β-catenin mediates behavioral resilience through Dicer1/microRNA regulation

β-catenin is a multi-functional protein that plays an important role in the mature central nervous system; its dysfunction has been implicated in several neuropsychiatric disorders, including depression. Here we show that β-catenin mediates pro-resilient and anxiolytic effects in mice in the nucleus accumbens, a key brain reward region, an effect mediated by D2-type medium spiny neurons. Using genome-wide β-catenin enrichment mapping, we identify Dicer1—important in small RNA (e.g., microRNA) biogenesis—as a β-catenin target gene that mediates resilience. Small RNA profiling after excising β-catenin from nucleus accumbens in the context of chronic stress reveals β-catenin-dependent microRNA regulation associated with resilience. Together, these findings establish β-catenin as a critical regulator in the development of behavioral resilience, activating a network that includes Dicer1 and downstream microRNAs. We thus present a foundation for the development of novel therapeutic targets to promote stress resilience.