Sex-linked biochemical pathway leads to mellower female mice

By Deborah Wormser

UT Southwestern Medical Center researchers have demonstrated that increasing the size of daily swings in stress hormone levels without changing the amounts released leads to mellower mice, but the effect is seen only in aging females.

The adrenal glands secrete a class of stress hormones called glucocorticoids and do so on a cyclical basis each day, said Dr. Masashi Yanagisawa, Professor of Molecular Genetics and a Howard Hughes Medical Institute Investigator at UT Southwestern, and senior author of the paper published Dec. 5 in the journal Cell.

“We found that in female mice with a condition called subcapsular cell hyperplasia (SCH) the total amount of glucocorticoids released doesn’t change, but the amplitude of the daily variation is enhanced. These changes in turn caused the mice to be less anxious,” he said.

SCH is a thickening of the surface layer of cells that surrounds each adrenal gland and occurs in aging mice of both sexes. SCH, however, is linked to larger circadian stress-hormone oscillations (the daily cycles of peaks and valleys) only in female mice.

“We found that mice showing these larger oscillations were less anxious in a maze test,” Dr. Yanagisawa said “We then conducted additional experiments that identified a new, sex-linked biochemical pathway through which the production of stress hormones is controlled in the adrenal glands.”

The researchers were able to mimic the effects of SCH in female mice without the condition by injecting a small molecule that activated the new biochemical pathway. The mice showed stress hormone oscillation changes similar to those seen in the aged female mice with SCH and were less anxious in the maze tests.

Drs. Masashi Yanagisawa (left) and Yuichi Ikeda
Drs. Masashi Yanagisawa (left) and Yuichi Ikeda looked at subtle changes in stress hormone levels in mice that resulted in less anxiety in maze testing.

Dr. Yanagisawa said the findings may point to a new drug target for calming mammals of both sexes. In humans, two conditions – Cushing’s syndrome and Addison’s disease – are associated with alterations in stress hormone production.

This is the first study to link physiological or behavioral changes to SCH, Dr. Yanagisawa said. It is too soon to tell whether the findings in rodents will translate to humans, he added.

Dr. Yuichi Ikeda, a research associate in Dr. Yanagisawa’s lab and lead author of the study, emphasized that the scientists looked at subtle changes in stress hormone levels similar to those seen during a typical day rather than the speedy, intense hormonal spikes associated with a “fight-or-flight” response to sudden, intense threats in the environment.

The new pathway the researchers identified centers around a receptor protein called CXCR7 in the adrenal gland, which seemed to be more plentiful in the stress hormone-producing cells of aged female mice. Furthermore, the scientists showed that CXCR7 is activated by some opioid peptides.

Opioid peptides occur throughout the nervous system and in the adrenal glands. They are best known for binding to opioid receptors in the brain, where they exert effects on mood and emotion. The opiate class of drugs, which includes potent painkillers like morphine, bind to the same receptors in the brain, but CXCR7 is a receptor totally different from these “classical” opioid receptors, Dr. Yanagisawa explained.

“Our results suggest that the opioid-CXCR7-stress hormone pathway is a signaling axis linking a subtle change in the adrenal gland to reduced anxiety,” said Dr. Yanagisawa, who has a joint appointment at the University of Tsukuba in Japan. “It appears that changes in the degree of daily oscillations of naturally occurring stress hormones affect the brains of the aging female mice to alter their emotions. This effect is very intriguing.”

The study received support from the Perot Foundation, the Japan Science and Technology Agency through the Exploratory Research for Advanced Technology Office (ERATO), the Japan Society for the Promotion of Science through the Funding Program for World-Leading Innovative R&D on Science and Technology (FIRST Program), and the HHMI.

Other UT Southwestern researchers involved in the investigation included former postdoctoral researcher and instructor Dr. Hidetoshi Kumagai, now at the University of Tsukuba; research specialist Amber Skach; and graduate student Makito Sato, all in the Department of Molecular Genetics.


Dr. Yanagisawa holds the Patrick E. Haggerty Distinguished Chair in Basic Biomedical Science.