Oxytocin Receptors and Social Behavior

描述(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，包括母亲的养育、社会信息处理和社会依恋。在人类中，鼻腔给药增加了对社交暗示的关注，凝视着眼睛，推断他人的情绪，信任和社会强化的学习。一些研究表明，OT增强了自闭症谱系障碍(ASD)患者的某些方面的社会功能，OT系统是增强ASD社会功能的潜在药理靶点。此外，有证据表明，ASD患者的OT系统发生了变化，包括血浆中OT浓度的降低，ASD与OT受体基因(OXTR)多态性的遗传关联，以及ASD受试者脑中OXTRmRNA的减少。在ASD和健康受试者中，OXTR基因的遗传多态与社会认知的变化有关。社会上一夫一妻制的草原田鼠为OT在调节社会行为中的作用提供了很好的见解。催产素作用于伏隔核(NAcc)，促进异地营养和配偶之间的配对结合。NAcc中OXTR密度的变化与异位行为和配对结合的变化相关。在这个项目中，我们将探索OXTR基因的自然遗传变异对社会行为和对早期社会应激源的易感性的贡献。第一个目的是确定草原田鼠OXTR基因中预测纹状体(如NAcc和尾壳核)OXTR表达的单核苷酸多态性是否与多个发育时期的雄性和雌性草原田鼠的社会行为变化有关。在第二个目标中，我们将在发育早期将针对OXTR的shRNA病毒载体注入高表达OXTR的基因型田鼠的NAcc中，以确定OXTR敲除NAcc是否概括了目标1中观察到的表型-基因型关系。第三个目标将检验NAcc中低水平OXTR的动物更严重地受到早期社会剥夺的影响的假设，模拟基因x环境交互作用。最后，我们将探索一种刺激OT释放的药理学方法可以挽救由OXTR基因多态和早期社会剥夺所产生的社会缺陷的可能性。我们将考察三个不同的发展窗口，用于基于慢性OT的治疗以及成人对伴侣偏好形成的急性治疗。这些研究将提供对OXTR信号对一系列社会行为的急性和发育影响的详细洞察，确定OXTR在调节社会行为的大脑区域表达变化的影响，并开始探索一种潜在的药物干预措施，以增强OXTR功能受损的个体的OXTR信号。这项工作将为未来发展新的治疗策略提供信息，以增强自闭症和其他精神障碍的社会功能。 公共卫生相关性：在动物模型中，神经肽催产素增强了社会动机和社会依恋，并改善了被诊断为自闭症谱系障碍的人类的社会功能。这个项目使用社会一夫一妻制的草原田鼠来探索催产素受体变异影响社会行为的神经机制。这些实验将提供对催产素系统受损后果的洞察，并可能为改善自闭症和其他精神障碍的社会功能提供新的治疗策略。

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.