While innate behaviors are conserved throughout the animal kingdom, it is unknown whether common signaling pathways regulate the development of neuronal populations mediating these behaviors in diverse organisms. But as brain anatomy and connectivity change through evolution, it is possible that a single pathway could act through diverse molecular and cellular targets to establish a single behavioral output, which is the ultimate constraint on gene function.
Now, in this direction, the researchers from the University of Utah have discovered that eliminating a particular gene from the brains of mice and zebrafish causes these animals to become more anxious than normal. They removed the gene Wnt/ß-catenin effector Lef1, thereby disrupting the development of certain nerve cells in the hypothalamus that affect stress and anxiety. These results are the first implication that Lef1 functions in the hypothalamus to mediate behavior, knowledge that could prove useful for diagnosing and treating human brain disorders.
“Anxiety is an essential behavior that is much more complex than we thought,” says first author Yuanyuan Xie, who led the research in collaboration with senior author Richard Dorsky, 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. “This work is making us think about how brain structures control behavior in a different way,” Xie says.During the course of the study, the lead researchers noted that the absence of Lef1 in the brains of fish did not make much of a difference except there were cells missing from a region called the hypothalamus. This part of the brain controls many “hard-wired” behaviors such as sleep and feeding, as well as hormone release through the pituitary gland. “Before we did the experiments we had no idea that the neurons impacted by Lef1 would preferentially impact one type of behavior,” says Dorsky.
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.
“When you think about genes with a conserved function you think everything that gene does must be the same in all animals. But our study shows that that isn’t necessarily true,” says Dr. Dorsky, who adds that the team’s work could explain how a gene that specifies a particular behavior can adapt to accommodate changes in brain circuitry that happen over evolutionary time. “Our results suggest that during evolution, the brain can innovate different ways to get to the same outcome.”
