Oxytocin receptor knockout prairie voles generated by CRISPR/Cas9 editing show reduced preference for social novelty and exaggerated repetitive behaviors

• Type of Material: Article
• Authors: Kengo Horie, Emory University; Kiyoshi Inoue, Emory University; Shingo Suzuki, Tohoku University; Saki Adachi, Tohoku University; Saori Yada, Tohoku University; Takashi Hirayama, Juntendo University; Shizu Hidema, Tohoku University; Larry Young, Emory University; Katsuhiko Nishimori, Tohoku University
• Language: English
• Date: 2019-05-01
• Publisher: ACADEMIC PRESS INC ELSEVIER SCIENCE
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2018 Elsevier Inc.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.yhbeh.2018.10.011
• Title of Journal or Parent Work: HORMONES AND BEHAVIOR
• Volume: 111
• Start Page: 60
• End Page: 69
• Grant/Funding Information: This research was supported by JSPS Grant-in-Aid for Scientific Research (A) [Grant Numbers 15H02442 (2015-2018)], JSPS Grant-in-Aid for challenging Exploratory Research [Grant Numbers 16K15698 (2016-2017)], JSPS Grant in Aid for JSPS Research Fellow [Grant Number 16J05070 (2016-2019)], MEXT Grant-in-Aid for Scientific Research on Innovative Areas “the evolutionary origin and neural basis of the empathetic systems” [Grant Numbers 16H01480 (2016-2017)], and Strategic Research Program for Brain Sciences from Japan Agency for Medical Research and development (AMED) [Grant Numbers 18dm0107076h0003 (2016-2020)]. KI and LJY’s contribution to this work was supported by NM grants R01MH096983, R01MH112788, R01MH112788 and P50MH100023 to LJY and P510D11132 to YNPRC.
• Keywords: Prairie voles; SPONTANEOUS MATERNAL-BEHAVIOR; ANXIETY; VASOPRESSIN; Behavioral Sciences; ONE-STEP GENERATION; Science & Technology; CRISPR/Cas9; MICE; Life Sciences & Biomedicine; ULTRASONIC VOCALIZATIONS; RNA; Endocrinology & Metabolism; MOUSE MODELS; Non-traditional models; Social novelty preference; NUCLEUS-ACCUMBENS; ATTACHMENT; Autism spectrum disorder; Social behavior; Genome editing; Oxytocin receptor
• Research Categories: Health Sciences, Nutrition; Psychology, Cognitive; Biology, Neuroscience; Biology, Genetics; Psychology, Behavioral

Abstract

Behavioral neuroendocrinology has benefited tremendously from the use of a wide range of model organisms that are ideally suited for particular questions. However, in recent years the ability to manipulate the genomes of laboratory strains of mice has led to rapid advances in our understanding of the role of specific genes, circuits and neural populations in regulating behavior. While genome manipulation in mice has been a boon for behavioral neuroscience, the intensive focus on the mouse restricts the diversity in behavioral questions that can be investigated using state-of-the-art techniques. The CRISPR/Cas9 system has great potential for efficiently generating mutants in non-traditional animal models and consequently to reinvigorate comparative behavioral neuroendocrinology. Here we describe the efficient generation of oxytocin receptor (Oxtr)mutant prairie voles (Microtus ochrogaster)using the CRISPR/Cas9 system, and describe initial behavioral phenotyping focusing on behaviors relevant to autism. Oxtr mutant male voles show no disruption in pup ultrasonic vocalization, anxiety as measured by the open field test, alloparental behavior, or sociability in the three chamber test. Mutants did however show a modest elevation in repetitive behavior in the marble burying test, and an impairment in preference for social novelty. The ability to efficiently generate targeted mutations in the prairie vole genome will greatly expand the utility of this model organism for discovering the genetic and circuit mechanisms underlying complex social behaviors, and serves as a proof of principle for expanding this approach to other non-traditional model organisms.