'Social Smell' Discovered In Mice; One Chemical That Defines Maleness

These neurons were discovered in the main olfactory system, a group of brain structures used to process smell. Until now, it has been believed that most chemical social signals in mammals are detected by a different system, the accessory olfactory system, that is absent in humans. The researchers said their findings that mice also use their main olfactory system to detect social signals suggest that humans too may communicate via social odors, because humans possess the same set of brain regions.

The researchers, led by Howard Hughes Medical Institute investigator Lawrence Katz at Duke University Medical Center, published their findings February 20, 2005, in the advanced online edition of the journal Nature. Lead author was Da Yu Lin in Katz's laboratory, and co-authors were chemistry professor Eric Block and post-doctoral fellow Shao-Zhong Zhang of the State University of New York at Albany.

The researchers used a new combination of analytical techniques to isolate volatile compounds from mouse urine and trace their effects on the neural odor-processing circuitry. Besides mapping the odor effects in the brain, they also isolated an important chemical that may enable mice to identify another individual as male or female.They demonstrated that the presence of this chemical in male mouse urine substantially enhances the attractiveness of males to female mice. Importantly, they said, this chemical is only found in male mouse urine, not in female mice or in male mice that lack sex hormones, that is, castrated males.

In their technique, the researchers first used gas chromatography to separate a multitude of individual volatile compounds in mouse urine. They then exposed mice to the individual compounds and measured the electrophysiological response of neurons across the regions of the olfactory bulb -- the brain structure where olfactory information is initially processed.

"These represent the first comprehensive study of how a complex social stimulus like urine is represented in the olfactory bulb, which is a system that both humans and other mammals possess," said Katz. "We weren't at all sure how these neurons would respond -- whether they would each respond to individual components; whether each would respond to multiple components, or whether neurons would require multiple simultaneous components to respond.

"But the results were very clear and really quite surprising," he said. "We found that in a complex mixture like urine, which has at least a hundred compounds in it, an individual nerve cell in the olfactory bulb acted as a detector for just one of those compounds.

"This finding will help settle a continuing debate among scientists studying the olfactory system -- whether olfactory neurons are broadly tuned, responding to many different compounds, or whether they act as olfactory feature detectors," said Katz.

The researchers' mapping revealed that only a very small area of the olfactory bulb responded to the urine volatiles, said Katz. "We were mapping the olfactory bulb just as a cartographer might map the geography of a region," said Katz. "And we were surprised to find that, despite the complexity of this stimulus, the responses were concentrated in a relatively small area of the olfactory bulb."

In particular, Lin and Katz noticed that one component present in only infinitesimal amounts and only in male urine nevertheless evoked a particularly strong response in the mouse neurons. Their analysis suggested the presence of a novel sulfur-containing compound. To confirm the compound's identity, chemists Zhang and Block synthesized possible candidate molecules, and the researchers tested their effects on neuronal responses. This analysis revealed the compound to be (methylthio)methanethiol, or MTMT. The researchers found MTMT in the urine of intact male mice, but not in females or castrated males.

Indeed, when the researchers tested the behavioral response of female mice, they found that the females were much more attracted to urine containing MTMT, but not to urine that did not contain the compound, Katz said.

"We also found that female mice weren't particularly interested in MTMT itself but only when it was present in male urine," said Katz. "So, it's as if their brains first need to know that that the animal is smelling mouse urine, and then it can focus on the presence of particular molecules. This suggests that multiple components are needed to construct the odor 'picture' distinguishing a male from a female mouse."

Katz said their evidence shows that construction of such an odor picture is probably not taking place in the olfactory bulb, but in higher regions of the olfactory cortex of the brain. He and his colleagues are now exploring the nature of that processing. Katz also said the findings have important implications for understanding olfactory communications in humans.

"Humans do not have the vomeronasal organ, which is responsible for pheromone communications in most mammals," said Katz. "Yet there are persistent reports about the influence of odorant communications in all sorts of behavior in humans -- mothers recognizing infants, wives recognizing husbands and of course the influence of perfumes and colognes.

"Since we've found that mice -- which are well known to use odors for social communications -- do so using the main olfactory system, this strongly suggests that sex-specific volatile chemicals in our bodily secretions could also be detected by similar circuitry," he said.

In further studies, Katz and his colleagues are using a vast array of odors, both synthetic and natural, to decipher the olfactory "code" by which the brain constructs elaborate olfactory scenes from combinations of odorants. They also seek to understand how mice combine information from multiple odors to recognize other individual mice, much as humans recognize other individuals by their faces. Such studies may yield insights into the formation of human perception, which enables recognition of specific objects in the environment by combining multiple components, be they visual, auditory or olfactory, said Katz.

"The question is how do you know a rose is different from a skunk, or how a merlot is different from a cabernet?" asked Katz. "It's because we have a sophisticated olfactory discrimination system that relies on detecting and integrating information from a distinctive set of chemicals."

Katz noted, however, that the same chemicals are unlikely to be used for olfactory social communications in mice and humans. For example, MTMT, which is also found in small amounts in shiitake mushrooms, has a garlicky smell that is better suited for cooking than cologne, he said.