Chromosomal and gonadal sex have differing effects on social motivation in mice
Authors: Chaturvedi Sneha M. , Sarafinovska Simona , Selmanovic Din , McCullough Katherine B. , Swift Raylynn G. , Maloney Susan E. , Dougherty Joseph D. 
Published: October 2024

AbstractPlain English SummaryAs our brain develops, many factors influence how we behave later in life. The brain forms differently in males and females, potentially leading to sex variation seen in many behaviors including sociability. In addition, conditions defined by differences in social behaviors, such as autism, are diagnosed more in males than females. However, researchers don’t know exactly how distinct sex factors, such as hormones and sex chromosome genes, lead to different behaviors in males and females. In this study, we used mouse models and tests of mouse behavior to explore these differences. Results show that sex hormones primarily contributed to differences in social motivation between sexes. Yet when we repeated these same assays in a mouse model of genetic liability for a human neurodevelopmental syndrome, we found that sex chromosome genes rather than sex hormones played a larger role in the behavioral consequences of impaired neurodevelopment. These insights can inform future research on the biological mechanisms of social behavior in the context of genetic liability for neurodevelopmental disorders.HighlightsFour-core genotype mouse model crossed with MYT1L heterozygous mouse revealed independent effects of chromosomal and gonadal sex on social motivation.Myt1lhaploinsufficiency was associated with increased activity in both males and females.While females are more active, contributions of chromosomes and gonadal hormones to this sex effect are environment dependent.Presence of ovaries was associated with increased measures of social seeking and orienting regardless of genotype.Chromosomal sex interacted with MYT1L genotype, with increased social orienting and seeking specifically in XX MYT1L heterozygous mice.BackgroundSex differences in brain development are thought to lead to sex variation in social behavior. Sex differences are fundamentally driven by both gonadal (i.e., hormonal) and chromosomal sex, yet little is known about the independent effects of each on social behavior. Further, mouse models of the genetic liability for the neurodevelopmental disorder MYT1L Syndrome have shown sex specific deficits in social motivation. In this study, we aimed to determine if hormonal or chromosomal sex primarily mediate the sex differences seen in mouse social behavior, both at baseline and in the context ofMyt1lhaploinsufficiency.MethodsFour-core genotype (FCG) mice, which uncouple gonadal and chromosomal sex, were crossed with MYT1L heterozygous mice to create eight different groups with unique combinations of sex factors and MYT1L genotype. A total of 131 mice from all eight groups were assayed for activity and social behavior via the open field and social operant paradigms. Measures of social seeking and orienting were analyzed for main effects of chromosome, gonads, and their interactions withMyt1lmutation.ResultsThe FCGxMYT1L cross revealed independent effects of both gonadal and chromosomal sex on activity and social behavior. Specifically, the presence of ovaries, and by extension the presence of ovarian hormones, increased overall activity, social seeking, and social orienting regardless of genotype. In contrast, sex chromosomes affected social behavior mainly in the MYT1L heterozygous group, with XX sex karyotype when combined with MYT1L genotype contributing to increased social orienting and seeking.ConclusionsGonadal and chromosomal sex have independent mechanisms of driving increased social motivation in females. Additionally, sex chromosomes may interact with neurodevelopmental mutations to influence sex variation in atypical social behavior.