COURTESY OF ERIC NESTLER
EDITOR'S CHOICE IN NEUROSCIENCE
C. Dias et al., “β-catenin mediates stress resilience through Dicer1/microRNA regulation,” Nature, 516:51-55, 2014.
In one mouse model of depression, mice are subjected to repeated encounters with more-aggressive counterparts. After such “chronic social defeat stress,” most mice become antisocial, but some come out fine. What sets the resilient mice apart? In 2011, Eric Nestler of the Icahn School of Medicine at Mount Sinai in New York City and colleagues reported that within the brain’s nucleus accumbens, elements of the Wnt signaling cascade are essential for staving off stress responses. Among other cellular roles, the protein β-catenin acts as a transcription factor in the Wnt pathway, so the researchers decided to explore its role in resilience.
Following social defeat stress, mice overexpressing β-catenin in the nucleus accumbens had milder depressive symptoms than controls. β-catenin’s antidepressant-like effects are “particularly interesting” because the Wnt pathway is already a target of psychiatric drugs, such as lithium, says Emory University’s Kerry Ressler.
When Nestler and his team examined where β-catenin bound DNA in nucleus accumbens cells, they spotted Dicer1, a gene required for microRNA processing. A series of experiments demonstrated that Dicer1’s expression, activated by β-catenin, was key to the sanguine mice’s fortitude.
Exploring the roles of microRNAs and their targets in resilience is a direction for future work, says the study’s first author, Caroline Dias. The results also suggest new avenues for drug development. “As we do it now, we mostly are targeting neurotransmitter systems and things that have gone wrong in depression,” says Dias, an MD/PhD student in Nestler’s lab. This “approaches it from a different way and says, ‘Well, what do we know about what goes right when things are working well?’”