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Manipulating A Single Gene Defines a New Pathway to Anxiety

저자:   업로드:2017-08-28  조회수:

    Removing a single gene from the brains of mice and zebrafish causes these animals to become more anxious than normal. Researchers from University of Utah Health show that eliminating the gene encoding Lef1 disrupts the development of certain nerve cells in the hypothalamus that affect stress and anxiety.  Their study ("Lef1-Dependent Hypothalamic Neurogenesis Inhibits Anxiety"), which appears in PLOS Biology, suggests that Lef1 functions in the hypothalamus to mediate behavior. The team believes this knowledge could prove useful for diagnosing and treating human brain disorders.


    "...we demonstrate that the Wnt/ß-catenin effector Lef1 is required for the differentiation of anxiolytic hypothalamic neurons in zebrafish and mice, although the identity of Lef1-dependent genes and neurons differ between these 2 species. We further show that zebrafish and Drosophila have common Lef1-dependent gene expression in their respective neuroendocrine organs, consistent with a conserved pathway that has diverged in the mouse," write the investigators.




    "Finally, orthologs of Lef1-dependent genes from both zebrafish and mouse show highly correlated hypothalamic expression in marmosets and humans, suggesting co-regulation of 2 parallel anxiolytic pathways in primates. These findings demonstrate that during evolution, a transcription factor can act through multiple mechanisms to generate a common behavioral output, and that Lef1 regulates circuit development that is fundamentally important for mediating anxiety in a wide variety of animal species."


    "Anxiety is an essential behavior that is much more complex than we thought," says 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 University of Urah Health.  "This work is making us think about how brain structures control behavior in a different way."


    Anxiety happens in humans, mice, fish, and flies. It's not always a bad thing. Anxiety in zebrafish causes them to stop moving so they can hide in plain sight from predators. But being anxious at inappropriate times is counterproductive and can be a sign of unnecessary stress, a characterization that holds true not only for fish but also for people, say the researchers.


    When Drs. Xie and Dorsky began their investigation, nothing was known about a role for Lef1  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," says Dr. Dorsky.

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