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

Introduction

Mental health disorders affect 84 million people across Europe and are associated with an economic burden of €600 billion/year. New evidence from clinical trials suggests that a single treatment with psychedelic compounds, such as psilocybin, can produce a fast (hours) and sustained (months) antidepressant (AD) response.

Challenges in Understanding Mechanisms

However, many questions still remain about its mechanism of action, due to methodological challenges such as:

• Lack of knowledge of the brain cells and circuits where AD effects are taking place
• Limitations of the behavioral tests used to examine AD activity in rodents

Project Overview

Combining molecular, behavioral, and advanced computational tools, FASTer will establish a groundbreaking and automatic behavioral tracking system to deconstruct the behavioral “language” associated with treatment response.

Objectives

In addition, FASTer will identify the brain cells and circuits responsible for the fast-acting and sustained AD effects of psilocybin. This is a move away from the traditional assessment of single behavioral readouts to:

1. Unconventional group behaviors
2. Endophenotypes in a translationally-relevant context

This approach will cause a paradigm shift and revolutionize the field of behavioral phenotyping.

Methodology

Thanks to my unique know-how in bridging human and pre-clinical psychiatry, and to go beyond the state-of-the-art, I will combine:

• Activity-dependent labeling techniques
• Single-cell methods

These will be used to identify the genes and brain circuits engaged during psilocybin treatment.

Addressing Psychiatric Disorders

To address the multidimensional nature of psychiatric disorders, I will manipulate gene networks related to the AD effects of psilocybin.

Potential Impact

The ambitious and innovative studies proposed here have the potential to change our understanding of psychiatric disorders and transform the field of behavioral neuroscience. Ultimately, FASTer holds tremendous promise for the translatability of preclinical findings and impacting the development of fast-acting and efficacious treatments for psychiatric disorders.