Death and sex in the brain. Male mice lacking a gene involved in apoptosis (right) have more neurons in their AVPV than do normal males (left), and they have as many as their female counterparts.

Building a Sex-Specific Brain

Sex hormones influence brain development, establishing differences between male and female brains. The hormones may do this by telling neurons in certain brain regions whether to kill themselves, according to a new study that finds that male and female brains are much more similar than usual in mice missing a cell-suicide gene.

During mammalian development, testosterone and its chemical cousins give males more neurons in some brain regions and leave females with more in others. Previous work hinted that testosterone does this by triggering programmed cell death, or apoptosis, in certain regions but repressing it in others. However, other mechanisms--such as rates of cell birth, migration, or maturation--had not been ruled out.

To investigate the role of apoptosis, neurobiologist Nancy Forger of the University of Massachusetts, Amherst, and her colleagues examined the brains of mice missing a gene called Bax. Previous studies had found that knocking out Bax eradicates cell death completely. The team counted cells in two forebrain regions that normally differ in male and female mice: the principal nucleus of the bed nucleus of the stria terminalis, where males normally have more neurons, and the anteroventral periventricular nucleus (AVPV), where females have more neurons.

Bax deletion completely eliminated these differences, even though hormone levels in the mice were normal, the researchers report this week in the Proceedings of the National Academy of Sciences. Each of these areas must have a different molecular "switch," Forger says, so that testosterone activates apoptosis in the AVPV but represses death in the bed nucleus. Removing Bax didn't eradicate all differences between the sexes, however: Bax-less females, like their genetically normal counterparts, still had a greater proportion of dopamine-releasing neurons in the AVPV than did males.

The study is a "very elegant confirmation of what several of us have hypothesized" about how apoptosis might regulate brain structure based on sex, says Roger Gorski, who studies sex differences in the rat brain at the University of California, Los Angeles. The next step, says C. Michael Knudson of the University of Iowa in Iowa City, whose group created the Bax knockout mice, will be to study the behavior of these mice. "It would be very interesting to me if these neuronal changes do somehow tie into altered sexual behaviors," Knudson says.

Related sites
Sex Differences in the Brain, from the Society for Women's Health Research
Programmed Cell Death in Development, from the University of Calgary
About Apoptosis, from NIH
More about apoptosis, at C. Michael Knudson's home page