Social Novelty Recruits a Dysfunctional Nucleus Accumbens Ensemble That Drives Social Avoidance in a Shank3-/- Autism Model
Social behavior deficits are a common symptom of neuropsychiatric disorders, including autism spectrum disorder (ASD), but there are limited pharmacological treatments for these symptoms. Understanding how neurons encode social information will give insight into identifying novel pharmacological targets to address this unmet need. SHANK3 encodes a postsynaptic scaffold protein and is a common risk gene for several neuropsychiatric disorders characterized by social deficits, including ASD. Our lab previously developed the Shank3{Delta}e4-22 mouse model, which shows a loss of social preference and altered connectivity in the nucleus accumbens (NAc), a critical region for social behaviors. However, it remains unknown how Shank3 deletion alters the encoding of social cues in the NAc. To address this gap in knowledge, we characterized the function of neurons activated by social interaction, or social ensembles, in WT and Shank3{Delta}e4-22 mice using a combination of genetic capture techniques, chemogenetics, optogenetics, and one-photon calcium imaging. We show that NAc social ensembles of WTs and Shank3{Delta}e4-22 mice drive opposing social behaviors: while NAc social ensembles encode appetitive social cues in WT mice, they encode avoidance in Shank3{Delta}e4-22 mice. We further find that, in Shank3{Delta}e4-22 mice, NAc neurons are hyperactive and have hypermodulatory responses to social novelty. Suppressing the activity of social ensembles during social novelty prevents future social avoidance and restores social investigation in Shank3{Delta}e4-22 mice. Taken together, our data show that Shank3{Delta}e4-22 mice have an enhanced NAc response to social novelty that actively drives social aversion, rather than a loss of social motivation.