Published online 7 November 2007 | Nature | doi:10.1038/news.2007.224

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Fear no smell

Researchers make mice unafraid of the scent of danger.

Altered mice won't run away from the feline scent of danger.Ko and Reiko Kobayakawa

Just a whiff of the urine from snow leopards sends shivers down the spines of normal mice. But deleting a key group of olfactory cells turns mice fearless in the face of this odour — even though the mice can still smell it, and be taught to fear it later in life.

The surprising result suggests that smells pass through distinct circuits along the path from nose to brain: one for innate fear, another for the learned kind. A single smell could activate both paths at the same time.

When a scent — noxious or pleasant — hits the nose of a mouse or any mammal, it activates a combination of olfactory neurons. Mice boast about a thousand types of these neurons, which reach from the nose to the brain. The combination of cells activated, like the notes in a piano chord, determines the scent experienced by the animal.

The olfactory neurons are located in a special structure in the nasal cavity called the olfactory epithelium, which has two major regions: dorsal and ventral. The olfactory neurons in each region differ at the molecular level, but until now, no one had much idea how the regions differed in their wiring.

From the olfactory epithelium, the neurons connect to a brain structure called the olfactory bulb. The organization of neurons in the epithelium is mimicked in the brain — the neurons are mapped out in the same way.

Eau de fox

To determine the difference between the dorsal and ventral neurons, Hitoshi Sakano, a neuroscientist at the University of Tokyo, and his team engineered a strain of mice that had no olfactory neurons in their dorsal epithelium. They then tested the mice for their response to a handful smells, good and bad.

Normal mice were drawn to smells of peanut butter and mouse urine; but couldn’t flee fast enough from the scents of rotting food, fox glands, and the urine of snow leopards.

But mice without these neurons showed less interest in the sweet smells and little aversion to spine-tingling ones, the team reports in Nature1. The mice could still detect these smells, the researchers found, and could learn to hate the odours if researchers made the mice sick while delivering the 'nasty' smells.

The team concludes that the dorsal olfactory neurons transmit innate fear responses to the brain, whereas the ventral neurons convey learned aversion.

The team could also see a difference in the brain. In normal mice, a scent secreted by fox anal glands called trimethyl-thiazoline stimulates the brain to make adrenocorticotropic hormone, a sign of stress. The fearless mutants showed no such stimulation in response to the scent.

The work is a big step forward in explaining how odours are translated into actions, says Catherine Dulac, a neuroscientist at Harvard University in Cambridge, Massachusetts.

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Humans probably have a similar system for discerning smells, says Sakano. But learned behaviours can sometimes over-rule innate ones, he notes. Natto — fermented soya beans — is a popular snack in Tokyo, despite its rancid smell. "I think an innate smell will tell us it's dangerous and don't eat it," says Sakano. "But based on the associative learning, some people in the Tokyo area learn to like it." 

  • References

    1. Kobayakawa, K. et al. Nature doi:10.1038/nature06281 (2007).
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