Identifying the Fast-acting Antidepressant Signatures of Treatment Response with psychedelic compounds using a novel behavioral tracking system and single-cell resolution

Project Information

FASTer

Grant agreement ID: 101116064

DOI

10.3030/101116064

EC signature date 17 November 2023

Start date 1 January 2024

End date 31 December 2028

Funded under

• European Research Council (ERC)

Total cost

€ 1 500 000,00

EU contribution

€ 1 500 000,00

Coordinated by

KAROLINSKA INSTITUTET
Sweden

Periodic Reporting for period 1 - FASTer (Identifying the Fast-acting Antidepressant Signatures of Treatment Response with psychedelic compounds using a novel behavioral tracking system and single-cell resolution)

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

Summary of the context and overall objectives of the project

Depression is one of the most widespread and disabling health conditions, and many people do not respond to current treatments. Even when antidepressants work, they often take weeks before any improvement is felt. Recent scientific studies have shown that certain psychedelic compounds, such as psilocybin, can produce much faster and longer lasting improvements. However, we still do not understand how these effects arise in the brain, why only some individuals benefit, or why recovery patterns differ between males and females.

The FASTer project aims to address these knowledge gaps by investigating the biological mechanisms that support the fast acting antidepressant effects of psilocybin. The project studies how chronic stress affects behaviour and brain function, and how a single treatment can trigger recovery. It focuses on three main goals: identifying behavioural changes linked to treatment response, mapping the brain circuits activated during recovery, and understanding how specific cell types and molecular pathways contribute to these effects.

To achieve this, FASTer combines several advanced approaches. A large scale, semi naturalistic behavioural system, known as the “Social Box”, is used to monitor how mice interact and behave over long periods in enriched environments. These behavioural patterns are then linked to changes in defined brain circuits using modern tracing and activity mapping techniques. Finally, single cell molecular tools are applied to identify the genes and cell types that respond to stress and treatment.

By connecting behaviour, brain circuits and molecular signatures, FASTer aims to build the first integrated picture of how rapid antidepressant effects emerge. The expected impact includes new insights into why treatments work for some individuals but not others, and the identification of biological features that could guide the development of faster and more precise therapies in the future. The project also introduces new behavioural analysis technologies that may benefit the broader neuroscience community.

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

Since the start of the project, FASTer has completed all major preparations needed to study how psilocybin produces rapid improvements in mood in a model of chronic stress. A key achievement was the establishment of a large‑scale behavioural system known as the Social Box. This high‑throughput setup, now operating with multiple parallel systems, is the first of its kind in Sweden and Scandinavia. It allows groups of mice to live together in enriched environments while being continuously recorded over long periods. Using this platform, the project generated its first long‑term behavioural datasets, capturing natural social interactions, exploration patterns, and changes that occur after treatment. Early analyses show that some animals display clear signs of recovery after receiving psilocybin, while others do not, providing the first clues toward understanding differences in treatment response.

In parallel, FASTer developed the tools needed to examine the underlying brain mechanisms. Specialised viral tools were optimised and validated to tag neurons that respond during the fast‑acting phase of treatment. The project also refined methods to isolate specific cell types from the brain and analyse their gene‑expression patterns at single‑cell resolution. These advances make it possible to connect behavioural changes with changes in defined brain circuits and cell populations.

All required ethical approvals and controlled substances were secured, and all planned collaborations with international partners were established. As a result, the project now has a complete experimental and analytical pipeline in place, ranging from naturalistic behaviour monitoring to molecular profiling. Together, these achievements create a strong foundation for uncovering the biological processes that support rapid antidepressant effects and for identifying the features that distinguish responders from non‑responders.

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)

FASTer has already produced several results that go beyond current practices in neuroscience and mental‑health research. One of the most important achievements is the introduction of a new way to study behaviour in animals. The Social Box system, now running in multiple parallel units at Karolinska Institutet, allows animals to live in enriched environments while being continuously monitored. This approach replaces short, artificial tests with long‑term observations of natural social behaviour. Combined with machine‑learning tools, this system can detect subtle behavioural changes that were previously impossible to capture. This represents a major step forward for behavioural science and opens the door to more realistic and reliable models of psychiatric conditions.

The project has also advanced methods for studying the brain at very high resolution. By using specialised genetic tools, FASTer can identify which groups of neurons are activated during the fast‑acting phase of psilocybin’s effects. In addition, improved single‑cell molecular techniques now make it possible to study thousands of individual cells and understand how they respond to stress and treatment. These innovations contribute to a deeper understanding of how complex behaviours arise from coordinated activity across different brain regions and cell types.

Together, these developments create a powerful framework for uncovering why some individuals respond to rapid‑acting antidepressants while others do not. The results may guide the design of new treatments that work faster, are more targeted, and have fewer side effects. They also generate new tools, such as automated behaviour‑analysis pipelines, that can be used by other researchers, increasing the project’s impact beyond its immediate scientific goals.
In the long term, the knowledge produced by FASTer may help inform future research programs, support the development of improved therapies, and encourage broader use of advanced behavioural and molecular technologies in mental‑health research.