Search

Abstract Background Sex differences in brain development are thought to lead to sex variation in social behavior. Sex differences are fundamentally driven by both gonadal hormones and sex chromosomes, 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 gonadal hormones or sex chromosomes primarily mediate the sex differences seen in mouse social behavior, both at baseline and in the context of Myt1l haploinsufficiency. Methods Four-core genotypes (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 with Myt1l mutation. Results The FCGxMYT1L cross revealed independent effects of both gonadal and chromosomal sex on activity and social behavior. Specifically, the presence of ovarian hormones led to greater overall activity, social seeking, and social orienting regardless of MYT1L genotype. In contrast, sex chromosomes affected social behavior mainly in the MYT1L heterozygous group, with XX MYT1L mutant mice demonstrating elevated levels of social orienting and seeking compared to XY MYT1L mutant mice. Conclusions Gonadal and chromosomal sex have independent mechanisms of driving greater social motivation in females. Additionally, genes on the sex chromosomes may interact with neurodevelopmental risk genes to influence sex variation in atypical social behavior.

Abstract Background Sex differences in the brain may play an important role in sex-differential prevalence of neuropsychiatric conditions. Methods In order to understand the transcriptional basis of sex differences, we analyzed multiple, large-scale, human postmortem brain RNA-Seq datasets using both within-region and pan-regional frameworks. Results We find evidence of sex-biased transcription in many autosomal genes, some of which provide evidence for pathways and cell population differences between chromosomally male and female individuals. These analyses also highlight regional differences in the extent of sex-differential gene expression. We observe an increase in specific neuronal transcripts in male brains and an increase in immune and glial function-related transcripts in female brains. Integration with single-nucleus data suggests this corresponds to sex differences in cellular states rather than cell abundance. Integration with case–control gene expression studies suggests a female molecular predisposition towards Alzheimer’s disease, a female-biased disease. Autism, a male-biased diagnosis, does not exhibit a male predisposition pattern in our analysis. Conclusion Overall, these analyses highlight mechanisms by which sex differences may interact with sex-biased conditions in the brain. Furthermore, we provide region-specific analyses of sex differences in brain gene expression to enable additional studies at the interface of gene expression and diagnostic differences. Graphical Abstract