Single-Cell Dissection of Ensembles and Cell Types Mediating Opioid Action in the Rodent Brain

啮齿动物大脑中介导阿片类药物作用的细胞群和细胞类型的单细胞解剖

基本信息

批准号：
10627737
负责人：
Veronica A Alvarez
金额：
$ 61.66万
依托单位：
MASSACHUSETTS INSTITUTE OF TECHNOLOGY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-06-01 至 2027-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10627737
关键词：
Acute Addictive Behavior Affect Animals Area Behavior Behavioral Brain Brain region Candidate Disease Gene Cells Cellular Structures Chronic Communities Corpus striatum structure Data Data Analyses Dependence Development Dimensions Dissection Dopamine Dorsal Gender Genes Goals Human In Situ Hybridization Knowledge Mediating Methods Midbrain structure Minor Molecular Molecular Profiling Morphine Mus Nature Neuroglia Neurons Nucleic Acid Regulatory Sequences Nucleus Accumbens Opiate Addiction Opioid Pathway interactions Pattern Pharmacotherapy Phenotype Play Process Proteins Protocols documentation RNA Resolution Rewards Rodent Role Sampling Self Administration Societies Specificity Stimulus Substance Use Disorder Substantia nigra structure Testing Transgenic Mice Validation Ventral Tegmental Area Viral Withdrawal addiction advanced analytics analytical tool approach behavior candidate identification causal variant cell type complex data differential expression dopamine system epigenomics experimental group in vivo mouse model mu opioid receptors multimodal data novel opioid exposure opioid use opioid use disorder pars compacta response single-cell RNA sequencing striosome substance use therapeutic target transcriptomics

项目摘要

Substance use disorder (SUD) is a debilitating condition characterized by compulsive use of a substance, in spite of the subjective recognition of the drawbacks associated with its use. Chronic use of the substance leads to the development of withdrawal and dependence, hindering intentional controls over its use. Among all substances, opioids are among the ones that pose the greatest negative impact on our society. Animal and human studies have implicated several brain regions involved in opioid use disorder (OUD), in particular various components of the dopamine system. Major dopamine-containing neurons are clustered in regions of the midbrain called the substantia nigra pars compacta (SNc) and ventral tegmental area (VTA). Classically, their activities correlate with valence, e.g., promoting approach behavior to rewarding stimuli. Upstream of them, two major circuits are involved: one including the nucleus accumbens projecting onto the VTA, and the other including the dorsal striatum projecting onto the SNc. The scope of this study is thus to conduct in-depth transcriptomics across the cells of these two circuits to dissect genes, pathways, and cell types mediating opioid action in the mouse brain. We will use these data to predict driver genes, regulatory regions, pathways, and cell types involved in the emergence of opioid addiction behaviors. Finally, to test the causal role of these predicted drivers, we will use opioid self-administration, a classical paradigm used in the field of addiction. By combining a rich set of behavioral protocols with state-of-the-art transcriptomics, epigenomics, and computational data analysis, we aim to obtain multi-modal data with an unprecedented level of single-cell resolution for identifying genes, pathways, and cell types affected in mouse models of OUD.

药物使用障碍（SUD）是一种令人衰弱的疾病，尽管对与其使用相关的缺点的主观识别，但具有强迫使用物质的特征。长期使用该物质会导致戒断和依赖性的发展，阻碍对其使用的故意控制。在所有物质中，阿片类药物是对我们社会造成最大负面影响的那些物质。动物和人类研究暗示了参与阿片类药物使用障碍（OUD）的几个大脑区域，特别是多巴胺系统的各种组成部分。含多巴胺的主要神经元聚集在称为黑质的Nigra pars compacta（SNC）和腹侧段区域（VTA）的区域。从经典上讲，它们的活动与价相关，例如促进奖励刺激的方法行为。它们的上游涉及两个主要电路：一个包括伏隔核的核，另一个投射到VTA上，另一个包括投射到SNC上的背纹状体。因此，这项研究的范围是在这两个电路的细胞上进行深入的转录组学，以剖析介导小鼠脑中阿片类药物作用的基因，途径和细胞类型。我们将使用这些数据来预测阿片类成瘾行为出现的驱动基因，调节区域，途径和细胞类型。最后，为了测试这些预测的驱动因素的因果作用，我们将使用阿片类药物自我管理，这是成瘾领域中使用的经典范式。通过将一组丰富的行为方案与最新的转录组学，表观基因组学和计算数据分析相结合，我们旨在获得具有前所未有的单细胞分辨率的多模式数据，用于识别小鼠模型中受影响的基因，途径和细胞类型。