Sniffing at what the nose knows

When it comes to dating and mating, how much more can we learn from what we smell?

More than you might think. Lab mice, for example, can't invite each other out for a drink. But new research suggests they can communicate how dry they are through a previously unknown sensory mechanism in their noses.


The discovery might help scientists gain new understanding of how other mammals, including humans, share information about their health, genetics and sexual availability by reading chemical signals picked up by the nose.

Research has already shown that women tend to synchronize their menstrual cycles thanks to hormones in underarm odors. They may also be able to detect genetic differences among potential mates by sniffing male body odors.


In the new mouse study, led by a University of Maryland neurobiologist, the signals appear to come from hormones the rodents excrete in their urine -- intestinal hormones that help regulate salt and water levels in their bodies.

Other mice detect the signals with specialized receptors in their noses, and scientists suspect they use the information to discern how much food or water their cousins have found in the area. That would help ensure their own survival.

"Information is power, and the more information we know about what we're facing out there, the more ready we are to survive and reproduce," said Steven D. Munger, of the University of Maryland School of Medicine.

The mouse research was reported in last week's Proceedings of the National Academy of Science.

"The chemicals that stimulate these neurons have been a mystery for a decade," said Minghong Ma, a neuroscientist at the University of Pennsylvania who was not part of Munger's team. His study, and another published this summer showing the same cells react to carbon dioxide, she said, "shed light on the function of this distinct olfactory subsystem."

Munger is an associate professor of anatomy and neurobiology at the UM School of Medicine. His co-authors include Randall R. Reed of the Johns Hopkins School of Medicine and colleagues in Texas and Germany.

Scientists have long known that animals, and in some cases humans, can detect many kinds of chemicals through their sense of smell. The presence of food and water, predators and prey, the gender, sexual status and proximity of potential mates and rivals can all be transmitted by their odors.

Odors -- simple, volatile chemicals and small pieces of proteins wafted into the air -- are inhaled and land on specialized receptor cells that line the nasal passages.


When the odor molecules match the receptors, like a lock and key, the link triggers a cascade of chemical reactions in the cell, changing its electrical balance and sending a signal pattern to a part of the brain right behind the nose.

"It's a pattern we recognize, like a picture, that would say, 'This is ice cream,' or 'This is rotting fish'," Munger said. "We might equate this with our experience -- something that's bad, something that's good. We then act on it."

Scientists thought they understood how and where all this took place, Munger said. But "over the last few years, it's become much more clear that the number of different subsystems, or subdivisions of the smell and taste systems, was greater than we first suspected."

One of Munger's co-authors, the late David L. Garbers at the University of Texas, discovered one particular receptor protein, called GC-D, that seemed to be present in only a very small segment of nasal sensory cells -- fewer than one-tenth of 1 percent and separate from the better-known "main olfactory system." They looked like cells with a very specialized sensory mission.

"Except we had no idea what stimuli might be turning these cells on," Munger said.

To find out, they started manipulating the genes of lab mice to produce a strain that could not manufacture GC-D. Then they screened those mice with a variety of chemicals found in mouse urine to see what odors they could no longer detect.


With some additional techniques, they eventually identified two chemicals, called uroguanylin and guanylin, that seemed to set a normal mouse's GC-D receptors ringing.

What intrigued investigators about the discovery was that uroguanylin and guanylin help regulate the critical flow of water and salts across the cell walls in the intestines and kidneys.

"Since these hormones have such an important role in metabolism and basic bodily functions, and also now appear to be able to act as odor communication from one animal to another," Munger said, "we can speculate that the information they're trying to impart is something about the metabolism of the animal that left the signal there."

Since the hormone levels rise and fall when the mice are hungry or full, thirsty or not, they reasoned, perhaps the mice are communicating the presence of absence of food and water.

A strong signal in urine might prod a mouse to keep looking for his cousin's food stash. Or, "if the signal is low, there may be nothing around, and he would rest and conserve energy until something comes along," Munger said.

Curiously, a Rockefeller University team studying the same GC-D receptors reported evidence this summer that they respond to carbon dioxide -- perhaps to warn mice of nearby predators or crowding in a confined space.


"It's possible we're wrong and they're right," Munger said, laughing. "Another possibility is that the cells are serving two functions."

That may be the case, said Ma, the Penn neuroscientist. "It is not uncommon for the same set of olfactory sensory neurons to respond to multiple chemicals," she said.

Munger said his work marks the first time the two intestinal hormones have been identified as odor signals. It also showed that these receptors use an entirely novel chemistry to convert odors into electrical signals, he said.

This sensory ability appears to be lost in humans. Two of the three genes in mice and rats that produce the GC-D receptor proteins are unused in people, Munger said. The third, curiously, is expressed in cells of the eye's retina and helps us sense colors.

That suggests that our evolutionary ancestors' reliance on their sense of smell diminished when they evolved from nocturnal beings into highly sight-dependent, daytime animals who are active when color is more important.

Munger said insights provided by this research might eventually improve our understanding of the human sense of smell.


"It's clear our sense of smell is a lot more than how we smell our food," he said.

When Martha McClintock was an undergraduate at Wellesley College in the 1960s, she noticed that women in her dormitory who spent the most time together seemed to synchronize their menstrual periods -- just as mice do. She published her findings in the journal Nature in 1971.

In 1998, as a senior researcher at the University of Chicago, McClintock showed that chemicals called pheromones, from women's underarms, transmit the signals that bring about this menstrual "synchrony."

It's not entirely clear why evolution favored synchronized ovulation. But McClintock noted that rat pups born to females who ovulated and gave birth in synchrony with the group were bigger and more likely to survive than those born out of synch.

In 2002, McClintock's group also exposed women to a variety of male body odors (from dirty T-shirts) and asked them which they would prefer if they had to smell one of them all the time.

She found the women prefered the odors of those men with whom they shared the greatest genetic identity, without being identical. They rejected those more genetically distant, or identical.


Mice show similar preferences.

Just where in the nose such signals are sensed isn't clear. In lower mammals, a structure in the nose called the vermonasal organ is important in detecting odor signals that communicate social information, such as gender, sexual availability and dominance.

For years, scientists looked for the organ in humans, sparking hope in other circles for a scent that could stimulate sexual interest through the vermonasal organ.

But Diego Restrepo, a neuroscientist at the University of Colorado Health Sciences Center, said there's no evidence the human vermonasal organ is even connected to the brain. Many people seem to lack it entirely.

On the other hand, he said "some vermonasal receptors have been found" elsewhere in the nose. "That would suggest ... that that function has been taken over by the main olfactory system."