Genes may be a factor dictating levels of anxiety, according to a study on the brains of mice and zebrafish conducted by researchers at the University of Utah.
Yuanyuan Xie, who previously attended and worked at the U and is currently a researcher at the University of Pennsylvania School of Medicine, initiated the study in 2013. Faculty and students from various departments at the U, including neurology, pediatrics, ophthalmology and human genetics, collaborated on the project.
The study focused on the Lef1 gene, a component of the Wnt signaling pathway. Richard Dorsky, a co-author of the study and professor of neurobiology and anatomy at the U’s School of Medicine, said he has been interested in this part of the brain since 2001. The researchers knew that Lef1 was involved in forming the hypothalamus during fetal development — the component of the brain that influences hunger, thirst, body temperature and emotional activity — but they wanted to know exactly what effect the gene had on the formation of the nerve cells and spinal cord specifically.
“We knocked out the [Lef1] gene in the zebrafish to see what would happen,” Dorsky said. “We noticed that a set of nerve cells were missing and then analyzed the brain to figure out which genes were not turned on correctly. Computational analysis of this list of genes led us toward anxiety.”
The study confirmed that in the zebrafish, the loss of the Lef1 gene led to changes in behavior. In this trial though, researchers weren’t able to target the hypothalamus directly, so they turned to mice.
“In mice, we could knock the gene out in just that part of the brain, and we still saw anxiety-related behavior defects,” Dorsky said. “The combination of experiments in fish and mice enabled us to conclude that Lef1’s function might be the same in many animals.”
According to the study, published under the title “Lef1-dependent hypothalamic neurogenesis inhibits anxiety” in the journal PLOS Biology, “Humans, mice, fish and even flies exhibit anxiety-like behavior despite the fact that their brain anatomy varies widely.”
The consistency of the behavior of various brain structures showed that the gene can develop many different pathways during evolution in order to reach the same outcome.
“Anxiety may be such a fundamentally important behavior for animal survival. Evolution has maintained a common gene pathway to build the brain structures regulating this behavior,” Dorsky explained. “However, we found that Lef1 can control the formation of different nerve cells in different species, meaning that there might be multiple ways to establish a single behavior.”
Now that the researchers have made the connection between specific sets of cells and anxiety behaviors, future studies will target mood disorders in humans, which they believe could be related to Lef1 mutations. The results of this study will be applied to better understand lithium, a drug used to treat bipolar disorder. While lithium can be successful in treating some psychological disorders, researchers are not entirely sure how it functions in the treatment of patients. However, as lithium acts on the same pathway as Lef1, these results are poised to better explain its success, and it could ultimately assist in the effort to develop new drugs to target similar disorders.