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

在此输入文本，它是应用程序的新摘要信息。此部分不得超过30行文本。 阿片类药物成瘾现在是美国增长最快的毒品问题。阿片类药物的长期使用会导致阿片类药物依赖，其特征是在药物使用终止后出现极其令人不快的生理和心理症状。阿片类药物使用者学会将阿片类药物摄入与缓解负面的身体和情感状态联系起来。这些习得的关联是成功戒毒的主要障碍，因为即使在长期戒断之后，再次接触这些线索往往会引发对药物的渴望和重新寻求药物。因此，阿片类药物戒断的神经回路可能是预防复发的有效靶点。事实上，我们最近揭示了丘脑室旁核（PVT）到丘脑核（NAc）通路在介导阿片类药物戒断症状中的重要作用。重复阿片类药物暴露导致PVT→NAc通路的长时程增强，此外，该通路的沉默破坏阿片类药物相关记忆，并导致持久的保护，防止阿片类药物使用复发。然而，PVT和NAc都是功能异质性结构，与其上下游脑区有复杂的解剖学联系。除了阿片类药物成瘾，PVT→NAc通路还调节动机行为，如进食和睡眠。不同的功能可能由该通路中不同的神经元亚群介导。因此，我们组建了一支在表观基因组测序、空间成像技术和药物成瘾神经生物学方面具有丰富专业知识的团队。我们建议（1）结合联合收割机单细胞转录组学和表观基因组学成像技术建立PVT和NAc中空间分辨的单细胞图谱;（2）鉴定PVT中阿片样物质成瘾的不同阶段中阿片样物质应答细胞类型和阿片样物质诱导的染色质可及性和基因表达的变化;（3）使用细胞类型特异性基因操作来确定阿片诱导的基因表达变化对重复阿片暴露和戒断引起的行为适应的贡献。总之，我们的研究结果将有助于确定治疗阿片类药物成瘾的新分子靶点。

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.