ABSTRACT Loss of control (LOC) eating, the sense of being unable to control one’s intake, is a hallmark of binge eating and a defining, causal antecedent of binge-type eating disorders 1,2. LOC eating also predicts anxiety disorders and depression and, as a core symptom of food addiction is seen in millions of overweight individuals 8,12,17-21. Clinically, the severity of LOC eating predicts more eating disorder pathology and emotion dysregulation; impulsivity and impaired inhibitory control; and less weight loss post-bariatric surgery 22-30. LOC predicts these measures independent from and more effectively than does the amount eaten 28,31-41 and foretells weight gain and metabolic syndrome risk 1,2,29,45-51. Recent psychometric finding also suggest that behavioral signs of LOC correlate more with eating disorder pathology and binge eating than do cognitive or affective LOC criteria 43. We thus developed a novel model of LOC eating in which rats with intermittent, extended access to palatable food show hallmarks of behavioral LOC in human scales, including increased food-directed effort and intake despite negative consequences, In the present application we will develop the model further to obtain additional, translationally-relevant measures of behavioral LOC (Aim 1). We also will use a sensitive, specific AAV E-SARE to enable neuronal activity-dependent targeted recombination in active populations (TRAP) (Aim 2) in order to dissect a recently identified anterior insula neuronal ensemble implicated in LOC-like eating. The studies will inform the role of intermittent, extended access in the etiology and modeling of behavioral LOC for translational studies. They also will identify the LOC-associated ensemble’s location, molecular markers and causal role. Finally, by leveraging ensemble translatome results with UK Biobank gene association data, the project may identify novel therapeutic targets for LOC eating.

NARRATIVE This multidisciplinary project involves a team of expert collaborators who will further develop a novel animal model to identify a neuronal ensemble in the anterior insula implicated in the behavioral loss of control over eating. Guided by preliminary data, we will use targeted recombination in active populations (TRAP) to find the ensemble’s location, use ribosomal profiling to identify associated gene expression differences, and use somatic optoinhibition to test the ensemble’s causal role. The work will advance understanding of the anterior insula’s role in loss of control eating, identify novel translatome targets, and extend a clinically-informed model of loss of control eating that is relevant to binge-type eating disorders.