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遗传特征，对健康和疾病造成很高的身体和情感代价。它的定义是在短时间内不受控制地过度食用大量可口的食物。暴饮暴食具有很强的遗传成分，并与情绪，焦虑和物质滥用障碍共病。这项计划的主要目的是确定新的遗传因素，有助于暴食及其动机成分的小鼠。与Pietro Cottone博士合作，我们开发了一个暴饮暴食的消费性和条件性奖励特性的模型，其中远系繁殖的小鼠在可口食物的消费方面表现出九倍的增长，这与可口食物配对环境的条件性位置偏好程度密切相关。此外，我们观察到明显的暴饮暴食和条件奖励的焦虑倾向的C57 BL/6 NJ株，但没有在密切相关的C57 BL/6 J亚株。由于亲本亚系在遗传上几乎相同，在实验F2杂交（简化复杂性杂交; RCC）中进行数量性状位点（QTL）定位将极大地促进新遗传因子的鉴定 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、条件性食物奖励和焦虑样行为的易感性与恢复力之间存在因果关系。我们假设共享的QTL将影响暴食的完成和食欲动机方面，并且QTL的子集将有助于病前焦虑样行为，这反过来又增加了暴食的风险。在目标2中，我们将通过mRNA测序（RNA-seq）对对照小鼠和来自亲本C57 BL/6 J和C57 BL/6 NJ亚系的适口食物训练小鼠的中皮质边缘脑区和杏仁核进行转录组分析。对照小鼠发病前的转录组将作为一个有用的工具，用于识别未来基因组编辑的候选基因，这些基因差异表达并构成行为QTL的基础，以及提供对神经生物学背景的基因组洞察，这些神经生物学背景影响对暴饮暴食的易感性与恢复力。作为PF消耗量增加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。拟议的研究将导致识别影响暴饮暴食风险与恢复力的新遗传因素。此外，结合遗传学和转录组分析可能会导致新的下游分子靶点的药物开发的识别。

 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.