Project Summary/Abstract Over the last decade, use of illicit substances in United States has decreased for most drugs, except for marijuana that remains the most commonly abused by 7.5% of the population, especially among adolescents. Emerging evidence indicates a link between cannabis exposure and elevated risk of psychosis. However, the precise genetic and molecular components underpinning this association remain largely unresolved. The long-term goal of this research program is to use rodent models of schizophrenia susceptibility, targeting the Reelin pathway, to investigate the complex multifactorial nature of cannabis-psychosis association, with the ultimate goal of developing preventive and therapeutic strategies for cannabis use disorders. As the first step toward this goal, animal models that enable the selective isolation of specific neuronal subtypes will be generated. An integrated strategy, based on behavioral paradigms and epigenomic profiling, will be used to test whether and to what extent different components of cannabis (e.g D9-tetrahydrocannabinol and cannabidiol) affect the development of specific behaviors relevant to cognitive impairments observed in schizophrenia. A wide range of transcriptomic and epigenomic tools, based on next- generation sequencing technologies, will be applied to investigate the molecular changes induced by cannabis exposure. Extensive bioinformatics analysis of the genome-wide datasets generated by this project will likely lay the groundwork for future research programs focused on novel neuroepigenetic mechanisms underpinning cannabis use disorders.