BioEd Online

A single genetic change can render mice immune to the consequences of hostile bullying, and this may point the way to drugs for social phobias and depression.

Mice, somewhat like people, become withdrawn and unhappy when they are exposed to other, aggressive mice. Now a team led by Eric Nestler at the University of Texas Southwestern Medical Center in Dallas has exposed what is going on in the brains of these introverted animals.

The researchers placed a small, brown mouse of one strain in a cage with a larger, white, aggressive mouse from another. "They're just naturally mean mice," Nestler says of the intimidating white strain.

After ten daily bouts with a different tyrant, the brown mice seemed socially scarred. Even a month after the bullying sessions, normally gregarious animals clung to the corner of their cage, shying away from both white mice and familiar brown ones.

The researchers showed that these social problems are controlled by a reward circuit in the brain that is known to tell the animals that food, sex and drugs are gratifying. They did this by taking a group of mice and removing a key protein called brain-derived neurotrophic factor (BDNF) from this reward circuit.

Mice lacking BDNF were no longer browbeaten by the aggressive mice, they found. The researchers suggest that BDNF is needed for the animals to learn that bullying mice are very far from rewarding, and are actually horrible.

Mice that were given antidepressants such as Prozac similarly escaped the detrimental effects of bullying, the team report in Science¹.

Social engineering

The results suggest that drugs that tinker with this reward circuit might benefit people with social difficulties, such as the withdrawal often seen during depression, post-traumatic stress disorder and social phobia. Some doctors already prescribe antidepressants for social phobia, in which sufferers can be crippled by interactions with other people.

It is even possible that these brain circuits and underlying molecules might be partly responsible for milder behavioural problems, such as extreme shyness or a strong need for social contact, speculates Nestler.

Better targets

It is unlikely that drug seekers would try to block BDNF directly, as the team did in the mice, because the gene is active in several brain regions. Blocking it would probably come with unwanted side effects.

Instead, researchers would like to find other molecules with which BDNF interacts, specifically in the reward circuit, and use drugs to alter their activity.

As a step towards this, Nestler's team identified a slew of genes whose activity jumps or drops in the reward circuits of bullied mice — changes that were mostly reversed by eliminating BDNF or using antidepressants. "That opens the door to tens if not hundreds of new targets," says Robert Malenka, who studies neural circuits at Stanford University, California.

There is pressure to find better antidepressants because many people do not respond to the ones already available, or experience side effects. "This helps focus the field on a new area," Nestler says.

Earlier animal studies of depression have concentrated on other symptoms such as lack of appetite or general apathy. Looking for drugs that treat the social aspects of depression could provide new treatments that combat the condition as a whole.

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