Anxiety is a feeling of uneasiness and worry. We all want to avoid this unpleasant feeling. In fact, anxiety possesses cognitive function: it serves to maintain high levels of vigilance for danger. Therefore, it is thought that anxiety is an adaptive response that helps animals survive under threat. But chronic or long-lasting anxiety at inappropriate times is harmful and is related to many mental and physical disorders in humans.
Working with mice and zebrafish, researchers from the University of Pennsylvania, University of Utah, University of Iowa, and Vanderbilt University School of Medicine have demonstrated that the gene encoding the transcription factor Lef1
is required for the differentiation of neurons that affect anxiety. Published August 24 in PLoS Biology, the study (Lef1-dependent hypothalamic neurogenesis inhibits anxiety) may be useful for the diagnosis and treatment of anxiety disorders.
Anxiety is more complex than thought and this study helps understand how the brain controls behavior, according to first author Yuanyuan Xie.
Recent studies have suggested that innate behaviors are conserved across species. Until now, however, molecular signaling pathways that regulate the formation of neurons mediating these behaviors remain elusive.
The Wnt signaling pathway is known to regulate brain development, and it acts through Tcf/Lef transcription factors.
In this work, Xie and colleagues looked at the Wnt signaling pathway in order to study the link between gene regulation and behavioral circuits. They found that Lef1-mediated hypothalamic Wnt signaling has a key role in regulating the formation of anxiolytic neurons in both mice and zebrafish.
Both mice and zebrafish whose brains lacked Lef1 exhibited signs of anxiety, suggesting that Lef1 inhibits anxiety.
For zebrafish lef1 mutants, Lef1 loss led to lower amounts of neurons in the brain structure hypothalamus. This indicated that Lef1 is required for the formation of hypothalamic neurons. RNA sequencing analysis of the hypothalamus revealed a number of genes affected by Lef1 loss. Subsequent analyses suggested that these Lef1-dependent genes are associated with anxiety.
Likewise, gene knockout experiments in mice underscored the importance of Lef1 in the generation of hypothalamic neurons.
The data demonstrate that the transcription factor Lef1 functions to regulate hypothalamic neuron formation and inhibit anxiety in both mice and zebrafish. The newly-unveiled discovery would have implications for the treatment of anxiety disorders.