EDITORS: Color photographs of mice in the experimental maze are available on request.

ANN ARBOR—Stressed-out mice created at the University of Michigan Medical School are helping scientists understand how a hormone that triggers the body’s fight-or-flight response to stress also may be involved in depression, anxiety disorders and anorexia.

U-M scientists created the new mouse strain by deleting a gene that controls production of one protein. This protein binds to corticotropin-releasing hormone or CRH, a key neuroregulatory hormone produced by all mammals under stress. Binding prevents CRH from activating receptors that trigger the release of other stress hormones, as well as changes in metabolism and behavior.

Male mice without the gene for CRH-binding protein gained less weight and showed more anxiety-like behavior than littermates that could produce the protein.

Genetically-altered mice in the study were less likely to leave the protection of an enclosed chamber.”These mice exhibit anxiety-like behavior all the time—not just in response to an external stressor,” says Audrey F. Seasholtz, Ph.D., a senior associate research scientist in the U-M’s Mental Health Research Institute and an associate professor of biological chemistry in the U-M Medical School.

The initial U-M study documenting behavioral changes in mice without CRH-binding protein will be published in the Sept. 28 issue of the Proceedings of the National Academy of Sciences.

In the study, Seasholtz and her U-M colleagues used standard tests to document levels of stress hormones and anxiety-like behavior in mice without the gene for CRH-binding protein and compare them to test results in normal littermate controls.

Even though they were housed together and given identical access to food and water, male mice without the CRH-BP gene gained less weight between 7-9 weeks of age than did male control mice. Weight gain differences between experimental males and controls became even more significant from 10 to 15 weeks of age.

Normal mice were more likely to leave the chamber and explore the open arms of the maze.During tests for anxiety-like behavior, male mice without the CRH-BP gene were less likely to leave a protected chamber and spent much less time exploring open areas of an experimental maze than did normal male mice. “This test is based on the animal’s natural tendency to explore its environment in the absence of a perceived threat and to retreat to an enclosed area when fearful,” Seasholtz explains.

Experimental and control animals produced nearly the same amounts of the stress hormones ACTH and corticosterone during and immediately after acute restraint stress tests.

“Our data suggest CRH-BP is an important modulator of corticotropin-releasing hormone and other CRH-like peptides, such as urocortin, produced in the brains of mice,” says Seasholtz. “Our hypothesis is that CRH-BP binds to CRH or other CRH-like hormones in animals and prevents these hormones from activating receptors in the pituitary and brain.”

In future research, Seasholtz and her colleagues plan to continue working with the U-M mouse model to understand how all the stress hormones and receptors involved in the CRH system work together to produce anxiety-like behavior. The mice also may prove to be a valuable research model for testing new anti-anxiety drugs.

Seasholtz also plans to examine the relationship between CRH, its binding protein, and depression or anxiety disorders in humans. “We know very little about the role of CRH-BP in humans. In a new study, we hope to determine if individuals with major depression produce altered levels of the binding protein for CRH.”

Jill Karolyi, U-M research associate, and Sally A. Camper, Ph.D., U-M professor of human genetics, created the CRH-BP deficient mouse model used in the study. Additional U-M collaborators included graduate students Heather Burrows and Eunju Seong, former post-doctoral fellows Tennore Ramesh and Masaharu Nakajima and former research assistant J. Shonee Lesh.

The study was funded by the National Institutes of Health and the U-M Rackham Association of Fellows.

Photos by Paul Jaronski, U-M Photo Services.

Jill KarolyiNational Institutes of Health