Neural circuit mechanisms of memory destabilization

Project Information

DstablizeMemory

Grant agreement ID: 950480

DOI

10.3030/950480

EC signature date 7 October 2020

Start date 1 February 2021

End date 31 July 2026

Funded under

• EXCELLENT SCIENCE - European Research Council (ERC)

Total cost

€ 1 500 000,00

EU contribution

€ 1 500 000,00

Coordinated by

FRIEDRICH MIESCHER INSTITUTE FOR BIOMEDICAL RESEARCH FONDATION
Switzerland

Periodic Reporting for period 3 - DstablizeMemory (Neural circuit mechanisms of memory destabilization)

Reporting period: 2024-02-01 to 2025-07-31

Summary of the context and overall objectives of the project

Animals and humans constantly reassess their learned information. Inaccurate predictions encountered during memory retrieval indicate that the world has changed and that previously acquired information is inadequate. Such a mismatch can lead to revaluation and consequently to a change in the stored information. Modifying memories through such a retrieval-dependent process shows great promise for treating maladaptive memories in humans, such as traumatic fear or drug-related memories. In fact, the utility of specifically targeting the memory update mechanism of reconsolidation has already been demonstrated to have therapeutic value. The crucial step in changing memory is the initiation of reconsolidation, which is the retrieval-induced destabilization of memory. However, not every retrieval elicits memory destabilization. Whether recalling a memory triggers reconsolidation or alternative processes such as memory extinction seems to be highly dependent on the size of the prediction error and the quality of the initial memory. In patients and experimental model systems, titrating retrieval conditions to trigger destabilization is key to effectively changing maladaptive memory. Thus, understanding the fundamental mechanisms of memory destabilization is key to improving retrieval-based therapies. To successfully decipher the circuit mechanisms that allow or deny memory reconsolidation and destabilization, it is necessary to know where and how memory is stored. In the fruit fly Drosophila melanogaster, it has been shown that olfactory memories are established as changes in synaptic connections between odor coding Kenyon cells and valence coding mushroom body output neurons. These changes are established by specific pathways in the dopaminergic system. All parts of the memory system are genetically accessible. Thus, we combine in vivo multi-photon imaging, the rich toolbox of Drosophila genetics and newly established behavioral paradigms to investigate the neural circuit mechanisms underlying the retrieval-induced memory destabilization.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

Parts of the projects are now at an advanced stage despite the severe setbacks caused by the COVID-19 pandemic and related experimental challenges. The work has led to three manuscripts, one of which is accepted in principle and another currently under revision. Our findings indicate that the neural circuits recruited during learning determine how memory becomes sensitive to destabilization. This suggests that the conditions present during learning set the stage for whether and how memory reconsolidation can be triggered, ultimately influencing memory stability. Importantly, these principles appear to be general and apply across different types of memory. Furthermore, we find that memory reconsolidation is not restricted to accessible memories but can impact the recovery of forgotten memories and change their content.
Although speculative at this stage, if these mechanisms prove to be conserved across species, they could have important translational implications. In human patients, detailed assessment of the learning conditions under which maladaptive memories were formed may improve treatment strategies. For instance, clinical studies have shown that drugs such as propranolol can interfere with memory reconsolidation; however, if destabilization is not triggered, such treatments may be ineffective. Understanding the factors that enable or prevent destabilization could therefore enhance therapeutic outcomes, inform expectation management, and guide the use of alternative interventions. Moreover, if retrieval protocols can address subjectively forgotten memories, strategies to target remote maladaptive memories may need to be reconsidered.
More broadly, the ability to bias memories toward being rewritten has implications beyond clinical contexts. Adjusting learned behaviors and modifying stored information are essential for adaptive decision-making in everyday life. Thus, elucidating how memories can be selectively destabilized and updated may ultimately benefit individuals suffering from traumatic experiences as well as those seeking to overcome maladaptive behavioral routines.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

The projects are at an intermediate stage after severe drawbacks had to be overcome, e.g. the impact of the COVID-19 pandemic. However, our findings suggest that the circuits recruited during learning define how a memory is sensitive to destabilization. This suggests that the conditions during learning set the stage if and how memory reconsolidation can be triggered, and memory can be destabilized. We find that these principles are general and hold true across different types of memory. Although extremely speculative at this stage, if these principles can be further generalized across species, it might be useful to assess and categorize learning conditions in human patients extensively to support treatments. Case studies in humans have shown that treatment with drugs such as propranolol can interfere with memory reconsolidation. However, if destabilization is not triggered in the first place, drug treatment will not affect the persistence of memory. Thus, exploring the different conditions under which maladaptive memories have been established and relating them to treatment efficiency might provide important insights for expectation management and application of alternative treatments. Despite maladaptive memories, adjusting learned behavior and related stored information is crucial to adapt to new situations. Thus, understanding how to bias memories to be re-written will not only help patients suffering from traumatic experiences but also might help to change unwanted behavioral routines in everyday life.