Ventral pallidal transcriptional adaptations underlying punishment-resistant opioid intake

腹侧苍白球转录适应是抗惩罚阿片类药物摄入的基础

基本信息

批准号：
10775468
负责人：
Meaghan C Creed
金额：
$ 80.89万
依托单位：
WASHINGTON 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/10775468
关键词：
Address Affect American Anatomy Area Atlases Basal Ganglia Behavior Behavioral Binding Brain Candidate Disease Gene Catalogs Cell Differentiation process Cell Nucleus Cells Censuses Centers for Disease Control and Prevention (U.S.)Classification Communities Conflict (Psychology)Data Set Development Disease Drug Exposure Drug resistance Drug usage Epigenetic Process Equilibrium Event Exhibits Exposure to Extinction Foundations Future Gene Expression Profile Genetic Genetic Transcription Genomics Globus Pallidus Glutamates Goals Habenula Health Immediate-Early Genes Individual Individual Differences Intake Investigation Lateral Measures Modeling Molecular Motivation Mus Neurons Nucleus Accumbens Opioid Outcome Oxycodone Patients Peptide Initiation Factors Persons Pharmaceutical Preparations Phenotype Play Population Predisposition Public Health Punishment Relapse Reporting Resistance Resolution Resources Rewards Risk Rodent Role Self Administration Series Shock Specificity Structure Surveys Symptoms Taxonomy Technology Testing Therapeutic Time Translating Ventral Tegmental Area Viral Vector Virus Work adverse outcome candidate identification cell type drug seeking behavior epigenomics experience experimental study foot individual variation insight mRNA Expression motivated behavior neural neural circuit neurochemistry neuromechanism novel opioid exposure opioid therapy opioid use opioid use disorder overdose death pharmacologic prescription opioid prescription opioid abuse prescription opioid misuse prevent programs recruit single cell sequencing targeted treatment transcription factor transcriptome transcriptomics

项目摘要

PROJECT SUMMARY Opioid use disorder (OUD) is an escalating public health concern that has resulted in over 570,000 overdose deaths between 1999 and 2020. Exposure to prescription opioids (such as oxycodone) is frequently an initiating factor in OUD, with 9.9 million people reporting misusing prescription opioids annually (Centers for Disease Control). While many individuals can use opioids as prescribed, a subset of individuals transition to problematic drug use, which is defined as continued drug intake despite negative consequences and is a hallmark feature of OUD. These individual differences have been modeled in rodents: most subjects will readily self-administer opioids but will suppress drug intake when drug seeking is paired with punishment such as a foot shock (punishment-sensitive). Conversely, ~20-30% of individuals will persist in drug seeking despite this punishment (punishment-resistant). Elucidating the neural mechanisms underlying individual differences in punishment-resistant drug seeking is critical for understanding susceptibility to compulsive drug use in OUD. The ventral pallidum (VP) has emerged as a central brain area for encoding the relative value and motivation for rewards and translating this motivation into action. Recent work has also established that VP activity is necessary for drug seeking and relapse, and critically modulates reward seeking under conflict. The VP is an incredibly heterogeneous nucleus, with distinct neurochemically- and anatomically-defined populations playing discrete and dissociable roles in behavior. However, our understanding of how the VP subpopulations work in concert to orchestrate motivated behavior in the context of OUD is severely limited by the inability to identify functionally-relevant VP populations. Here we will use state-of-the-art omics platform to obtain high resolution cellular information of comprehensive cell types in the VP and their role in OUD. Our long-term goal is to elucidate the molecular and neural circuit basis of punishment-resistant opioid self- administration, and to leverage this understanding to develop targeted therapies to prevent or reverse the transition to punishment-resistant opioid intake in patients with OUD. The outcomes of this proposal will lay the foundation for this goal by creating a comprehensive cellular atlas of the VP and characterizing transcriptional adaptations induced by self-administration of oxycodone (Aim 1), and by profiling ensembles of VP neurons that are activated in the context of oxycodone self-administration (Aim 2). By profiling transcription factor binding using cutting edge “calling card” technology, we will establish whether transcriptional profiles distinguishing punishment sensitive- and resistant- individuals emerge with repeated self-administration, or whether these differences are antecedent to opioid exposure and only revealed upon introduction of punishment (Aim 3). This work will help inform future therapies for OUD and will identify molecules capable of modulating functionally-relevant ensembles of VP neurons as a therapeutic strategy for OUD.

项目概要阿片类药物使用障碍 (OUD) 是一个不断升级的公共卫生问题，已导致超过 570,000 人服用过量 1999 年至 2020 年间死亡人数。接触处方阿片类药物（如羟考酮）通常是一种 OUD 的引发因素，每年有 990 万人报告滥用处方阿片类药物（中心虽然许多人可以按照处方使用阿片类药物，但仍有一部分人会转向使用阿片类药物。有问题的药物使用，被定义为不顾负面后果而继续服用药物，是一种 OUD 的标志性特征已在啮齿类动物中进行了建模：大多数受试者很容易理解。自我施用阿片类药物，但当寻求毒品与惩罚（例如，足部休克（对惩罚敏感），尽管如此，约 20-30% 的人仍会继续寻求毒品。阐明个体差异背后的神经机制。抗惩罚性药物寻求对于了解对强迫性药物的敏感性至关重要腹侧苍白球 (VP) 已成为编码相对值的中枢大脑区域。最近的工作也证实了这一点。 VP 活动对于药物寻求和复发是必要的，并且严格调节冲突下的奖励寻求。 VP 是一个极其异质的核，具有独特的神经化学和解剖学定义然而，我们对 VP 的理解却是不同的。在 OUD 背景下，亚群体协同协调动机行为受到严重限制无法识别功能相关的 VP 群体。在这里，我们将使用最先进的组学平台来识别。获得 VP 中全面细胞类型的高分辨率细胞信息及其在 OUD 中的作用。长期目标是阐明抗惩罚阿片类药物自我调节的分子和神经回路基础管理，并利用这种理解来开发靶向疗法来预防或逆转 OUD 患者转向耐受惩罚的阿片类药物摄入。该提案的结果将奠定基础。通过创建 VP 的综合细胞图谱并表征转录特征，为实现这一目标奠定了基础通过自我施用羟考酮（目标 1）以及通过分析 VP 神经元集合诱导的适应在羟考酮自我给药的情况下被激活（目标 2）。使用尖端的“名片”技术进行绑定，我们将确定转录图谱是否区分惩罚敏感和抵抗的个体通过反复的自我管理而出现，或者这些差异是否先于阿片类药物暴露，并且仅在引入阿片类药物后才显现出来惩罚（目标 3）。这项工作将有助于为 OUD 的未来治疗提供信息，并将识别能够进行惩罚的分子。调节功能相关的 VP 神经元集合作为 OUD 的治疗策略。