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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要当前的阿片类药物危机是一个重大的公共卫生问题，尽管有食品和药物的供应，但它仍然持续存在药物管理局批准的治疗（美沙酮、丁丙诺啡和纳曲酮）是一个关键的挑战。接受治疗的患者出现复发或复发，特别是考虑到复发会带来用药过量的风险。因此，推进新的替代干预措施的需求尚未得到满足，这些干预措施可以克服现有技术的局限性。目前针对阿片类药物使用障碍（OUD）的可用治疗方案成功率有限。 OUD 的治疗是复杂且多因素的，一个潜在的限制可归因于经典治疗。我们最近开发了一种很少包含社会因素的 OUD 动物模型。海洛因和社交互动之间的选择表明：（1）老鼠强烈喜欢操作性社交互动对海洛因的依赖，以及 (2) 社会选择引起的戒断（自愿戒断）可防止长期寻求海洛因（在药物渴望模型中）介导社会保护作用的遗传和回路机制。对海洛因渴望的奖励尚不清楚该提案的首要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作用我们将重点关注中央核心。杏仁核 (CeA) 及其预测基于我们对 CeA 在孵化中的作用的发现社会选择引起的自愿戒断后对精神兴奋剂的渴望及其在其中的作用的先前研究在目标 1 中，我们将生成单一的药物渴望。来自 CeA 的细胞核 RNA-seq 及其预测（使用顺行跨突触病毒）此外，我们还将解释基于社会的自愿或强制禁欲后的孵化测试。来自 BRAIN 的每个大脑区域的转录组细胞类型详细本体中的转录组数据主动细胞普查网络，以及死后杏仁核和人类胰岛素的 snRNA-seq HIV 背景下单细胞阿片类药物反应 (SCORCH) 中患有阿片类药物使用障碍的捐赠者在目标 2 中，我们将使用逆行腺相关病毒来标记 CeA 投射神经元核。并将转录组数据与来自大型联盟的互补转录组数据集整合。 3、我们将把我们的翻译相关社会选择动物模型与先进的 CRISPRa 结合起来 CRISPRi AAV 工具可操纵 CeA 或投影区域中关键中心基因的转录证明它们对基于社会的海洛因渴望保护的因果作用我们的提案将提供新的内容。深入了解基因组分析及其社会奖励对海洛因保护作用的机制这些结果将提高我们对该角色的机械理解。 OUD 中的社交互动。