How do drug-associated contexts drive behaviour? The role of entorhinal circuitry in addiction

Project Information

DrugsAndMemory

Grant agreement ID: 101117791

DOI

10.3030/101117791

EC signature date 12 October 2023

Start date 1 January 2024

End date 31 December 2028

Funded under

• European Research Council (ERC)

Total cost

€ 1 498 475,00

EU contribution

€ 1 498 475,00

Coordinated by

UNIVERSITATSKLINIKUM HEIDELBERG
Germany

Periodic Reporting for period 1 - DrugsAndMemory (How do drug-associated contexts drive behaviour? The role of entorhinal circuitry in addiction)

Reporting period: 2024-01-01 to 2026-06-30

Summary of the context and overall objectives of the project

Addiction is a major brain disorder with profound consequences for individuals and society. One of the main challenges in treating addiction is that places or situations previously associated with drug use can trigger relapse even after long periods of abstinence. For example, a recovering alcoholic who returns to a familiar pub may experience a sudden and powerful urge to drink again. This project investigates how the brain links rewarding drug experiences to contextual memories and how these memories later influence behaviour. It focuses on how brain systems involved in memory and motivation interact to support the persistence of drug-associated memories. To address this question, the project combines behavioural studies in mice with modern methods for monitoring and manipulating neural activity during learning. By identifying the principles through which drug-associated memories are formed and expressed, the project aims to improve our understanding of relapse-related brain mechanisms and to support the development of better strategies for intervention in the future.

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

The project investigates how the brain links drug-related experiences to contextual memories and how such memories later influence behaviour. A central focus is on understanding how brain systems involved in memory, spatial representation, and motivation interact during the formation and expression of drug-associated memories.

During the reporting period, the main activities focused on establishing and applying behavioural and neurophysiological paradigms in mice that make it possible to study these questions in a controlled way. This included the development of experimental settings in which contextual information or specific environmental features can be associated with drug-related or dopamine-related signals, as well as the collection of large-scale neuronal recordings from several brain regions involved in memory and motivation.

A major achievement has been the successful generation of extensive datasets from key brain regions relevant to the project. These datasets provide the basis for analysing how contextual and motivational information is represented in the brain and how these representations are altered by dopamine-related manipulations and drug exposure. The project has also established a new behavioural framework to compare natural reward-related behaviour with drug-related behaviour more directly. This is important because natural rewards are normally limited by satiety, whereas addictive drugs can lead to persistent seeking behaviour without the same physiological constraints.

The work has already revealed that neural systems involved in spatial and contextual representation are more flexible and sensitive to motivational state than previously assumed. In particular, the findings indicate that dopamine-related signals can alter the precision of neural codes linked to orientation and contextual processing. These results open new perspectives on how memory-related brain circuits contribute not only to navigation and contextual representation, but also to drug-related learning and relapse-like behaviour.

Overall, the work performed during the reporting period has established the core experimental platforms of the project, generated substantial datasets across multiple brain systems, and provided important first insights into how drug-related and reward-related experiences shape neural representations relevant to relapse.

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 results obtained so far suggest that brain systems involved in contextual and spatial memory are more closely linked to motivational and drug-related processes than is generally assumed. This is important because relapse is often triggered by environments previously associated with drug use, yet the underlying brain mechanisms are still not well understood. By showing how memory-related brain activity can be influenced by dopamine-related signals and drug exposure, the project opens new perspectives on how relapse-related memories are formed and maintained.

Beyond advancing basic knowledge, these findings may have longer-term implications for the development of improved strategies to prevent relapse. A better understanding of how contextual drug memories are encoded and expressed could help identify new entry points for therapeutic intervention, especially in cases where environmental triggers play a major role in renewed drug seeking. The project therefore contributes to a broader effort to connect fundamental neuroscience with clinically relevant questions in addiction research.

At this stage, the main need for further uptake is continued research to consolidate and extend the findings. In particular, it will be important to determine how the mechanisms identified so far relate to more advanced stages of drug use and addiction-like behaviour, and to assess how general these principles are across different behavioural conditions. Further progress will also depend on the continued integration of behavioural, physiological, and circuit-level approaches. In the longer term, the knowledge generated by the project may provide a foundation for translational work aimed at improving intervention strategies for relapse-related disorders.