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Gene-Silencing Makes Female Mice Avoid Sex

The technology, called RNAi, can pinpoint the genetic origins of behavior in the brain.

Female mice are rendered totally unresponsive to the overtures of their mates when a specific gene is silenced in a small part of the brain. The findings demonstrate the power of a relatively new gene-silencing technique called RNA interference, or RNAi, for mapping out the genes and brain regions that underlie behavior. And it could eventually shed light on the role of estrogen in human sexuality.

Sorting out the genes and brain networks responsible for complex behaviors such as sexual arousal is a tricky process. Genes are expressed in different locations and at different times during development, often playing multiple roles in the brain or other organs. But this new technique gives scientists the unprecedented ability to selectively shut genes on and off at will in specific parts of the body.

[This brief video shows a female mouse with no sexual response due to the gene-silencing technique, compared with a normal mouse.]

Messenger RNA is the go-between used to translate a gene into a protein. RNAi takes advantage of a natural process in cells, in which the presence of a short piece of double-stranded RNA leads the cell to destroy messenger RNA that matches its sequence. As long as a gene’s sequence is known, scientists can block its middleman with RNAi and effectively silence its activity.

Scientists are developing RNAi-based therapies for macular degeneration, cancer, and HIV, and have also used RNAi to study genetic pathways in lower organisms such as worms and fruit flies. But this is one of the first uses of the technique to study such a complex behavior as mating in living mammals.

The hormone estrogen provokes a reaction in female mice called lordosis, which is an arching of the spine in preparation for mating. This behavioral response is mediated in the brain by estrogen receptor alpha (ER-alpha), which sits on the surface of cells and binds to estrogen when it passes through the bloodstream.

Previous work has shown that mice engineered to lack ER-alpha do not exhibit lordosis and aggressively reject males when the males try to mate with them. However, these “knocked-out” mice are missing the gene throughout life in every cell of the body, which makes it difficult to pinpoint exactly how the gene governs the mating behavior.

The study published online this week in Proceedings of the National Academy of Sciences uses RNAi to show that one brain region and one gene are completely responsible for the female sexual response in mice. The researchers, led by Sonoko Ogawa, a behavioral neuroscientist at the University of Tsukuba in Japan, used RNAi to block ER-alpha only in a small region of the hypothalamus in the mouse brain, which is thought to be the seat of female sexual behavior.

They then injected the mice with estrogen to cause them to go into heat. As shown in this short video, mice treated with RNAi (in bottom cage in the movie) had no sexual response – they not only didn’t exhibit lordosis, but did not allow male mice to mount, sometimes aggressively resisting by running around and kicking. In contrast, untreated female mice (in top cage), readily allowed males to mate with them.

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.”

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