b-Catenin Mediates the Development of Behavioral Resilience [ChIP-Seq]

Here we show that β-catenin mediates pro-resilient and anxiolytic effects in mice in the nucleus accumbens (NAc), a key brain reward region, an effect that is mediated by β-catenin signaling in D2-type medium spiny neurons (MSNs) specifically. Conversely, blocking β-catenin function in NAc promotes susceptibility to chronic stress, and we show evidence of robust suppression of β-catenin transcriptional activity in the NAc both of depressed humans examined postmortem as well as of mice that display a susceptible phenotype after chronic stress, with a converse upregulation in mice that are stress resilient. Using ChIP-seq, we demonstrate a global, genome-wide enrichment of β-catenin in the NAc of resilient mice, and specifically identify Dicer1—important in small RNA (e.g., microRNA [miRNA]) biogenesis—as a critical β-catenin target gene involved in mediating a resilient phenotype. Small RNA-seq after excising β-catenin from the NAc in the context of chronic stress reveals dynamic β-catenin-dependent miRNA regulation associated with resilience. Control: 2 samples, Resilient: 2 samples, Susceptible: 2 samples; DNA input: 1 sample.