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

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.

SUBMITTER: Horie K

PROVIDER: S-EPMC6506400 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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

Horie Kengo K Inoue Kiyoshi K Suzuki Shingo S Adachi Saki S Yada Saori S Hirayama Takashi T Hidema Shizu S Young Larry J LJ Nishimori Katsuhiko K

Hormones and behavior 20181108

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 restri ...[more]

PMID: 30713102

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Project description:There is much interest in targeting the activity in the oxytocin system to regulate social bonding. However, studies with exogenous administration of oxytocin face the caveats of its low stability, poor brain permeability and insufficient receptor specificity. The use of a small-molecule oxytocin receptor-specific agonist could overcome these caveats. Prior to testing the potential effects of a brain-penetrant oxytocin receptor agonist in clinical settings, it is important to assess how such an agonist would affect social bonds in animal models. The facultatively monogamous prairie voles (Microtus ochrogaster), capable of forming long-term social attachments between adult individuals, are an ideal rodent model for such testing. Therefore, in a series of experiments we investigated the effects of the recently developed oxytocin receptor-specific agonist LIT-001 on the acquisition and expression of partner preference, a well-established model of pair bonding, in prairie voles. LIT-001 (10 mg/kg, intraperitoneal), as expected, facilitated the acquisition of partner preference when administered prior to a 4hr cohabitation. In contrast, while animals injected with vehicle after the 4hr cohabitation exhibited significant partner preference, animals that were injected with LIT-001 did not show such partner preference. This result suggests that OXTR activation during expression of pair bonding can inhibit partner preference. The difference in effects of LIT-001 on acquisition versus expression was not due to basal differences in partner preference between the experiments, as LIT-001 had no significant effects on expression of partner preference if administered following a shorter (2hr-long) cohabitation. Instead, this difference agrees with the hypothesis that the activation of oxytocin receptors acts as a signal of presence of a social partner. Our results indicate that the effects of pharmacological activation of oxytocin receptors crucially depend on the phase of social attachments.

Dataset Information

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

Publications

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

Similar Datasets

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