Strain-Dependent Network Activity Differences Underlie Social Decision-Making in Male Mice

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, with mPFC activity positively correlating with selfish choices. 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 exhibited distinct prefrontal-subcortical network configurations during social decision-making. Together, these findings identify distributed cortical-subcortical network dynamics underlying social choice bias and suggest that differences in the neural architecture associated with prosocial and selfish behavior are influenced by strain in male mice.