Genomic profiling mediating the protective effect of social reward on opioid craving

基因组分析介导社会奖励对阿片类药物渴望的保护作用

• 批准号: 10671062
• 负责人: Seth Abrams Ament
• 金额: $ 65.62万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10671062
• 关键词: Abstinence; Amygdaloid structure; Animal Model; Anterior; Autopsy; BRAIN initiative; Behavior; Behavior Therapy; Brain region; Buffers; Buprenorphine; CRISPR interference; CRISPR-mediated transcriptional activation; Cell Nucleus; Cells; Censuses; Clinical; Clinical Research; Cocaine; Communities; Complex; Cues; DSM-IV; Data; Dependovirus; Dorsal; Drug Addiction; Drug Modelings; Gene Expression; Genes; Genetic; Genetic Markers; Genetic Transcription; Genomics; Goals; HIV; Heroin; Home; Human; Immunohistochemistry; Incubated; Insula of Reil; Intervention; Label; Lateral; Literature; Measures; Mediating; Messenger RNA; Methadone; Methamphetamine; Modeling; Molecular; Naltrexone; Neurons; Ontology; Opiate Addiction; Opioid; Patients; Pharmaceutical Preparations; Physiological; Procedures; Psychological reinforcement; Public Health; Rattus; Relapse; Research; Rewards; Rodent; Role; Self Administration; Social Interaction; Somatostatin; Stimulus; Stress; Structure of paraventricular nucleus of thalamus; Support Groups; Testing; Time; Translating; United States Food and Drug Administration; Virus; Withdrawal; addiction; cell type; craving; drug abstinence; drug craving; drug reward; improved; insight; large datasets; model design; neural; novel; opioid epidemic; opioid use disorder; overdose risk; peer; prevent; professional atmosphere; protective effect; psychostimulant; recruit; reinforcer; relapse risk; response; single nucleus RNA-sequencing; social; social factors; success; tool; transcriptomics; translational approach; translational impact

Project Summary The current opioid crisis is a major public health problem, and it persists despite the availability of Food and Drug Administration–approved treatments (methadone, buprenorphine, and naltrexone). A critical challenge is the occurrence of lapses or relapses in treated patients, especially given that relapses carry a risk of overdose. Therefore, there is an unmet need to advance novel alternative interventions that may overcome limitations of currently available treatment options for opioid use disorders (OUDs). The reason for the limited success of treatments for OUDs are complex and multifactorial. One potential limitation could be attributed to classical animal model of OUDs which rarely incorporate social factors. We recently developed an operant rat model of choice between heroin and social interaction and showed that: (1) rats strongly prefer operant social interaction over heroin, and (2) social choice-induced abstinence (voluntary abstinence) prevents heroin seeking over time (in a model of drug craving). The genetic and circuit mechanisms mediating the protective effect of social reward on heroin craving are unknown. The overarching goal of this proposal is to study the genomic profiling contributing to the buffering effect of social interaction on heroin craving. We will focus on the central nucleus of the amygdala (CeA) and its projections based on our findings on the role of CeA in incubation of psychostimulant craving after social choice-induced voluntary abstinence and previous studies on its role in incubation of drug craving after forced abstinence across drug classes. In Aim 1, we will generate single- nucleus RNA-seq from CeA and its projections (using anterograde transynaptic viruses) in rats during the incubation’s tests after either social-based voluntary or forced abstinence. Additionally. we will interpret the transcriptomic data within detailed ontologies of transcriptomic cell types in each brain region from the BRAIN Initiative Cell Census Network, as well as with snRNA-seq of post-mortem amygdala and insula of human donors with opioid use disorder from the Single-Cell Opioid Responses in the Context of HIV (SCORCH) consortium. In Aim 2, we will use retrograde adeno-associated viruses to label CeA projection neuron nuclei and integrate the transcriptomic data with complementary transcriptomic datasets from large consortia. In Aim 3, we will combine our translationally relevant social choice animal model with advanced CRISPRa and CRISPRi AAV tools to manipulate transcription of key hub genes in either CeA or projection regions to demonstrate their causal role on social-based protection of heroin craving. Our proposal will provide new insights into genomic profiling and its mechanisms underlying the protective effect of social reward on heroin craving in a novel social-based rat model. These results will improve our mechanistic understanding of the role of social interaction in OUDs.

项目摘要 当前的阿片类药物危机是一个主要的公共卫生问题，它仍然是食物的可用性和 药物管理批准的治疗（美沙酮，丁丙诺啡和纳曲酮）。一个关键的挑战是 治疗患者的失去或继电器的发生，尤其是考虑到继电器有过量的风险。 因此，有未满足的需要推进新颖的替代干预措施，以克服可能的局限性 目前可用于绿化疾病（OUDS）的可用治疗选择。取得有限成功的原因 Ouds的处理是复杂且多因素的。一个潜在的限制可以归因于经典 Oud的动物模型，很少纳入社会因素。我们最近开发了一个操作大鼠模型 海洛因和社交互动之间的选择，并表明：（1）大鼠强烈喜欢操作社交互动 超过海洛因和（2）社会选择引起的禁欲（自愿节制）阻止海洛因随着时间的流逝而寻求 （在毒品渴望的模型中）。介导社会保护作用的遗传和电路机制 渴望海洛因的奖励是未知的。该提案的总体目标是研究基因组分析 有助于社会互动对海洛因渴望的缓冲效果。我们将专注于中央核 根据我们关于CEA在孵化的作用的发现，杏仁核（CEA）及其项目 在社会选择引起的自愿节制和以前的研究中，心理刺激症的渴望以及其在其中的作用 在毒品类别中强迫戒酒后，渴望药物渴望。在AIM 1中，我们将产生单一 CEA的核RNA-Seq及其在大鼠中的投影（使用跨反性病毒）在大鼠中 在基于社会的自愿或强迫戒酒之后，孵化的测试。此外。我们将解释 来自大脑每个大脑区域中转录组细胞类型的详细本体论中的转录组数据 主动性细胞人口普查网络，以及人类杏仁核的SnRNA-seq 艾滋病毒（Scorch）中单细胞阿片类药物反应的阿片类药物使用障碍的供体 财团。在AIM 2中，我们将使用逆行腺相关病毒来标记CEA投影神经元核 并将转录组数据与来自大联盟的完整转录组数据集集成在一起。目标 3，我们将将我们翻译相关的社会选择动物模型与先进的Crispra结合在一起 CRISPRI AAV工具可操纵CEA或投影区域中关键集线器基因的转录 展示了他们在基于社会的海洛因渴望保护方面的因果作用。我们的建议将提供新的 对基因组分析及其机制的洞察力及其在社会奖励对海洛因的保护作用的基础 渴望以一种新型的基于社交的大鼠模型。这些结果将提高我们对角色的机械理解 Ouds中的社交互动。