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 目前的阿片类药物危机是一个重大的公共卫生问题，尽管有食物和药物供应，但这种情况依然存在。 药品监督管理局批准的治疗方法(美沙酮、丁丙诺啡和纳曲酮)。一个关键的挑战是 在接受治疗的患者中出现失误或复发，特别是考虑到复发有过量服药的风险。 因此，有一种尚未得到满足的需求，即提出可能克服以下限制的新的替代干预措施 目前可用于阿片类药物使用障碍(OUD)的治疗选择。成功有限的原因是 OUD的治疗是复杂的和多因素的。一个潜在的限制可以归因于古典 OUDS的动物模型，很少纳入社会因素。我们最近开发了一种可操作的大鼠模型 在海洛因和社会交往之间的选择表明：(1)大鼠更喜欢操作性社会交往 而不是海洛因，以及(2)社会选择诱导的禁欲(自愿禁欲)会随着时间的推移阻止海洛因的寻找 (在一种药物渴望的模型中)。社会保护作用的遗传和环路机制 对海洛因渴求的奖励是未知的。这项建议的首要目标是研究基因组图谱 有助于社会互动对海洛因渴求的缓冲作用。我们将重点关注中央核 杏仁核(CEA)及其投射基于我们对CEA在孵化 社会选择后心理刺激渴求诱导的自愿戒断及其作用的研究进展 跨药物类别强制戒毒后潜伏的药物渴求。在目标1中，我们将生成单个- 大鼠胚胎癌胚抗原核糖核酸序列及其投射(顺行跨突触病毒) 在基于社会的自愿或强制禁欲后的孵化测试。另外。我们将解读 大脑每个区域的转录细胞类型的详细本体中的转录数据 主动细胞普查网络以及人死后杏仁核和岛叶的SnRNA-seq 艾滋病毒背景下单细胞阿片类药物反应所致的阿片类药物使用障碍捐献者(SCOCH) 财团。在目标2中，我们将使用腺相关逆行病毒来标记CEA投射神经元核。 并将转录数据与来自大联盟的互补转录数据集相结合。在AIM 3，我们将把我们的翻译相关的社会选择动物模型与先进的CRISPRA和 CRISPRi AAV工具可操作CEA或投影区中关键HUB基因的转录，以 展示其在以社会为基础的海洛因渴求保护方面的因果作用。我们的提案将提供新的 社会奖励对海洛因保护作用的基因组图谱及其机制研究 渴望一种新的基于社交的老鼠模型。这些结果将提高我们对角色的机械性理解 在ODS中的社交互动。