A MOTIVATION-BASED DIATHESIS-STRESS MODEL OF ANOREXIA-NERVOSA IN MICE

Exercise hypermotivation, an endophenotype of restricted anorexia nervosa (RAN) in female adolescents, accompanies - when it does not precede - feeding hypomotivation. Although RAN is the most lethal psychiatric disease, its neurobiological bases are still unknown due to the lack of animal models with translational value. Indeed, the most documented model of RAN, namely the activity-based anorexia (ABA) model, lacks face validity owing to (i) the use of free exercise (i.e. wheel-running) performance as a proxy for exercise motivation, and (ii) external, rather than self-imposed, food limitation. Moreover, the etiological bases of RAN, which include genetics and prior trauma, are often discarded. To answer these limits, we used females from different mouse lines which were exposed to chronic stress before living in operant chambers. Therein, mice had conditioned access to a standard food diet and a running wheel under fixed ratio (FR) reinforcement schedules which increased from FR1 to FR30. Stressed BALB/c females were the most anxious whilst displaying the highest motivation for exercise. When required to perform low efforts for exercise but high efforts for feeding (as for RAN patients), BALB/c females prioritized exercise over feeding despite body weight losses. When acutely tested for exercise motivation, as assessed under progressive ratio reinforcement schedules, or for exercise craving, as modelled by conditioned reinstatement following an extinction period, female BALB/c mice were not the best performers. By means of a paradigm with high translational value, this innovative study paves the way for the identification of the neurobiological bases of RAN.