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，导致了超过570,000的过量 1999年至2020年之间的死亡。暴露于处方阿片类药物（例如羟考酮）通常是 启动因素，有990万人报告每年错过处方阿片类药物（中心 疾病控制）。尽管许多人可以使用规定的阿片类药物，但一部分个人过渡到 使用有问题的药物使用，该药物被定义为持续的药物摄入目的地负面后果，是一个 Oud的标志性功能。这些个体差异是在啮齿动物中建模的：大多数受试者很容易 自我辅助阿片类药物，但会抑制药物搜查与惩罚（例如 脚冲击（对惩罚敏感）。相反，约有20-30％的人会坚持寻求毒品 惩罚（抗惩罚）。阐明个体差异的基础神经机制 在抗惩罚的药物中，寻求毒品对于理解强迫毒品的易感性至关重要 在Oud中使用。腹侧颗粒（VP）已成为用于编码相对值的中央大脑区域 以及奖励并将这种动机转化为行动的动机。最近的工作还确定了 副总裁活动对于寻求药物和继电器是必需的，并严格调节在冲突下寻求奖励。 副总裁是一种令人难以置信的异质核，具有独特的神经化学和解剖学定义 人群在行为中扮演离散和可分离的角色。但是，我们对副总裁的理解 在OUD的背景下，亚群协同协调动机行为受到严重限制 无法识别与功能相关的VP人群。在这里，我们将使用最先进的OMICS平台进行 获取VP中综合细胞类型的高分辨率细胞信息及其在OUD中的作用。我们的 长期目标是阐明抗惩罚性阿片类药物的分子和神经回路基础 管理，并利用这种理解来开发有针对性的疗法，以防止或扭转 OUD患者的耐药阿片类药物摄入过渡。该提议的结果将为 通过创建副总裁的全面蜂窝图集并表征转录的基础 由羟考酮自我给药（AIM 1）和VP神经元的组合引起的适应 在羟考酮自我管理的背景下被激活（AIM 2）。通过分析转录因子 使用尖端的“电话卡”技术绑定，我们将确定转录配置文件是否 通过反复的自我管理或 这些差异是否是阿片类药物暴露的前提，仅在引入时才揭示 惩罚（目标3）。这项工作将有助于告知未来的OUD疗法，并确定能够的分子 调节副总裁神经元功能相关的合奏，作为OUD的治疗策略。