Discovery of genetic and genomic mechanisms driving the relationship between social reward and cocaine addiction

项目摘要 吸毒成瘾是一种严重的公共健康危机，它强烈地受到基因的驱动。人类的根本驱动力 上瘾是一种反复选择以牺牲社会奖励为代价来追求毒品奖励的行为，这是一种强有力的强化 非成瘾个体的人类行为。尽管这一现象在人类中很重要 成瘾--对社会奖赏而不是药物偏好发生变化的遗传机制 奖励(此后的社会奖励偏好)完全没有被探索，因为 相应的小鼠模型。建立一个社会奖励偏好的老鼠模型将能够利用 大量的小鼠遗传学工具包，用于发现和描述驱动这一特征的机制，在其 极端情况下，代表对关键成瘾媒介的脆弱性和抵抗力。为此，我们建议 利用先进的老鼠种群前所未有的遗传多样性和特殊的结构- 静脉注射可卡因自我给药范例在发现遗传和基因组机制方面的有效性 推动社会奖励偏好。为了量化鼠标中的社会奖励偏好，我们将使用最近的 为大鼠引入的范式，在该范式中，受试者做出二元选择：(1)静脉自我给药 使人上瘾的药物或(2)与同种药物短暂地相互作用。捕捉最大的表型变异和 为了能够发现驱动社会奖励偏好的遗传机制，我们将使用来自 协作杂交(CC)小鼠小组，包含90%的小鼠物种和 实现跨研究的基因组和表现学数据集的集成。在目标1中，我们将量化 八种CC品系雄性和雌性小鼠对社会奖励相对于可卡因奖励的偏好。我们会 量化这些表型的遗传力，并确定表现出对社会的脆弱性和抵抗性的菌株 奖励偏好表型(例如，相对于社会奖励，对可卡因奖励的强烈偏好，以及 反之亦然)。在目标2中，我们将量化基因在伏隔核中的表达 对社会奖励的管理，对社会奖励的束缚暴露，以及对社会奖励的虚假暴露 我们将对8个CC菌株进行RNA-seq和scRNA-seq 两株极端CC菌株的SEQ。我们将整合基因表达数据(目标2)和行为数据(目标1)，以 识别预测社会奖励偏好的细胞类型特定基因表达特征。成功者 这些目标的完成将为今后深入描述已确定的机制奠定基础 小鼠潜在的社会奖励偏好；(2)使遗传相关的持久社区资源 跨表型、实验和实验室对CC菌株的子集进行分析；以及(3)精制的 以及强大的管道，用于未来在整个60个CC菌株小组中表征社会奖励偏好。 最终，这项工作将有助于开发新的、更有效的成瘾治疗方法。

PROJECT ABSTRACT Drug addiction is a critical public health crisis that is strongly genetically driven. A fundamental driver of human addiction is the repeated choice to pursue a drug reward at the expense of a social reward, a strong reinforcer of human behavior in non-addicted individuals. Despite the importance of this phenomenon in human addiction, the genetic mechanisms underlying variation in the preference for a social reward over a drug reward (henceforth social reward preference) have been totally unexplored because of the absence of a relevant mouse model. Establishing a mouse model of social reward preference would enable leveraging the vast mouse genetics toolkit for discovery and characterization of the mechanisms driving this trait, which, at its extremes, represents vulnerability to and resistance to a key addiction vector. To this end, we propose to harness the unprecedented genetic diversity of advanced mouse populations and the exceptional construct- validity of the intravenous cocaine self-administration paradigm to discover genetic and genomic mechanisms driving social reward preference. To quantify social reward preference in the mouse, we will use a recently introduced paradigm for the rat in which the subject makes a binary choice to (1) intravenously self-administer an addictive drug or (2) briefly interact with a conspecific. To capture maximum phenotypic variation and enable discovery of genetic mechanisms driving social reward preference, we will use mice from the Collaborative Cross (CC) mouse panel which contains 90% of the genetic diversity in the mouse species and enables the integration of genomic and phenomic datasets across studies. In Aim 1 we will quantify the preference for social reward relative to cocaine reward in male and female mice from eight CC strains. We will quantify heritability of these phenotypes and identify strains exhibiting vulnerability and resistance to social reward preference phenotypes (e.g., strong preference for a cocaine reward relative to a social reward, and vice versa). In Aim 2 we will quantify gene expression in the nucleus accumbens following operant self- administration of a social reward, yoked exposure to a social reward, and sham exposure to a social reward in mice from the same eight CC strains used in Aim 1. We will perform RNA-seq in eight CC strains and scRNA- seq in two extreme CC strains. We will integrate gene expression data (Aim 2) with behavioral data (Aim 1) to identify cell-type specific gene expression signatures predictive of social reward preference. The successful completion of these aims will provide (1) a foundation for future deep characterization of identified mechanisms underlying social reward preference in mice; (2) a lasting community resource enabling genetic correlational analysis among a subset of the CC strains across phenotypes, experiments, and laboratories; and (3) a refined and robust pipeline for future characterization of social reward preference in the full panel of 60 CC strains. Ultimately, this work will contribute to the development of novel, more effective addiction treatments.