Developing an Ex Vivo Model of the Mesolimbic Pathway for Studying Addiction Phenotypes

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Project Summary Drug abuse and addiction continues to be a major and growing societal problem. It develops during repeated drug use which causes a series of molecular, transcriptomic, and epigenetic modifications which remodel the neurons in the mesolimbic pathway leading addictive behavior. Despite extensive studies, treatment options remain limited in part because the underlying mechanisms contributing to addictive behavior are still not fully understood. Most previous research to study underlying molecular mechanisms have been performed in animal models specifically mice and rats, which allow scientists to manipulate a specific variable and assess alterations in drug seeking responses. Despite the power of these models, there are limitations to how well mice molecular through tissue physiologies correlate to humans. For example, there are significant differences in the number, cell type compositions, and functions of their respective mesolimbic pathway neurons. Therefore, there is a need for ex vivo model systems which capture the human genetic, epigenetic, transcriptional, and multicellular properties of mesolimbic cell types and connections. We will contribute to this goal by differentiating human stem cells into organoids containing dopaminergic and medium spiny neurons of the mesolimbic pathway and generate functional synapses between the two. The model will be interrogated by exposing the cultured neurons to cocaine and studying their molecular, transcriptional, and epigenetic responses and comparing these responses to available mice and human data. With this model, we can further understand the key underlying mechanisms that contribute to addiction formation potentially leading to specific targets for drug development.