Abstract: The opioid crisis remains a major public health problem. Opioid withdrawal is a major driver of risky opioid use and relapse due to aversive states during acute withdrawal and long-lasting maladaptive behaviors that emerge during protracted abstinence. However, the neural mechanisms linking these phases remain poorly understood. I have identified a distinct population of neurons in the nucleus accumbens (NAc), enriched with mu opioid receptors and the transcription factor Tshz1, that contributes to both the aversive nature of acute withdrawal and maladaptive behaviors of protracted abstinence. NAc Tshz1 neurons are activated during acute withdrawal and locally suppress dopamine release, mediating aversive withdrawal learning and memory. The activity of these neurons is also critical for social interaction deficits and anxiety during protracted abstinence, through an unknown mechanism that may involve local modulation of dopamine and serotonin release. Transcriptomic analysis of Tshz1 neurons revealed a molecular target whose activation ameliorated both acute withdrawal aversion and protracted abstinence deficits. These findings reveal how distinct cell-types and neuromodulator systems are recruited across different phases of opioid use disorder. My future lab will build on this work using single-cell imaging and transcriptomics to examine key cell-types and circuit mechanisms that underlie maladaptive withdrawal states with the ultimate goal of identifying novel druggable targets.