Oxytocin Receptors and Social Behavior

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重要作用，包括母亲养育、社会信息处理和社会依恋。鼻内施用OT可以增加对社交线索的注意力，凝视眼睛，推断他人的情绪，信任和社会强化学习。一些研究表明，OT增强自闭症谱系障碍（ASD）个体的社会功能的某些方面，OT系统是增强ASD社会功能的潜在药理学靶点。此外，有证据表明ASD中OT系统改变，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化相关。社会性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。催产素作用于丘脑核（NAcc），以促进异性养育和配偶之间的配对。NAcc中OXTR密度的变化与同种异体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压力的易感性的贡献。第一个目标将确定是否在草原田鼠oxtr基因的单核苷酸多态性，预测OXTR在纹状体（如NAcc和尾壳核）的表达与社会行为的变化在男性和女性草原田鼠在多个发展时期。在第二个目标中，我们将在发育早期在高OXTR表达基因型田鼠的NAcc中注入靶向OXTR的shRNA病毒载体，以确定OXTR敲低NAcc是否重现了在目标1中观察到的表型-基因型关系。第三个目标将测试假设，即在NAcc中具有低水平OXTR的动物更严重地受到早期社会剥夺的影响，模拟基因x环境相互作用。最后，我们将探讨刺激OT释放的药理学方法可以挽救由OXTR多态性和早期社会剥夺产生的社会缺陷的可能性。我们将研究三个不同的发展窗口慢性OT为基础的治疗，以及急性治疗成人对合作伙伴的偏好形成。这些研究将提供对OXTR信号传导对一系列社会行为的急性和发育影响的详细了解，确定已知调节社会行为的脑区域中OXTR表达变化的影响，并开始探索潜在的药理学干预以增强具有受损OXTR功能的个体中的OXTR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ASD和其他精神疾病的社会功能。

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.