While lordosis is a relatively simple behavior, “the technique that we offer will be useful for studying more complex behaviors,” says Donald Pfaff, a neuroendocrinologist at Rockefeller University and one of the study’s co-authors.
Emilie Rissman, a behavioral endocrinologist at University of Virginia, says the results themselves are not surprising – but neuroscientists will be eyeing this technique as a way to sort out more puzzling problems, such as the different roles that ER-alpha and the other estrogen receptor, ER-beta, play in determining behavior.
Studying estrogen and its receptors in mice may help shed light on some of the more complex effects of these molecules on human sexuality – for instance, the increase in libido that some women experience from hormone replacement therapy. David Rubinow, a psychiatrist at the University of North Carolina who specializes in reproductive neuroscience, says that both ER-alpha and ER-beta “undoubtedly contribute to a variety of cognitive and affective processes in humans.”
The study used a method that overcomes two key problems of delivering RNAi directly: the difficulty of getting RNA into cells and its transitory effect. First-author Sergei Musotov, now a research scientist at Neurologix, Inc., a biotech company in Fort Lee, NJ, used an altered virus, which can easily infect cells but does not cause a dangerous immune response, to deliver DNA sequences from the ER-alpha gene to cells. When the gene is turned into RNA, the molecule folds in half and the two complementary sides zip together, joined by a tiny hairpin loop that’s snipped by proteins in the cell, creating a short double-stranded RNA. When delivered by virus, the small hairpin RNA, or shRNA, is produced indefinitely in cells. The treatment must be delivered surgically in order to reach a precise location.
According to Phil Sharp, biologist and RNAi expert at MIT, in addition to its advantage of specificity, the RNAi technique has important implications for studying genetics and behavior beyond the mouse. To study the role of genes in different behaviors, scientists have traditionally knocked out the gene from the genome, rendering it silent. However, this technique’s use is restricted almost exclusively to mice, whose genes can be easily manipulated. It can’t, for instance, help uncover the genes responsible for a songbird’s song or decision-making in a monkey. In animals that are not easily manipulated genetically, Sharp says, RNAi “really becomes the only way of doing these types of experiments.”