PROJECT SUMMARY Current therapies for opioid use disorder are focused on alleviating withdrawal symptoms associated with cessation of opioid use, which has led to improved treatment outcomes. An important emerging approach to tackling the opioid crisis focuses on prevention efforts. A better understanding of the factors that contribute to the transition from the initial opioid exposure to development of a substance use disorder is needed to improve existing preventative measures. In this proposal, we combine rodent behavioral models of early life adversity, which are known to influence addiction-related endophenotypes, with combined cell type-specific transcriptomics and epigenomics to develop a more complete picture of the molecular signatures that are predictive of resilience to substance abuse. The brain is highly heterogeneous and revealing the cell-type specific changes in gene expression and chromatin accessibility constitutes a potentially transformative advance that can be leveraged to tailor pain management and initial opioid treatments. The proposal focuses on the nucleus accumbens core, a brain region critical for impulsivity and addiction-related behaviors. This grant lays to foundation for reducing the transition from initial exposure to uncontrolled and compulsive use in individuals treated with opioids. Deliverables under this award include detailed cell-type specific maps of the effect of early life stress on the transcriptome and epigenome of the nucleus accumbens core and identification of the neural cell types associated with human impulsivity, a reliable proxy for addiction liability and susceptibility.