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

暴食的遗传基础及其在降低复杂性交叉中的动机成分

基本信息

批准号：
8969230
负责人：
CAMRON D BRYANT
金额：
$ 25.92万
依托单位：
BOSTON UNIVERSITY MEDICAL CAMPUS
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-15 至 2017-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8969230
关键词：
Amygdaloid structure Animal Model Anxiety Architecture Area Behavior Behavioral Behavioral Paradigm Binge Eating Brain Brain region Candidate Disease Gene Chromosome Mapping Collaborations Complex Congenic Mice Consumption Corpus striatum structure Data Development Disease Eating Eating Disorders Emotional Environment Exhibits Food Future Gene Expression Gene Expression Profile Gene Expression Profiling Genes Genetic Genetic Variation Genetic study Genomic Segment Genomics Glutamates Health Human Inbreeding Laboratories Lead Letters Link Maps Measures Mediating Messenger RNA Methamphetamine Midbrain structure Modeling Molecular Molecular Target Moods Mus Neurobiology Neuronal Plasticity Nucleotides Pathway interactions Predisposition Prevention Procedures Property Quantitative Trait Loci Reporting Resistance Rewards Risk Sampling Signal Transduction Substance Use Disorder Substance abuse problem Therapeutic Time Tissue-Specific Gene Expression Training Variant anxiety-like behavior base clinically relevant cost differential expression dopaminergic neuron experience frontal lobe genome editing innovation insight mortality nervous system development neurobiological mechanism neuron development neuropsychiatry noradrenergic novel preference prevent public health relevance resilience tool trait transcriptome sequencing treatment strategy

项目摘要

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.

描述（由适用提供）：暴饮暴食是饮食失调的可遗传特征，对健康和疾病的身体和情感成本高。它是由不受控制的，过量消耗大量可口食品的时间来定义的。暴饮暴食潜力是强大的遗传成分，并与情绪，焦虑和滥用药物疾病合并。该提案的主要目的是确定有助于贝格样饮食及其动机成分的新型遗传因素。与Pietro Cottone博士合作，我们开发了一种完整的模型和Benge饮食的条件奖励性能，在该模型中，杂种小鼠在食用可口食品时表现出了9倍升级，与可口的可口食品食品面积食品偏爱的程度密切相关。此外，我们观察到易于焦虑的C57BL/6NJ菌株中明显的Benge进食和条件奖励，但在密切相关的C57BL/6J基质中没有。由于父母的底物几乎在遗传上是相同的，因此在实验F2交叉中（降低的复杂性交叉； RCC）中的定量性状基因座（QTL）映射将极大地支持新的遗传因素的鉴定。这是行为差异的基础。在AIM 1中，我们将使用RCC来绘制不幸的与易感性相对于暴饮暴食，条件食物奖励和类似动画的行为相关的基因组区域或QTL。 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 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父母C57BL/6J和C57BL/6NJ基质。对照小鼠中的病前转录组将成为有用的工具，既可以识别未来基因组编辑的候选基因，并且表达的基础是拟议的研究将导致鉴定出影响风险的新型遗传因素，从而影响风险与暴饮暴食的抵抗力。由于升级的PF消耗而表达的不同表达的基因将揭示与神经可塑性相关的转录组和支持暴饮暴食的动机动机行为的变化。吃。此外，结合遗传和转录组分析可能会导致鉴定出新的下游分子靶标的药物治疗性发育。