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. 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 and limitations of the behavioral tests used to examine AD activity in rodents. Combining molecular, behavioral and advanced computational tools, this project will establish a groundbreaking and automatic behavioral tracking system to deconstruct the behavioral “language” associated with treatment response. In addition, it 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 unconventional group behaviors and endophenotypes in a translationally-relevant context that will cause a paradigm shift and revolutionize the field of behavioral phenotyping. To go beyond the state-of-the-art, we will combine activity-dependent labelling techniques and single-cell methods to identify the genes and brain circuits engaged during psilocybin treatment. To address the multidimensional nature of psychiatric disorders, we will manipulate gene networks related to the AD effects of psilocybin. 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, this project holds tremendous promise for translatability of preclinical findings and impacting the development of fast-acting and efficacious treatments for psychiatric disorders.