Removing a single gene from the brains of mice and zebrafish causes these animals to become anxious, according to research published last week in PLOS Biology. 
Eliminating the gene encoding Lef1 disrupts the development of certain nerve cells in the hypothalamus that affect stress and anxiety, a team from University of Utah Health says.
"Anxiety is an essential behavior that is much more complex than we thought," explains first author Yuanyuan Xie, Ph.D., who led the research in collaboration with senior author Richard Dorsky, Ph.D., professor of neurobiology and anatomy at U of U Health. Lef1 is a component of the Wnt signaling pathway, which has roles in animal development, physiology, and disease.
When Xie and Dorsky started their investigation, they had no reason to believe that Lef1 had a specific role in anxiety. Brains of fish missing the gene were relatively normal except there were cells missing from the hypothalamus. "Before we did the experiments we had no idea that the neurons impacted by Lef1 would preferentially impact one type of behavior," Dorsky adds.
Tallying the genes that were most perturbed by loss of Lef1 in this brain region revealed that over 20 were involved in mood disorders like depression and anxiety. The scientists then noticed that the fish had telltale signs consistent with these disorders. The animals were reluctant to explore their environment when placed into a new tank, preferred to remain immobile at the bottom. And they grew slowly, another condition often related to elevated stress.
Despite the fact that brain structure and complexity vary greatly from flies to humans, Lef1 appears to mediate anxiety across species. The new study shows that unexpectedly, the gene utilizes diverse mechanisms to get the job done.
Similar to zebrafish, mice in which Lef1 had been removed from the hypothalamus showed signs of anxiety, including being smaller and a reluctance to explore. They also had fewer brain cells in the region where Lef1 is normally present. However, the missing cells make Pro-melanin concentrating hormone (Pmch), a brain signal that was not perturbed in zebrafish. By contrast, zebrafish and Drosophila fruit flies lacking their versions of Lef1 are missing cells that make Corticotropin releasing hormone binding protein (Crhbp), and these cells were unaffected in mice.
These results suggested that Lef1 could regulate anxiety through two different nerve cell signals. Support for this scenario was unexpectedly found in humans, where expression of Crhbp and Pmch are extremely closely linked in the hypothalamus, indicating they may actually be present in the same cells and together act downstream of Lef1 to regulate behavior.
Image of Zebrafish from Azul/Wikimedia Commons