Three Knockout Mice, See How They Cower

The farmer's wife wouldn't have to chase these mice. Genetically engineered mice that lack a gene for registering stress are even more anxious than their normal cousins, who are not known for their nerves of steel in the first place. The unexpected finding opens up a possible new route for investigating depressive and anxiety disorders.

When an animal is stressed, the hypothalamus spurts out corticotropin-releasing hormone (CRH). Two receptors in the pituitary gland pick up on the CRH signal. One, CRHR-1, passes on a signal to the rest of the body. You know the feeling: heightened blood pressure, pounding heart rate, and a surge of energy. Mice engineered to lack this receptor are called "mellow" mice, and drug companies are scrutinizing the receptor for ways to make mellowing agents for humans, which could potentially treat depression and anxiety. Researchers assumed the second receptor, CRHR-2, worked about the same way.

Now, three groups report that, to their surprise, the second receptor has an opposite effect: It calms normal mice down after the stress out. "They are the yin and the yang of the anxiety stress response," says molecular biologist Kuo-Fen Lee of the Salk Institute in La Jolla, California, author of one of three papers appearing in the April Nature Genetics. The teams all report that knockout mice lacking CRHR-2 have higher levels of stress hormones than normal mice that linger after a stressful event.

A team led by Mary Stenzel-Poore of the Oregon Health Sciences University in Portland found that the mice had high blood pressure. They didn't do too well on mazes, either--both Lee's and Stenzel-Poore's teams reported that the mice preferred to cower in the dark rather than explore. Normal mice groom themselves when they're calming down after a stressful episode, and Stenzel-Poore's team reports that the frazzled mice don't perform this laid-back behavior.

The variety of odd behaviors suggests that the animals can't tone down a stress response once it's started, says Stenzel-Poore. Neurobiologist and stress researcher Robert Sapolsky of Stanford University expressed surprise at the studies and says the results are "fascinating."