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January 31st, 2002. Investigators have found the first molecular clues that explain how a group of not very well understood chemical signals, called pheromones, allow male mice to distinguish female mice.

When shutting down the gene that acts as a receiver of pheromones in mice, investigators discovered that pheromones seem to be important for the recognition of sex. Removing the ability of male mice to recognize pheromones creates a lack of aggressiveness towards other males because they did not recognize them as males. They did however immediately attempt to mate as much with males as with females. Catherine Dulac of Howard Hughes Medical Institute at Harvard University, who is the senior author and investigator, provided the findings. The discoveries of Dulac and her colleagues at Harvard were published on the Internet on January 31st, 2002. This site, Science Express, is a website that offers a fast electronic form of publishing for selected articles that will soon appear in Science Magazine.

Dulac and her colleagues have been interested for a long time in the vomeronasal organ (OVN), which is a structure of chemical preceptors that are found in the nasal cavities of many animals. These preceptors are anatomically and functionally different from the olfactory system (sense of smell). OVN, has receivers that respond to secreted pheromones is connected with a different part of the brain.

“It was believed that the OVN controlled mating as well as aggression, in this way, when an animal received one type of pheromone it lead to mating and another type of pheromone lead to aggression”, stated Dulac. In order to better understand the OVN, scientists created desensitized mice that lacked the important ionic channel, called TRP2, which was thought to control the perception of pheromones in the OVN. Previous studies had revealed that the TRP2 was exclusively in the OVN.

“Surprisingly, at the beginning we found these desensitized males could mate with the females perfectly”, said Dulac. To understand why this happened, the coauthors, Markus Meister and Timothy Holy, made electrophysiological studies on in vitro tissue preparations of desensitized mouse OVN. Meister and Holy applied mouse urine containing a mixture of pheromones to the OVN tissue and used several electrodes to measure the electrical activity of the tissue obtained from the OVN. The studies confirmed that the OVN taken from the desensitized mice did not respond correctly to the signals of pheromones. Additional physiological studies in the desensitized mice revealed that the nerve connections of their OVNs seemed normal, which eliminated the possibility that a defect during development was the reason that desensitized mice persisted in mating behavior.

After the scientists established that the mice had OVNs whose only abnormality was that they could not respond to pheromones, the author, Lisa Stowers began to study the effects that the desensitizing of TRP2 had on the behavior of these mice. In an experiment, Stowers sprinkled the backs of the male mice with urine and introduced them in the desensitized mouse cages. The desensitized mice did not show aggressiveness towards their new companions in the cage.

“It is well known that if a male mouse is put in a cage for a while, it establishes the cage as his territory; and if another male is put in the cage, it will be attacked and this attack depends on the resident male's capacity to detect pheromones.”, Dulac said.

“In addition to this absence of aggressiveness from the desensitized mice, Lisa Stowers observed another very strange thing. Desensitized males tried to mate with the intruder males. It took time to realize what this meant. We theorized that the desensitized male could be sexually hyperactive; able to mate with any animal or it could not detect any difference” Dulac confided.

Scientists solved the puzzle when they placed the desensitized mice in cages with males or females and found that the desensitized mice tried to mate with any sex. Additional studies demonstrated that the desensitized mice emitted the same vocalizations of ultrasound related to mating when they were in the presence of males and females, demonstrating that a complete range of courtship behavior was affected by the loss of TRP2 sensitivity.

“Amazingly, we found that when desensitizing this receiver, somehow we were disconnecting the signals for mating behavior and the specificity of sex for mating. The discoveries are only applied to mice since the signaling by pheromones can be different in other rodents and mammals”, the scientist stated.

Dulac emphasized that the mice desensitized for TRP2 could have many other effects that scientists have still not observed in the controlled behavior by pheromones. “Probably we have only seen the tip of iceberg,” she said.

“We have not studied the effects of desensitizing females yet, and we want to discover at what moment the function of the OVN is required to establish normal behavior. It is possible to imagine that there is a period during the development when the mouse needs to have an OVN in operation, but after a period of time, the OVN is no longer necessary because the animal can count on other sensorial information. Moreover, the mice desensitized for TRP2 would allow the scientists to track the neuronal circuit by which the signals of pheromones allow the mice to discriminate sex”, Dulac indicated.