Neural circuitry underlying pathological body weight loss in a rat model of anorexia nervosa

Anorexia Nervosa (AN) has a mortality rate 12 times higher than the annual death rate from all causes in females aged 15 to 24. Currently, there is no effective treatment for AN, which is exacerbated by a reticence to appreciate the neurobiological contribution to the disorder. Despite this, brain imaging studies in AN patients reveal an imbalance between neural activity in regions associated with reward and cognition. The challenge in understanding the causes of AN is to take these observations made in humans and rigorously dissect what underlies them in experimental animal models, where brain circuits can be perturbed and anorexic behaviour can be interrogated. The most well-accepted animal model of AN, known as activity-based anorexia (ABA), exploits the innate motivation of laboratory rodents to run in wheels. When rats with access to running wheels are placed on a restricted feeding schedule, there is a paradoxical increase in running activity despite substantially decreased caloric intake, causing a profound reduction in body weight. The focus of this project is on manipulating brain circuits in the ABA model with a view to rescuing animals from debilitating weight loss. We utilise light- and drug-based approaches (known as optogenetics and chemogenetics) to selectively alter the activity of neural pathways in rats exposed to the ABA paradigm. Our recent studies confirm that both ventral reward and prefrontal cognitive circuits impact respectively on food intake and excessive exercise, both essential components of pathological body weight loss in the rat model and the human condition. The intention is to extend these discoveries toward a comprehensive framework of emotional and other cognitive brain pathways that control reward and hunger in ABA and ultimately AN. As with all studies using rodent models of human conditions, the goal is to uncover some aspect of brain function that is not only essential to the development of anorexia nervosa but also modifiable. Any such discovery would have a profound impact on the development of novel treatment strategies for a disorder that responds poorly to available therapeutics.