Venus and Mars revisited

Not being a fan of sensationalism, I was very intrigued when I read the first sentence of an abstract describing the Special Lecture, "Biological origins of sex differences in brain function and disease" in the SfN handbook.

"Each of us has a sex ..."

Yes, plain and simple. I like it. I was impressed, so went to see it on Sunday, October 18 at 11:30am in Hall B1. The speaker was AP Arnold from UCLA.

Take home message: Sex differences are not just hormonal. XX and XY cells are intrinsically different. We need to understand the interaction of various sex specific signals, not just hormonal signals.

We know that the sex differences between females and males originate primarily from the presence of 2 X chromosomes versus 1 X chromosome and 1 Y chromosome. These genotypes bring about different gonadal secretions that then act upon other tissue (including the brain). However, there are also genes located on the X and Y chromosomes that contribute cell-autonomous differences in the sexes as well. So what kind of phenotypic differences are brought about simply by the fact that every cell in my body contains 2 X chromosomes? Certain areas of research are currently devoted to identifying these genes.

In terms of the brain, there are numerous diseases that are more prevalent in one sex over the other. Here's just a few:

Occur more in females:

• Multiple sclerosis
• Depression
• Neural tube defects
• Systemic lupus erythematosus (and XX die faster than males who have SLE)

Occur more in males:

• Tourette's
• ADHD
• Parkinson's disease

Original doctrine stated that the female phenotype is the default. Arnold proposes that this dogma should be changed. If testosterone was added to a system, then the brain became more masculine. For example, cross section views of the spinal cord show a pretty dense region of nerves that control the penis in the male and there are much fewer of these in the female. Males deprived of testosterone, however, had a spinal cord that looked more feminine and females supplemented with testosterone had the dense region of penis innervating fibers that are more indicative of a male. This is a permanent differentiating effect of testosterone.

Arnold's work has investigated genotypes and phenotypes of zebra finches...

Male zebra finches have a large orange patch located on each cheek and zebra stripes decorating the neck and chest. He sings a characteristic song, which is intended to woo a female zebra finch so that they will build a nest and reproduce. The group made a bird that was half male, half female ... laterally. Look at one profile, there were zebra stripes and a bright orange patch; look at the bird from the other profile, and it looked just like the more un-colorful female (when I was a kid, my mom always told me the female bird had to do all the work, so she couldn't look as good as the male bird ... LOL!). They postulate that this lateral difference was not likely caused by hormones; instead it was probably caused by the genetic sex of the tissue.

The "e-male" had been created ... the genetic male had a masculine brain with male behavior but had an ovary. There were no signs of a testicle. Thus, sometimes sexual traits in the brain correlate with the genetic sex, not necessarily with the sex of the gonads.

It's true, XX and XY cells certainly have a different genome. Even though they only comprise less than 5% of the genetic material in each cell, these genetic differences cause changes in phenotype. Essentially, females overexpress the genes located on the X chromosome; they get a double does of these compared to males. Furthermore, the parental imprint of X chromosome is different ... males only get theirs from the maternal contribution.

In terms of somatic nociception, XX and XY gene differences caused a change in the reaction mice had to being placed on a hot plate. As the hot plate warms, mice will lick their paws; this action can be counted and analyzed. Males had more paw licks than females; this is not believed to be caused by gonadal hormones.

This was my first experience with the idea that it's not just the hormones that cause sex differences. I hadn't thought about it that way before, but it seems that the idea of differential genes on X and Y chromosomes is plausible in order to also contribute to female-male differences.