Behavioral approaches to probe value-based choice in genetic mouse models for neuropsychiatric disease

Goal-directed behaviors are interrelated neural functions that organize animal behavior with respect to the surrounding environment. In humans, abnormalities in goal-directed function greatly impair situational adaptability... [ view full abstract ]

Goal-directed behaviors are interrelated neural functions that organize animal behavior with respect to the surrounding environment. In humans, abnormalities in goal-directed function greatly impair situational adaptability and are frequently associated with neuropsychiatric disease. Mice, by virtue of numerous genetic tools, provide a unique opportunity to explore the molecular underpinnings of core neural circuits mediating goal-directed dysfunction. Towards this end, we generated dynamic operant foraging tasks that assess the selection of actions according to relative benefits and costs. We have modeled benefit as varying volumes of liquid reward and cost as increasing operant response schedules. After demonstrating that wildtype mice sensitively respond to both parameters, we explored how disease-associated mutations in the Neurexin1α synaptic adhesion molecule might compromise this function. Neurexin1α has a central role in organizing central synapses and is a significant genetic risk factor for schizophrenia, autism spectrum disorder and Tourette’s syndrome. We find that Neurexin1α mutant mice can acquire operant responding similarly to wildtype mice and exhibit normal flexibility during un-cued contingency changes. However, Neurexin1α mutants exhibit robust deficits in value-based choice. Specifically, mutant mice show significantly less bias towards higher benefit (larger reward volume) choices than wildtypes while also showing less bias towards lower effort (shorter operant schedule) choices. Furthermore, we observed blunted local modulation of response vigor by recent outcome in mutants. Overall, these data are consistent with perturbations either of neural systems for value representation or action selection according to outcome value, a focus of our ongoing work.