UCLA

The brains of males and females are different anatomically and chemically. There are also sex differences in neurological disease, cognition and behavior that are presumed to be downstream consequences. Two main factors have been implicated in sexual differentiation of the brain: gonadal hormones and direct genetic effects. Here, we explore the role of sex chromosomes in the brain and behavior and the molecular mechanisms mediating the effects of these factors.

We investigated the contribution of sex chromosomes to sex differences in brain and behavior by studying a novel mouse model of Klinefelter Syndrome (KS) termed the Sex Chromosome Trisomy (SCT) model. KS is characterized by the presence of an additional X chromosome in men. We investigated the extent of feminization in XXY male mice. We found that partner preference in XXY males is feminized and that these differences are likely due to interactions of the additional X chromosome with the Y. We also found that expression of a small but highly significant proportion of genes is feminized in the bed nucleus of the stria terminalis/preoptic area (BNST/POA) of XXY males, which represent strong candidates for dissecting the molecular pathways responsible for KS-specific phenotypes.

We also investigated whether DNA methylation could be one of the molecular mechanisms that mediate the long-lasting, irreversible effects of perinatal testosterone in the BNST/POA. Using a genome-wide approach, we found that methylation at 45 genes was affected three days after the exposure. This number ballooned to 740 in adult animals. There was also a shift to a more masculine pattern of DNA methylation during adulthood in females that had seen perinatal testosterone. These results strongly suggest that perinatal testosterone confers an initial imprint that is amplified over postnatal development. We also observed sex differences in methylation at numerous genes.

The interplay between gonadal hormones and sex chromosomes is a complex one. Collectively, our results provide further support for the theory of direct genetic effects in brain sexual differentiation and suggest that DNA methylation may be one mechanism that mediates not only the effects of gonadal hormones but also direct genetic effects.