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

介导阿片类药物戒断的空间分辨细胞类型的多模式分析

• 批准号: 10787010
• 负责人: Bogdan Bintu
• 金额: $ 76.6万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-30 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10787010
• 关键词: 3-Dimensional; ATAC-seq; Abstinence; Affective; Anatomy; Animals; Atlases; Behavioral; Biological; Brain; Brain region; Cell Nucleus; Cells; Chromatin; Chromatin Structure; Chronic; Complex; Cues; Data; Drug Addiction; Drug usage; Epigenetic Process; Exposure to; Gene Expression; Gene Expression Profile; Gene Expression Profiling; Gene Expression Regulation; Genes; Genetic Transcription; Image; Imaging technology; Label; Learning; Long-Term Potentiation; Maintenance; Mediating; Memory; Methods; Modification; Molecular; Molecular Target; Mus; Negative Reinforcer; Neurobiology; Neurons; Nucleus Accumbens; Opiate Addiction; Opioid; Opioid Analgesics; Pathway interactions; Pharmaceutical Preparations; Physiological; Recommendation; Regulatory Element; Relapse; Resolution; Retrieval; Role; Sampling; Sleep; Spatial Distribution; Structure; Structure of paraventricular nucleus of thalamus; Subgroup; Symptoms; Synapses; Synaptic Transmission; Text; United States; Visualization; Withdrawal; Withdrawal Symptom; Work; addiction; base; cell type; drug craving; drug relapse; drug seeking behavior; epigenomics; experimental study; feeding; fighting; genetic manipulation; knock-down; motivated behavior; multimodality; multiple omics; negative affect; neural network; neuronal circuitry; novel; novel strategies; opioid epidemic; opioid exposure; opioid mortality; opioid use; opioid user; opioid withdrawal; prescription opioid abuse; promoter; psychological symptom; relapse prevention; response; single cell analysis; single cell sequencing; single nucleus RNA-sequencing; single-cell RNA sequencing; transcriptome; transcriptomics

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.

在此输入文本，它是您的应用程序的新摘要信息。此部分不得超过30行文本。 阿片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依赖，其特征是停药后出现极不愉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的摄入与从消极的身体和情感状态中解脱联系起来。这些习得的关联是成功治疗成瘾的主要障碍，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再次寻求药物。因此，阿片类药物戒断背后的神经元回路可能是防止复发的有效靶点。事实上，我们最近揭示了丘脑室旁核(PVT)到伏隔核(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会导致PVT→NAC通路的长期增强，而且这一通路的沉默会扰乱阿片相关的记忆，并对阿片类药物的复发产生持久的保护作用。然而，PVT和NAC都是功能不同的结构，与其上下游脑区有着复杂的解剖联系。除了阿片成瘾，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的神经生物学方面拥有强大专业知识的团队。我们建议(1)结合单细胞转录和表观基因组成像来建立PVT和NAC的空间分辨单细胞图谱；(2)识别PVT中阿片反应细胞的类型以及阿片类药物在不同阿片成瘾阶段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阿片重复暴露和戒断引起的行为适应的贡献。总之，我们的结果将有助于确定治疗阿片成瘾的新分子靶点。