USING THE MICECRAFT SYSTEM TO STUDY SOCIAL MOTIVATION, COGNITION AND NEURONAL ACTIVITY IN AUTISM MOUSE MODELS

Autism is a neurodevelopmental condition characterized by atypical social interaction and communication, repetitive behaviors, and restricted interests. Genetic variations affecting SHANK (SH3 and multiple ankyrin repeat domains protein) synaptic scaffolding proteins are strongly associated with autism. While Shank2 and Shank3 knock-out (KO) mice robustly display hyper- and hypo-activity, respectively, their cognitive and social phenotypes remain less clear. Using the MiceCraft system, we developed a fully automated behavioral paradigm to assess social preference and motivation versus a palatable reward, along with instrumental and reversal learning. In this task, mice freely choose between two compartments providing access either to a social stimulus (conspecifics) or to a sucrose reward. Access to each compartment requires an operant nose-poke response to open the MiceCraft gate, with task difficulty progressively increasing across successive phases. Transitions between phases are automatically triggered based on individual performance, allowing continuous assessment over 48 hours. Using this paradigm, Shank2 KO mice display reduced social interaction and motivation compared to wild-type (WT) littermates, with mild cognitive impairments. In contrast, most Shank3 KO mice fail to complete the task, without showing social deficits compared to WT mice. Next, this setup was combined with fiber photometry to monitor neuronal activity in the nucleus accumbens during the task. Recordings were triggered by their entry in social and sucrose compartments. Altogether, this approach allows long-term assessment of social behaviors and cognition compatible with functional neuronal recordings in a complex environment, providing a tool to investigate motivational and cognitive differences in autism-related mouse models.