Genetic basis of binge eating and its motivational components in a reduced complexity cross

 描述(由申请人提供)：暴饮暴食是饮食失调的一种可遗传特征，会给健康和疾病带来高昂的身体和情感代价。它的定义是在短时间内不受控制地过度食用大量美味食物。暴饮暴食具有很强的遗传成分，并与情绪、焦虑和药物滥用障碍并存。这项建议的主要目标是确定导致小鼠暴饮暴食的新的遗传因素及其激励成分。在与皮埃特罗·科托内博士的合作下，我们开发了一个暴饮暴食的消耗性和条件性奖励特性的模型，在该模型中，异种小鼠的可口食物消耗量增加了9倍，这与对可口食物配对环境的条件化地点偏好程度密切相关。此外，我们在易焦虑的C57BL/6NJ株中观察到明显的暴食和条件性奖赏，但在密切相关的C57BL/6J亚株中没有观察到。由于亲本亚系在遗传上几乎相同，在实验F2杂交(降低复杂性杂交；RCC)中进行数量性状基因座(QTL)定位将极大地促进新遗传因素的识别 这是行为差异的基础。在目标1中，我们将使用RCC来绘制基因组区域或QTL，这些区域与暴饮暴食、条件化食物奖励和类焦虑行为的易感性和韧性之间存在因果关系。我们假设，共享的QTL将影响暴饮暴食的消耗性和食欲动机方面，并且QTL的子集将有助于病前焦虑样行为，这反过来又增加暴饮暴食的风险。在目标2中，我们将通过对C57BL/6J和C57BL/6NJ亚株的对照小鼠和可口食物训练小鼠的中皮质边缘脑区和杏仁核的mRNA测序(RNA-seq)进行转录组分析。对照组小鼠的病前转录组将成为一个有用的工具，既可以为未来的基因组编辑识别差异表达的候选基因，也可以为行为QTL提供基因组学洞察，了解影响暴食易感性和韧性的神经生物学背景。作为PF消费升级的结果而差异表达的基因将揭示与神经可塑性和支持暴饮暴食的食欲动机行为相关的转录组的变化。拟议中的研究将导致确定影响暴饮暴食风险和韧性的新遗传因素。此外，结合遗传和转录组分析可以为药物治疗开发识别新的下游分子靶点。

 DESCRIPTION (provided by applicant): Binge eating is a heritable trait of eating disorders that carries high physical and emotional costs on health and disease. It is defined by the uncontrolled, excessive consumption of a large amount of palatable food over a short period of time. Binge eating possesses a strong genetic component and is comorbid with mood, anxiety, and substance abuse disorders. The primary objective of this proposal is to identify novel genetic factors that contribute to binge-like eating and its motivational components in mice. In collaboration with Dr. Pietro Cottone, we developed a model of the consummatory and the conditioned rewarding properties of binge eating whereby outbred mice exhibited a nine-fold escalation in the consumption of palatable food that was tightly correlated with the degree of conditioned place preference for the palatable food-paired environment. Additionally, we observed pronounced binge eating and conditioned reward in the anxiety-prone C57BL/6NJ strain but not in the closely related C57BL/6J substrain. Because the parental substrains are nearly genetically identical, quantitative trait locus (QTL) mapping in an experimental F2 cross (Reduced Complexity Cross; RCC) will greatly facilitate the identification of novel genetic factors that underlie differences in behavior. In Aim 1, we will use the RCC to map genomic regions, or QTLs, that are causally associated with susceptibility versus resilience to binge eating, conditioned food reward, and anxiety-like behavior. We hypothesize that shared QTLs will influence the consummatory and appetitive-motivational aspects of binge-like eating and that a subset of QTLs will contribute to premorbid anxiety-like behavior which in turn, increases the risk for binge eating. In Aim 2, we will conduct transcriptome analysis via mRNA sequencing (RNA-seq) of mesocorticolimbic brain regions and the amygdala in control mice and palatable food-trained mice from the parental C57BL/6J and C57BL/6NJ substrains. The premorbid transcriptome in control mice will serve as a useful tool both in identifying candidate genes for future genome editing that are differentially expressed and underlie the behavioral QTLs as well as providing genomic insight into the neurobiological context that influences susceptibility versus resilience to binge eating. Genes that are differentially expressed as a consequence of escalated PF consumption will reveal changes in the transcriptome relevant to neural plasticity and the appetitive-motivational behaviors that support binge eating. The proposed studies will lead to the identification of novel genetic factors influencing risk versus resilience to binge eating. Furthermore, combining genetic and transcriptome analysis could lead to the identification of new downstream molecular targets for pharmacotherapeutic development.