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

Boston University Medical Campus, Boston MA

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Abstract

? 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.