Mouse strain and network-level activity differences underlie social decision-making.

Adaptive social behavior requires balancing self-interest with the welfare of others, a core axiom of social decision-making that determines whether actions are selfish or prosocial. Although the medial prefrontal cortex (mPFC) has been implicated in prosocial behavior, the broader cortical-subcortical networks that arbitrate between selfish and prosocial actions remain poorly understood. Moreover, most studies of social decision-making (at both the single-region and circuit levels) have focused on inbred C57BL/6 mice, leaving unclear whether similar neural mechanisms operate across genetically diverse populations. Here, we combined a social decision-making task with c-Fos mapping to examine activity across distributed cortical and subcortical regions in inbred C57BL/6 and outbred CD1 male mice during prosocial and selfish choices. We found that CD1 mice exhibited a stronger bias toward selfish behavior, whereas C57BL/6 mice were more prosocial. This behavioral divergence was associated with elevated c-Fos activity in the mPFC and nucleus accumbens core (NAcC) in CD1 mice compared with C57BL/6 mice, and mPFC activity positively correlated with selfish choice bias. At the network level, social decision-making selectively recruited coordinated activity among the distinct mPFC subregions, ventral tegmental area (VTA), and NAcC. Importantly, prosocial and selfish individuals recruited distinct prefrontal-subcortical network configurations during social decision-making. Together, these findings identify distributed cortical-subcortical network dynamics underlying social choice bias and reveal strain-dependent differences in the neural architecture supporting prosocial and selfish behavior. Significant statement: Social decisions require weighing personal benefit against the welfare of others, yet the neural circuits that bias individuals toward selfish versus prosocial choices remain poorly understood. Here, we show that two mouse strains with opposing social preferences recruit distinct cortical and subcortical network configurations during social choice, despite performing the same task. Rather than reflecting differences in single brain regions, social decision-making engaged coordinated activity across a prefrontal-striatal-midbrain circuit, with prosocial and selfish individuals recruiting different versions of this network. These findings reveal that social choice bias is encoded at the level of distributed circuit organization and that genetic background shapes how the brain implements social decisions.