Magel2-null mice demonstrate contradictory outcomes in body weight, impulsivity, and motivation during distinct fasted states.

Prader- Willi Syndrome (PWS) is a complex neuroendocrine disorder that presents with hyperphagia, obesity, and social and cognitive impairment. The cognitive impairment is comparatively under-researched in PWS and in the Magel2-null mouse model. Cognitive function is commonly trained and tested in mice after the manipulation of metabolic state to induce motivation, yet physiologic function in the Magel2-null mouse model is most commonly assessed in the fed state. This project evaluates Magel2-null mouse physiology in ad libitum, acute fast, and chronic restriction settings to establish a baseline prior to examining cognitive function in operant conditioning paradigms. As in prior work, when maintained on ad lib diet or fasted acutely overnight, there is no difference in food intake or body weight between the null and control mice. However, in the context of chronic restriction, the Magel2-null mice are resistant to weight loss and maintain elevated fat stores. In this state of chronic restriction, Magel2-null mice demonstrate a latency to form initial cue associations, reduced motivation to perform an operant task, and a preference for low effort responses. This decreased motivation and preference for low-effort responses suggest Magel2-null mice undervalue food rewards compared to littermate controls, likely due to their altered fat storage and corresponding metabolic state. Together this data shows that the Magel2-null mouse is a useful model for assessing cognitive function relative to metabolic physiologic changes that may be helpful to further understanding and treating the constellation of symptoms in people with PWS.