Anterior cingulate input tunes striatal dynamics for context-dependent social preference in a mouse model of autism

Social preference in autism spectrum disorder varies across contexts, but the underlying neural mechanisms remain unclear. Here we show that Shank3 knockout (KO) mice, an autism mouse model, exhibit reduced preference for social over nonsocial stimuli while retaining a preference for females over males. Calcium imaging reveals context-dependent differences between KO and wild-type (WT) mice in the organization of neuronal population dynamics in the dorsomedial striatum (DMS), corresponding to their behavioural preferences. Functional imaging and molecular analyses reveal reduced functional connectivity between the anterior cingulate cortex (ACC) and DMS and molecular alterations more pronounced in the striatal matrix. ACC inhibition eliminates genotype-dependent differences in DMS dynamics. Inhibiting the ACC–DMS pathway impairs social preference, whereas its activation in KO mice shifts DMS dynamics towards WT patterns and improves social preference. These findings identify a cortical pathway that shapes striatal population dynamics and context-dependent social preference in an autism mouse model. The mechanisms underlying social behavioural deficits in mouse models of autism are not fully understood. Here the authors link neural embedding geometry to context-dependent social deficits in the Shank3 knockout mouse.