TY - JOUR
T1 - Oxytocin receptor knockout prairie voles generated by CRISPR/Cas9 editing show reduced preference for social novelty and exaggerated repetitive behaviors
AU - Horie, Kengo
AU - Inoue, Kiyoshi
AU - Suzuki, Shingo
AU - Adachi, Saki
AU - Yada, Saori
AU - Hirayama, Takashi
AU - Hidema, Shizu
AU - Young, Larry J.
AU - Nishimori, Katsuhiko
N1 - Funding Information:
KH contributed all experiments. KI performed the OXTR autoradiography. SS performed TGFα shedding assay. LJY gave us prairie voles, consulted on experimental design and helped write the manuscript. TH, SY, SH supported management of the prairie voles. KN supervised our experiments. We thank Dr. Yuichi Hiraoka and Dr. Tomokazu Fukuda for comments and discussions. 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 NIH grants R01MH096983, R01MH112788, R21MH114151 and P50MH100023 to LJY and P51OD11132 to YNPRC.
Funding Information:
KH contributed all experiments. KI performed the OXTR autoradiography. SS performed TGFα shedding assay. LJY gave us prairie voles, consulted on experimental design and helped write the manuscript. TH, SY, SH supported management of the prairie voles. KN supervised our experiments. We thank Dr. Yuichi Hiraoka and Dr. Tomokazu Fukuda for comments and discussions. 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 NIH grants R01MH096983 , R01MH112788 , R21MH114151 and P50MH100023 to LJY and P51OD11132 to YNPRC.
PY - 2019/5
Y1 - 2019/5
N2 - 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.
AB - 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.
KW - Autism spectrum disorder
KW - CRISPR/Cas9
KW - Genome editing
KW - Non-traditional models
KW - Oxytocin receptor
KW - Prairie voles
KW - Social behavior
KW - Social novelty preference
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U2 - 10.1016/j.yhbeh.2018.10.011
DO - 10.1016/j.yhbeh.2018.10.011
M3 - Article
C2 - 30713102
AN - SCOPUS:85056224162
VL - 111
SP - 60
EP - 69
JO - Hormones and Behavior
JF - Hormones and Behavior
SN - 0018-506X
ER -