Motivation for starvation: understanding the neurobiology of anorexia nervosa

Anorexia nervosa (AN) has the highest mortality rate of any psychiatric disorder - 12 times higher than the death rate from all other causes in females aged 15-24. Despite this, there is currently no effective medicinal treatment for AN. Although brain-imaging studies have demonstrated specific disruptions in brain function in AN, this has not led to improvements in treatment because functional imaging studies are not able to reveal the biological mechanisms necessary for drug development. The challenge in understanding the neurobiological causes of AN is to take 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. A prevailing neurobiological hypothesis that may underpin the extreme behaviours seen in AN patients and is supported by experiment using the ABA rat model, involves an imbalance between reduced ventral reward signalling on the one hand and powerful inhibitory influences from the prefrontal cortex on the other. This project will investigate the neurochemical bases of this imbalance using techniques to manipulate and record from anatomically defined neural circuits (including chemogenetics, optogenetics and fiber photometry). In combination with cognitive testing using touchscreens and traditional behavioural testing, this study will provide a comprehensive framework of reward-processing and cognition that controls hunger and rapid weight loss 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.