Molecular Underpinnings of Sexual Dimorphism in the CNS

Sexual dimorphism, as a topic, has been investigated extensively by neuroscientists at the level of brain structures, but the molecular underpinnings of these sex differences have received much less attention. Below is a short post summarizing the state of affairs in this regard. The information is derived from an excellent 2010 review by Jazin & Cahill published in Nature Reviews: Neuroscience.

Perhaps the most fascinating development in molecular studies of CNS sexual dimorphism is the focus on sex-biased gene expression. Gene expression differences which appear to be independent of hormone action have been found in rodents and in certain invertebrates, notably the fruitfly, D. melanogaster, and the nematode, C. elegans. In the latter two, there are even sex-specific neuronal networks governing mating/courtship behaviors. 

Mechanisms for mammalian differential gene expression between the sexes are not known, but Jazin & Cahill (2010) summarize studies that have found sex-related phenotype differences in genetically modified mice (quite a feat, considering the scarcity of published research which tests animals of both sexes). Among these is the curious discovery that a knockout (KO) of the Apolipoprotein E gene - one of the rare established genes that carry risks of sporadic Alzheimer's - leads to cognitive impairments, which are more severe in female mice. Another strange finding is that a forebrain-specific conditional knockout of the BDNF gene appears to cause hyperactivity in male mice, whereas in females it leads to a depressive-like phenotype. With BDNF level changes being a common feature of depression and a proposed mechanism for antidepressant action, the behavioral sex differences in the absence of BDNF may prove to be of great importance. Other findings along these lines include increased serotonin synthesis in female compared to male serotonin transporter KO mice and male-specific memory impairment in Calcium/calmodulin-dependent protein kinase kinase 2 beta KO mice.

Some, if not most, of the above sex-differences in gene expression are probably hormone-dependent. Jazin & Cahill (2010) take this opportunity to summarize an ingenious method for separating out the hormone-dependent effects. This is done by creating transgenic mice which do not have the SRY (Sex-determining region Y) gene, responsible for the initiation of testicle formation, on the Y chromosome. Instead, the SRY gene is placed on one of the autosomes. When normal XX females are crossed with such males, they give birth to a few types of offspring, including XY individuals without SRY, which will show the male-specific phenotypical features if the dimorphism depends on the presence of a Y chromosome, and female ones, if the dimorphism is hormone-dependent.

Finally, there is an interesting hormone-independent way of achieving differential gene expression, namely by tweaking the regulatory mechanisms of gene expression on sex chromosomes. Jazin & Cahill (2010) describe X chromosome inactivation in mammals - a mechanism for ensuring that X-chromosome genes are expressed equally in both sexes, since females have one additional copy. Some genes do not fall under the purview of X inactivation, a characteristic known as "escape of X inactivation", and an interesting avenue for further research. 

Research on epigenetic control of sex-related gene expression in the CNS is in its absolute infancy, but it is suggestive that the genes for some histone demethylases are found on sex chromosomes and those may result in sexually dimorphic epigenetic mechanisms. Stay tuned. 

References

Jazin, E., & Cahill, L. (2010). Sex differences in molecular neuroscience: from fruit flies to humans. Nature Reviews Neuroscience, 11(1), 9-17.