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

Here we show that ß-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 ß-catenin signaling in D2-type medium spiny neurons (MSNs) specifically. Conversely, blocking ß-catenin function in NAc promotes susceptibility to chronic stress, and we show evidence of robust suppression of ß-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 ß-catenin in the NAc of resilient mice, and specifically identify Dicer1—important in small RNA (e.g., microRNA [miRNA]) biogenesis—as a critical ß-catenin target gene involved in mediating a resilient phenotype. Small RNA-seq after excising ß-catenin from the NAc in the context of chronic stress reveals dynamic ß-catenin-dependent miRNA regulation associated with resilience. Overall design: Control: 2 samples, Resilient: 2 samples, Susceptible: 2 samples; DNA input: 1 sample.