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.

在此处输入文本，这是您应用程序的新摘要信息。本节必须不超过30行文本。阿片类药物成瘾现在是美国增长最快的药物问题。慢性阿片类药物使用诱导阿片类药物依赖性，其特征是终止药物使用后极度不愉快的身体和心理症状。阿片类药物的用户学会将阿片类药物的摄入与负面的身体和情感状态相关联。这些学识渊博的关联是成功成瘾治疗的主要障碍，因为即使经过长时间的禁欲，重新暴露于这种触发药物的渴望并传达给毒品寻求药物。因此，阿片类药物戒断的基础神经元电路可能是预防继电器的潜在靶标。的确，我们最近揭示了丘脑（PVT）对核伏隔（NAC）途径介导阿片类药物戒断症状的重要作用。重复的阿片类药物暴露在PVT→NAC途径中引起长期潜力，此途径的沉默会破坏与阿片类药物相关的记忆，并导致持久的保护免于缓解阿片类药物的使用。然而，PVT和NAC都是功能性异质结构，其上流和下游大脑区域具有复杂的解剖连接。除阿片类药物成瘾外，PVT→NAC途径还调节动机行为，例如喂养和睡眠。在该途径中，不同的神经元亚组可能介导不同的功能。因此，我们成立了一个在表观基因组学测序，空间成像技术和药物添加神经生物学方面具有强大专业知识的团队。我们建议（1）结合单细胞转录组和表观基因组成像，以在PVT和NAC中建立空间分辨的单细胞图集；（2）在PVT中阿片类药物成瘾的不同阶段，确定阿片类药物反应性细胞类型和阿片类药物诱导的染色质访问性和基因表达的变化；（3）使用细胞类型特异性基因操纵来确定阿片类药物诱导的基因表达对由重复的阿片类药物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用于治疗阿片类药物成瘾的新分子靶标。