Multi-modal profiling of spatially resolved cell types mediating opioid withdrawal

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Enter the text here that is the new abstract information for your application. This section must be no longer than 30 lines of text. Opioid addiction is now the fastest growing drug problem in the United States. Chronic opioid use induces opioid dependence, which is characterized by extremely unpleasant physiological and psychological symptoms after drug use is terminated. Opioid users learn to associate opioid intake with relief from negative physical and affective states. These learned associations are major obstacles for successful addiction treatment, since even after a prolonged period of abstinence, re-exposure to such cues often triggers drug craving and relapse to drug seeking. Therefore, the neuronal circuits underlying opioid withdrawal might be a potent target for preventing relapse. Indeed, we recently revealed an essential role of the paraventricular nucleus of thalamus (PVT) to the nucleus accumbens (NAc) pathway in mediating opioid withdrawal symptoms. Repeated opioid exposure causes long-term potentiation in the PVT→NAc pathway, furthermore silencing of this pathway disrupts opioid-associated memory and causes enduring protection against relapse to opioid use. However, PVT and NAc are both functional heterogenous structures with complex anatomical connections with their up- and down- stream brain regions. Beside opioid addiction, the PVT→NAc pathway also regulates motivated behaviors, such as feeding and sleep. Different functions are likely mediated by distinct subgroup of neurons in this pathway. We thus have formed a team with strong expertise in epigenomics sequencing, spatial imaging technologies, and neurobiology of drug addiction. We propose to (1) combine single cell transcriptomic and epigenomic imaging to establish a spatial resolved single cell atlas in the PVT and NAc; (2) identify opioid-responsive cell types and opioid-induced changes in their chromatin accessibility and gene expression during different stages of opioid addiction in the PVT; (3) use cell type specific gene manipulation to determine the contribution of opioid-induced gene expression changes to behavioral adaptations caused by repetitive opioid exposure and withdrawal. Together, our results will help identify novel molecular targets for treating opioid addiction.