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Fear in the air

Biologists identify proteins that indicate the presence of predators to mice


One does not need to teach a mouse or a rat to be afraid of a cat. No sooner do they start walking than rodents are able to recognize predators’ traces in the environment and to realize when it is time to vanish. It is a known fact that, as is the case with most animals, mice get clues about danger in their vicinity almost always by air: chemical compounds released by the predator penetrate the prey’s nostrils and trigger a series of electrical signals in the brain that prepare the rodent’s body to fight or flee. However, in the past the scientists did not know what compounds were released or what part of the olfactory system they acted on. After conducting experiments for three years, the Brazilian biologist Fabio Papes and two researchers from the United States presented answers to some of these questions in the May 14 issue of the journal Cell, in an article important enough to be featured on the issue’s cover.

Together with Darren Logan and Lisa Stowers, from the Scripps Research Institute in California, Papes, a researcher at the State University of Campinas (Unicamp), conducted a series of tests in which he placed mice in contact with pieces of gauze that had been rubbed on the neck of a cat, moistened with the urine of a rat or rubbed on the skin of a snake – three of the natural predators of mice. In all cases, just sensing the odor increased the production of  stress hormones in the mice and made them more cautious: after just a whiff of the smell of one of the predators, the rodents would start to explore their environment much more carefully.

Investigating the mice’s olfactory system, Papes found that something in the smell of the predators stimulated a specific nasal area, the so-called vomeronasal organ. This structure is still rather enigmatic and consists of some thousands of nerve cells (neurons) that capture chemical information in the air and transform it into electrical impulses, triggering the brain’s fear circuits. The organ’s importance became evident when the researchers found that genetically modified mice, with a genetic alteration that rendered the vomeronasal organ’s neurons inactive, showed no fear when exposed to the smell of rats, snakes or cats.

The smell of danger
To find out whether this organ played a role only in identifying the smell of predators or whether it also picked up other unpleasant odors, the biologists repeated the tests, exposing the mice to naphthalene, the main ingredient of mothballs and a chemical that is released when wood is burnt. Animals associate it with the smell of fire. Both the rodents with active vomeronasal organs and those with deactivated organs avoided the gauze with naphthalene, a sign that the neurons that had been switched off could still play a part in the identification of natural enemies. “This result indicates that the organ is involved in the detection, if not specific, at least targeted, of the odor of predators,” says Papes, who teaches at Unicamp’s Biology Institute.

As the secretion of animals of different species provoked the same reaction in mice, the researchers suspected that there might be a common compound in the urine of rats, in the mucus on the skin of snakes and in the saliva that cats leave upon their fur after licking themselves. Back at Unicamp, after spending seven years in the United States, some at Lisa Stowers’ laboratory, Papes undertook a risky stage of the research, with a highly uncertain chance of getting results: the purification of the rat urine and cat saliva components. It was impossible to analyze the snakeskin mucus because this source of odors proved to be umanageable. He got lucky. He found a protein in cat saliva – Feld4 – that is quite similar to the most abundant protein in rat urine, Mup13 (Major Urinary Protein 13).

In a new series of tests, Papes and Darren Logan found that after inhaling solutions that only contained the isolated proteins, the mice were just as cautious as they were after smelling rat urine or cat saliva. “These proteins worked like kairomones, molecules that the organism of a species releases and that act upon another species, to the loss of the releasing species and to the benefit of the species getting the information,” explains Papes, who shared with Logan the authorship of the Cell article.

Papes is currently working on identifying the brain circuits activated by these odors. He believes that using this strategy, in the not too distant future, it will be possible to get a map of the sensory activation associated with behaviors such as the defense, maternal and reproductive ones, among others. “Knowing how the brain recognizes, interprets and responds to stimuli such as odors,” he comments, “may even help us to better understand diseases connected to sensory alterations.”

The project
Molecular biology of the olfactory system of mammals: study of the detection of odors and their neural representation in the brain (nº 2009/00473-0); Type Young Researcher; Coordinator Fabio Papes – IB/Unicamp; Investment R$ 725,763.03 (FAPESP)

Scientific article
PAPES, F. et al. The vomeronasal organ mediates interspecies defensive behaviors through detection of protein pheromone homologs. Cell. v. 141 (4), p. 692-703. 14 mai. 2010.