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

• 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
• 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

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.

项目摘要 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人过量服用 1999年至2020年期间死亡。暴露于处方阿片类药物（如羟考酮）通常是一种 OUD的启动因素，每年有990万人报告滥用处方阿片类药物（中心 疾病控制）。虽然许多人可以按规定使用阿片类药物，但有一部分人会过渡到 有问题的药物使用，其定义为尽管有负面后果但仍继续服用药物， OUD的标志性特征。这些个体差异已经在啮齿动物中建模：大多数受试者很容易 自我管理阿片类药物，但会抑制药物摄入时，药物寻求与惩罚，如 足部电击（惩罚敏感）。相反，尽管如此，约20-30%的人会坚持寻求药物 惩罚（punishment resistant）阐明个体差异背后的神经机制 在对惩罚抵抗性药物寻求中， 使用OUD。腹侧苍白球（VP）已成为编码相对值的中枢脑区 以及奖励的动机，并将这种动机转化为行动。最近的工作还确定， VP活动是药物寻求和复吸所必需的，并在冲突下严重调节奖励寻求。 VP是一个令人难以置信的异质核，具有不同的神经化学和解剖学定义 在行为中扮演离散和可分离角色的群体。然而，我们对VP如何的理解 在OUD的背景下，亚群协同工作以协调动机行为受到严重限制， 无法识别功能相关的VP人群。在这里，我们将使用最先进的组学平台， 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。我们 长期的目标是阐明抗惩罚阿片类自身的分子和神经回路基础， 管理，并利用这种理解来开发靶向治疗，以防止或逆转 OUD患者过渡到抗惩罚阿片类药物摄入。这项提案的结果将奠定 通过创建VP的全面细胞图谱并表征转录， 羟考酮自身给药（Aim 1）和VP神经元整体分析诱导的适应 在羟考酮自我给药的情况下被激活（目的2）。通过分析转录因子 结合使用尖端的“名片”技术，我们将建立是否转录谱 区分惩罚敏感-和抵抗-个人出现反复自我管理，或 这些差异是否在阿片类药物暴露之前，并且仅在引入 惩罚（目标3）。这项工作将有助于为OUD的未来治疗提供信息，并将确定能够 调节VP神经元的功能相关集合作为OUD的治疗策略。