Mixed genetic background better recapitulates developmental and psychiatric phenotypes and heterogeneity than inbred C57BL/6J mice.

Preclinical models of neurodevelopmental and psychiatric conditions often rely on inbred mouse strains like C57BL/6J (B6), which exhibit limited genetic and behavioral variability. This limitation hampers the modeling of phenotypic heterogeneity, characteristic of these conditions. Recent efforts have explored the use of multiple genetically diverse hybrid strains to address this. In this study, we examined whether one single mixed genetic mouse background, C57BL/6J;129S2/SvPas (B6;129), could simultaneously recapitulate behavioral variability and display improved phenotypes relevant to neurodevelopmental and psychiatric conditions. Compared to the inbred B6 strain, mixed B6;129 mice displayed enhanced sociability and self-grooming, two key discriminating parameters between the two mouse backgrounds and core features of such conditions, alongside a broader spectrum of individual behavioral variability. Although overall behavioral variability was comparable across backgrounds, B6;129 mice were less susceptible to the effects of chronic social isolation than their B6 counterparts. Together, these findings support that the B6;129 mixed background offers a more representative model of individual variability and behavioral traits associated with neurodevelopmental and psychiatric conditions, thereby enhancing its translational relevance in preclinical studies.