BioEd Online

You've walked your normal route home a thousand times. Twice, a lurking gang of teenagers jeered as you went by. Most people would see the threat of attack on any day for what it is — minimal. But a few would be too scared to risk the journey alone ever again.

Such over-anxious people tend to interpret a potentially dangerous situation as intolerably threatening, even when the risk is tiny. Researchers have now uncovered the neural circuits behind this inappropriate behaviour — at least in mice.

Humans probably have a similar system, say the researchers who made the discovery. Knowing the actual cells involved in one manifestation of anxiety might help those developing new therapies.

If normal mice are given an electric shock every time they are exposed to a flash of light, they will quickly learn to freeze with fear every time the light flashes. If they get the shock only occasionally, they will show less fear after the cue.

But mice lacking a particular receptor for the neurotransmitter serotonin, called 5-Htr1a, show the same level of fear in both cases. Such mice are anxious, and cannot evaluate the true threat of an ambiguous situation.

The mice were made by a team at the European Molecular Biology Laboratory in Monterotondo, Italy, led by behavioural geneticist Cornelius Gross. They report their findings in Nature Neuroscience¹.

"Mice need this receptor during development," says Gross. "If it is not there during this crucial period, their brains don't get wired up properly, and this affects their relationship with anxiety later in life."

Serotonin is known to be a key factor in anxiety. Antidepressants such as Prozac work by prolonging its action at neurons.

Fear no more

By shutting down a particular circuit in the hippocampus, a part of the brain that processes memories, Gross's team was able to make the genetically engineered mice respond normally to ambiguous threats.

The researchers achieved this with a drug that blocks firing only in neurons called dentate gyrus granule cells. These cells form part of one of the hippocampus's major neural circuits.

The results show that, as well as memory, the hippocampus assesses risk.

Humans probably have the same circuit in their hippocampus, says Gross. The brain's processing of basic, essential emotions such as fear is usually conserved between species. "The human brain is probably wired to evaluate potentially threatening situations in the same way as the mouse," he says.