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

基本信息

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
项目类别：
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

项目摘要

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.

在此输入您的申请的新摘要信息的文本。此部分的文本长度不得超过 30 行。阿片类药物成瘾现在是美国增长最快的药物问题，长期使用阿片类药物会导致阿片类药物依赖，其特点是在停止使用阿片类药物后出现极其不愉快的生理和心理症状。这些习得的关联是成功治疗成瘾的主要障碍，因为即使在长时间戒断之后，重新接触此类线索也常常会引发药物渴望和药物寻求复发。因此，阿片类药物的神经元回路事实上，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。然而，PVT 和 NAc 都是功能异质结构，与阿片类药物相关的记忆具有复杂的解剖学联系。除了阿片类药物成瘾之外，PVT→NAc 通路还调节动机行为，例如进食和睡眠。因此，我们组建了一个团队。凭借在表观基因组测序、空间成像技术和药物成瘾神经生物学方面的丰富专业知识，我们建议 (1) 结合单细胞转录组和表观基因组成像，建立 PVT 和 NAc 的空间分辨单细胞图谱 (2) 识别； (3) 使用细胞类型特异性基因操作来确定阿片类药物诱导的基因表达变化对重复阿片类药物暴露和戒断引起的行为适应的贡献，我们的结果将有助于确定治疗阿片类药物成瘾的新分子靶标。