Neural activity-based candidate gene identification to link eating disorders and drug addiction

PROJECT SUMMARY Binge-eating disorder (BED) and bulimia nervosa (BN) are potentially life-threatening eating disorders that share behavioral and brain similarities, genetic risk factors and higher-than-expected comorbidities with drug addiction – suggesting a common etiology. However, no mechanistic study has examined this possibility due in part to the lack of an animal model linking eating disorders and drug addiction. Like drug craving and use in drug addiction, food craving and eating in BED/BN persist despite adverse consequences (punishment). Our pilot data from rats indicate that extensive cocaine and alcohol histories, known to trigger addiction-like brain changes and punishment-resistant “compulsive” drug intake in rats, trigger punishment-resistant food intake or “compulsive appetite”. These results provide an animal model for studying the neurobiological mechanisms manifesting as compulsive behavior across eating disorders and drug addiction. Food motivation is thought to be regulated by both homeostatic (caloric) and non-homeostatic (hedonic/incentive) systems. The homeostatic system detects energy shortages and elicits food intake. However, like compulsive drug motivation, our data suggest that compulsive appetite is driven by non-homeostatic “motivational/habitual” dysregulation. Like cocaine and alcohol histories, obesogenic diet histories also led to compulsive appetite via non-homeostatic dysregulation. Thus, drug/diet-induced changes in brain sites that control non-homeostatic regulation, such as reward circuits, likely cause compulsive appetite. We previously found that appetitive behavior is, in part, controlled by ‘food-reactive’ neurons (as indicated by the activation marker Fos) in the infralimbic cortex (IL) – a part of reward circuits thought to regulate drug and food motivation independently of energy homeostasis; these neurons thus appear to function as “accelerators” for non-homeostatic appetite regulation. We have also found that extensive drug histories increase neural food-reactivities in IL and other brain sites within reward circuits while inducing gene expression changes linked to aberrant neural plasticity and addiction preferentially in food-reactive – rather than non-reactive – neurons. Such brain changes would entail more “acceleration” on food motivation via non-homeostatic dysregulation, thereby likely manifesting as compulsive appetite. Based on the rigor of previous research and premise above, this project will test the central hypothesis that extensive cocaine/alcohol/obesogenic diet histories induce compulsive appetite via gene expression changes unique to food-reactive neurons in the reward circuits. The reward circuits contain neurons selectively reactive to each specific behaviorally relevant stimuli – likely exerting different behavioral functions. We will thus utilize neural activity-specific gene expression profiling (Aim 1) and rescuing (Aim 2) to target food-reactive neurons. The expected results will determine genes expression changes functionally linked to compulsive appetite. Such knowledge may help identify novel therapeutic targets to counter compulsive behavior across eating disorders and drug addiction.