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（包括母体培养，社会信息处理和社会依恋）中起着重要作用。鼻内对人类的鼻内给药增加了人们对社会暗示的关注，凝视着眼睛，推断他人的情绪，信任和社会增强的学习。几项研究表明，OT可以增强自闭症谱系障碍（ASD）个体社会功能的某些方面，而OT系统是增强ASD社会功能的潜在药理目标。此外，有证据表明ASD中的OT系统发生了变化，包括血浆中OT浓度降低，OT受体基因（OXTR）中ASD和多态性之间的遗传关联以及ASD受试者大脑中OXTR mRNA的降低。 OXTR基因中的遗传多态性与ASD和健康受试者的社会认知变化有关。社会上一夫一妻制的草原沃尔（Vole）对OT在调节社会行为中的作用提供了很好的见解。 OT在伏隔核（NACC）中起作用，以促进伴侣之间的同种养育和配对。 NACC中OXTR密度的变化与同种类型行为和配对键的变化相关。在这个项目中，我们将探讨OXTR基因自然遗传变异对社会行为以及对早期生活压力源的敏感性的贡献。第一个目的将确定在草原vole Oxtr基因中预测纹状体中Oxtr表达的单个核苷酸多态性（例如NACC和尾状壳核）是否与多发育时期的男性和女性草原田鼠的社会行为变化有关。在第二个目标中，我们将注入针对高OXTR表达基因型NaCC的SHRNA病毒载体，以确定OXTR敲低的NACC是否在AIM 1中观察到的表型基因型关系是否会在AIM 1中观察到。第三个目标将在NACC中较低的NACC的动物在nacce的较早范围内对奈克斯的相互作用较低。最后，我们将探讨一种刺激OT释放的药理学方法可以挽救由Oxtr多态性和早期生活剥夺产生的社会缺陷的可能性。我们将检查基于长期OT治疗的三个不同的发育窗口，以及成人伴侣偏好形成的急性治疗。这些研究将详细介绍OXTR信号传导对社会行为的急性和发育影响，确定已知可调节社会行为的大脑区域中OXTR表达变异的影响，并开始探索潜在的药理干预措施，以增强OXTTR功能受损的个体中OXTR信号。这项工作将为未来的新型治疗策略开发，以增强ASD和其他精神疾病的社会功能。 公共卫生相关性：神经肽催产素可以增强动物模型中的社会动机和社会依恋，并改善被诊断为自闭症谱系障碍的人类的社会功能。该项目使用社会一夫一妻制的田鼠探索催产素受体变异会影响社会行为的神经机制。这些实验将为催产素系统的后果提供见解，并可能为改善自闭症和其他精神疾病的社会功能的新型治疗策略提供信息。