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, Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms Correspondence to: Eric J. Nestler, [email protected]. *These authors contributed equally to this work. Current Addresses: +Department of Physiology, Michigan State University, East Lansing, Michigan, USA ++Department of Psychology, UCLA College of Life Sciences, Los Angeles, California, USA +++Institut National de la Santé et de la Recherhe Médicale (INSERM) U1130; CNRS UMR8246; UPMC UM18, Neuroscience Paris Seine, Paris, France ++++Department of Basic Medical Sciences, The University of Arizona College of Medicine-Phoenix, Arizona, USA Supplementary Information is linked to the online version of the paper at www.nature.com/nature. Author Contributions CD and JF conceived the project, designed research, conducted experiments, interpreted the results, and wrote the manuscript; HS, MR, DDW, KS, RB, BL, ER, PK, VV, DF, CP, EC,JK and EM conducted experiments; SG, CT provided reagents and tools; RN conducted experiments and provided reagents; NS, XL performed bioinformatic analysis; LS performed and supervised bioinformatic analysis; EJN conceived the project, designed and supervised research, interpreted the results, and wrote the manuscript. All authors discussed the results and commented on the manuscript. Author Information All sequencing data have been deposited into the Gene Expression Omnibus with accession number GSE61294 and GSE61295. Reprints and permissions information is available at www.nature.com/reprints. The authors declare no competing financial interests. HHS Public Access Author manuscript Nature. Author manuscript; available in PMC 2015 June 04. Published in final edited form as: Nature. 2014 December 4; 516(7529): 51–55. doi:10.1038/nature13976. A uhor M anscript