Oxytocin Receptors and Social Behavior

催产素受体和社会行为

• 批准号: 8438790
• 负责人: Larry J Young
• 金额: $ 44.04万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-19 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8438790
• 关键词: Acute; Adolescent; Adult; Affect; Agonist; Alleles; Animal Model; Animals; Area; Attention; Autistic Disorder; Behavior; Behavioral; Binding; Brain; Brain region; Chronic; Clinical Trials; Corpus striatum structure; Cues; Development; Diagnosis; Elderly; Emotions; Empathy; Environment; Eye; Face; Female; Future; Genes; Genetic; Genetic Markers; Genetic Polymorphism; Genetic Variation; Genotype; Human; Individual; Intervention; Intranasal Administration; Learning; Life; Link; Mammals; Mediating; Melanocortin 4 Receptor; Mental disorders; Messenger RNA; Microtus; Modeling; Motivation; Neuropeptides; Nucleus Accumbens; OXT gene; Oxytocin; Oxytocin Receptor; Pair Bond; Partner in relationship; Patients; Pharmacotherapy; Phenotype; Plasma; Play; Predisposition; Proteins; Receptor Gene; Role; Signal Transduction; Single Nucleotide Polymorphism; Social Behavior; Social Functioning; Social isolation; Staging; Symptoms; System; Techniques; Testing; Trust; Variant; Viral Vector; Work; autism spectrum disorder; base; clinically relevant; density; gaze; genetic association; improved; information processing; innovation; insight; male; melanotan-II; neuromechanism; novel therapeutics; prairie vole; preference; putamen; research study; small hairpin RNA; social; social attachment; social cognition; social deprivation; stressor; translational approach

DESCRIPTION (provided by applicant): Oxytocin (OT) is a neuropeptide that plays an important role in regulating many aspects of social behavior, including maternal nurturing, social information processing, and social attachment. Intranasal administration of OT in humans increases attention to social cues, gazing into the eyes, inferring the emotions of others, trust and socially reinforced learning. Several studies have demonstrated that OT enhances some aspects of social functioning in individuals with autism spectrum disorder (ASD), and the OT system is a potential pharmacological target for enhancing social function in ASD. Furthermore, there is evidence of altered OT systems in ASD, including decreased concentrations of OT in plasma, genetic association between ASD and polymorphisms in the OT receptor gene (OXTR), and reduced OXTR mRNA in the brains of subjects with ASD. Genetic polymorphisms in the OXTR gene have been associated with variation in social cognition in both ASD and healthy subjects. The socially monogamous prairie vole has provided great insights into the role of OT in regulating social behavior. OT acts in the nucleus accumbens (NAcc) to promote alloparental nurturing and pair bonding between mates. Variation in OXTR density in the NAcc is correlated with variation in alloparental behavior and pair bonding. In this project we will explore the contribution of a natural genetic variation in the OXTR gene to social behavior and susceptibility to early-life social stressors. The first aim will determine whether a single nucleotide polymorphism in the prairie vole oxtr gene that predicts OXTR expression in the striatum (e.g. NAcc and caudate putamen) is associated with variation in social behavior in male and female prairie voles at multiple developmental epochs. In the second Aim, we will infuse an shRNA viral vector targeting the Oxtr in the NAcc of high OXTR expressing genotype voles early in development to determine whether OXTR knockdown the NAcc recapitulates the phenotype-genotype relationships observed in Aim 1. The third aim will test the hypothesis that animals with low levels of OXTR in the NAcc are more severely impacted by early-life social deprivation, modeling gene x environment interactions. Finally we will explore the possibility that a pharmacological approach to stimulate OT release can rescue the social deficits generated by the OXTR polymorphism and early-life social deprivation. We will examine three different developmental windows for chronic OT based therapy as well as an acute treatment in adults on partner preference formation. These studies will provide detailed insight into the acute and developmental impact of OXTR signaling on a suite of social behaviors, determine the effect of variation in OXTR expression in brain regions known to regulate social behavior, and begin to explore a potential pharmacological intervention to enhance OXTR signaling in individuals with compromised OXTR function. This work will inform future development of novel therapeutic strategies to enhance social function in ASD and other psychiatric disorders. PUBLIC HEALTH RELEVANCE: The neuropeptide oxytocin enhances social motivation and social attachment in animal models and improves social functioning in humans diagnosed with Autism Spectrum Disorder. This project uses socially monogamous prairie voles to explore the neural mechanisms by which variation in oxytocin receptors affects social behavior. The experiments will provide insights into the consequences of compromised oxytocin systems and may inform novel therapeutic strategies for improving social functioning in autism and other psychiatric disorders.

描述（由申请人提供）：催产素（OT）是一种神经肽，在调节社会行为的许多方面发挥着重要作用，包括母亲养育、社会信息处理和社会依恋。人类鼻内施用 OT 可以增加对社交线索、凝视眼睛、推断他人情绪、信任和社交强化学习的注意力。多项研究表明，OT 可以增强自闭症谱系障碍 (ASD) 患者社会功能的某些方面，并且 OT 系统是增强 ASD 社交功能的潜在药理学靶点。此外，有证据表明 ASD 中 OT 系统发生了改变，包括血浆中 OT 浓度降低、ASD 与 OT 受体基因 (OXTR) 多态性之间的遗传关联，以及 ASD 受试者大脑中 OXTR mRNA 的减少。 OXTR 基因的遗传多态性与 ASD 和健康受试者的社会认知变异有关。实行一夫一妻制的草原田鼠为了解 OT 在调节社会行为中的作用提供了深刻的见解。 OT 在伏隔核 (NAcc) 中发挥作用，促进异亲养育和配偶之间的配偶关系。 NAcc 中 OXTR 密度的变化与异亲行为和配对关系的变化相关。在这个项目中，我们将探讨 OXTR 基因的自然遗传变异对社会行为和对早期社会压力源的敏感性的贡献。第一个目标是确定草原田鼠 oxtr 基因中预测纹状体（例如 NAcc 和尾壳核）中 OXTR 表达的单核苷酸多态性是否与雄性和雌性草原田鼠在多个发育时期的社会行为变化相关。在第二个目标中，我们将在发育早期将针对 Oxtr 的 shRNA 病毒载体注入高 OXTR 表达基因型田鼠的 NAcc 中，以确定 OXTR 敲低 NAcc 是否重现目标 1 中观察到的表型-基因型关系。第三个目标将测试假设 NAcc 中 OXTR 水平较低的动物受到早期社会剥夺的影响更严重，模拟基因 x 环境相互作用。最后，我们将探讨刺激 OT 释放的药理学方法是否可以挽救 OXTR 多态性和早期社会剥夺造成的社会缺陷。我们将研究基于慢性 OT 治疗的三种不同的发育窗口，以及成人伴侣偏好形成的急性治疗。这些研究将详细了解 OXTR 信号传导对一系列社会行为的急性和发育影响，确定已知调节社会行为的大脑区域中 OXTR 表达变化的影响，并开始探索增强 OXTR 的潜在药物干预措施OXTR 功能受损个体的信号传导。这项工作将为未来开发新的治疗策略提供信息，以增强自闭症谱系障碍和其他精神疾病的社会功能。 公共卫生相关性：神经肽催产素可增强动物模型的社会动机和社会依恋，并改善被诊断患有自闭症谱系障碍的人类的社会功能。该项目利用社会一夫一妻制的草原田鼠来探索催产素受体的变化影响社会行为的神经机制。这些实验将深入了解催产素系统受损的后果，并可能为改善自闭症和其他精神疾病的社会功能提供新的治疗策略。