Variation in the Oxytocin Receptor Gene Predicts Brain Region-Specific Expression and Social Attachment.
Variation in the Oxytocin Receptor Gene Predicts Brain Region-Specific Expression and Social Attachment.
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DOI：
10.1016/j.biopsych.2015.12.008
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发表时间：
2016-07-15
影响因子：
10.6
通讯作者：
Young LJ
中科院分区：
文献类型：
--
作者：
King LB;Walum H;Inoue K;Eyrich NW;Young LJ
催产素（OXT）调节社会行为的几个方面。鼻内催产素是治疗自闭症谱系障碍（ASD）社交缺陷的主要候选药物，人类催产素受体（OXTR）的常见遗传变异与情绪识别、关系质量和ASD相关。动物模型表明，大脑中Oxtr表达的个体差异驱动着社会行为的变化。我们对遗传变异如何影响脑OXTR表达的理解非常有限。我们研究了Oxtr在一夫一妻制草原田鼠中的表达，草原田鼠具有很好的OXT系统。我们用既定的神经解剖学方法量化了Oxtr mRNA和Oxtr蛋白的脑区域特异性水平。我们使用焦磷酸测序来研究Oxtr mRNA的等位基因失衡，Oxtr mRNA是多态遗传调控元件的分子特征。我们进行了下一代测序，以发现Oxtr基因及其附近的变异。我们使用伴侣偏好测试来调查社会依恋。我们的等位基因失衡数据表明，遗传变异导致了Oxtr表达的个体差异，但仅在特定的大脑区域，包括伏隔核（NAcc）， Oxtr信号促进了社会依恋。新一代测序在Oxtr内含子中发现了一个多态性，靠近一个假定的顺式调控元件，可以解释纹状体Oxtr表达变异的74%。高表达等位基因的雄性纯合表现出增强的社会依恋。综上所述，这些发现为基因对Oxtr表达的强大影响提供了令人信服的证据，并为Oxtr的非编码多态性如何影响人类社会认知和行为的个体差异提供了新的见解
Oxytocin (OXT) modulates several aspects of social behavior. Intranasal OXT is a leading candidate for treating social deficits in autism spectrum disorder (ASD) and common genetic variants in the human oxytocin receptor (OXTR) are associated with emotion recognition, relationship quality and ASD. Animal models have revealed that individual differences in Oxtr expression in the brain drive social behavior variation. Our understanding of how genetic variation contributes to brain OXTR expression is very limited. We investigated Oxtr expression in monogamous prairie voles, which have a well characterized OXT system. We quantified brain region-specific levels of Oxtr mRNA and OXTR protein with established neuroanatomical methods. We used pyrosequencing to investigate allelic imbalance of Oxtr mRNA, a molecular signature of polymorphic genetic regulatory elements. We performed next-generation sequencing to discover variants in and near the Oxtr gene. We investigated social attachment using the partner preference test. Our allelic imbalance data demonstrates that genetic variants contribute to individual differences in Oxtr expression, but only in particular brain regions, including the nucleus accumbens (NAcc), where OXTR signaling facilitates social attachment. Next-generation sequencing identified one polymorphism in the Oxtr intron, near a putative cis-regulatory element, explaining 74% of the variance in striatal Oxtr expression specifically. Males homozygous for the high expressing allele display enhanced social attachment. Taken together, these findings provide convincing evidence for robust genetic influence on Oxtr expression and provide novel insights into how non-coding polymorphisms in the OXTR might influence individual differences in human social cognition and behavior