of memory encoding. This suggests that post-reminder amnesia does not need to result from memory erasure but may merely reflect impaired memory retrieval. Moreover, we found that both pharmacologically induced and other documented forms of post-reminder amnesia are often not readily replicable, for reasons that are only partially understood, and that the literature on this topic suffers from considerable publication bias. In combination with the observation that post-reminder amnesia is reversible, this suggests that the existing literature paints an overly optimistic picture of the potential for clinical translation.

Arbeit, die ab Beginn des Projekts bis zum Ende des durch den Bericht erfassten Berichtszeitraums geleistet wurde, und die wichtigsten bis dahin erzielten Ergebnisse

The main activities and major achievements of the project were as follows:

Through multiple series of experiments in humans and rats, complemented by meta-analytic work and computational reproducibility analysis, we demonstrated that the induction of post-retrieval amnesia using either pharmacological interventions (administration of amnestic drugs) or behavioural interventions (administration of extinction training) is less replicable than existing reports would suggest.

In other work, conducted in collaboration with researchers in Argentina, we demonstrated that similar conditions (i.e. an optimal level of prediction error at the time of retrieval) govern the sensitivity of retrieved emotional memories to pharmacological interventions (administration of amnestic drugs) and to behavioural interventions (administration of extinction training) for inducing amnesia in rats. We also established a neural marker of prediction error in humans and validated it against a benchmark model of prediction error processing in associative learning.

Through brain imaging work in humans, we established that post-reminder memory attenuation relies on partly different brain mechanisms than the attenuation obtained through standard memory attenuation procedures.

In further work, we demonstrated that pharmacologically induced amnesia does not readily transfer beyond the retrieval cues used to reactivate the memory prior to the pharmacological intervention. This poses a major challenge for the main storage deficit theory (the reconsolidation blockade account) as well as for the main retrieval deficit theory (the memory integration account) of post-retrieval amnesia. Our results also imply important limitations for the clinical application of post-retrieval amnesia alluded to above.

In yet another series of experiments, we explored a number of alternative ways to durably block the expression of emotional memories in humans and rats, some of which have yielded very promising results that we are now following up.

Fortschritte, die über den aktuellen Stand der Technik hinausgehen und voraussichtliche potenzielle Auswirkungen (einschließlich der bis dato erzielten sozioökonomischen Auswirkungen und weiter gefassten gesellschaftlichen Auswirkungen des Projekts)

Our finding that prediction error governs the sensitivity of retrieved memories not only to pharmacological but also to behavioural amnestic interventions helps to clarify the inconsistent replicability of previous findings.

Our observations regarding the lack of transfer of post-retrieval amnesia to cues not present during memory retrieval will force a new conceptualization of the nature of apparent memory erasure.

Our observation that foundational results in the field are not readily replicable and in one case not even computationally reproducible, along with the fact that post-retrieval amnesia may be reversible, severely reduces the scope for clinical translation of current approaches and calls for more caution in the development and dissemination of treatments based on a memory reconsolidation rationale.

Our findings that emotional memory expression can be attenuated through approaches that are fundamentally different from existing approaches, in humans and rats, shed new light on the mechanisms of and conditions for memory suppression and bear promise for the development of novel clinical interventions that circumvent fundamental problems of current approaches.

Our success in validating a neural marker of prediction error in humans and demonstrating that it confirms basic tenets of associative learning theory will have a considerable scientific impact and is bound to find widespread application by others in the field.

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