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Durham, N.C. -- In experiments with mice, neurobiologists have found the
first evidence of neurons responsive to social odors. They also have used a
new analytical approach to isolate one of these social odors -- a novel
chemical in urine that enables mice to distinguish between the sexes --
defining maleness in the mice.

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.