Genetic Regulation of Variability in Brain Oxytocin Receptors

项目摘要 催产素(OT)调节社会行为的许多方面，包括父母的养育、社会信息 加工和社交依恋。加班被认为通过提高知名度和影响社交行为 强化社会刺激的价值。人类鼻腔注射催产素会增加人们对社交线索的关注， 情绪检测和社会强化学习。鼻腔催产素增强社会功能的某些方面 在自闭症谱系障碍(ASD)患者中，OT系统是治疗 增强自闭症患者的社会功能。非编码区的单核苷酸多态性(SNPs) 人类OT受体基因(OXTR)与ASD的核心症状、脑活动模式改变、 和ASD的诊断。然而，人类基因关联研究并没有提供关于 OXTR基因的多态会导致大脑功能或社会行为的变化。社会一夫一妻制 草原田鼠是一种理想的模式生物，可以用来探索物种变异的精确分子机制。 OXTR基因可以导致大脑表型的改变，并导致下游的社会行为。OXTR信令传入 伏隔核(NAcc)在异地营养和社会纽带的形成中起重要作用。 草原田鼠。草原田鼠NAcc中OXTR的密度存在显着的个体差异，即 与社会行为的变化和对早年社会忽视的适应能力有关。中国的一组14个SNP 草原田鼠OXTR基因(OXTR)解释了NAcc中OXTR密度的80%的变异，但在NAcc中解释不了 其他脑区。这项提议的目标是用草原田鼠来探索OXTR的变异是如何影响 分子过程和大脑表型是假想影响下游的机制的一部分 行为表型。因为与NAcc OXTR密度密切相关的14个SNP处于完美状态 在到目前为止所研究的样本中，无法确定这些SNP中的哪一个是 最有可能影响OXTR的表达。第一个目标将检查候选SNPs的关联性 利用230只遗传多样性草原田鼠的NAcc OXTR密度确定与最强相关的SNPs 在NAcc中具有OXTR密度。第二个目标将检查候选SNPs及其 社会性互动中大脑协调活动的相关分子表型。第三个目标 将使用染色质免疫沉淀(CHIP)来表征NAcc和NAcc中OXTR的调控格局 其他大脑区域，以进一步完善最有可能影响大脑表型的SNP列表。 最后，CRISPR/Cas9基因组编辑系统将用于编辑最有可能在 以便找出对NAcc中OXTR密度影响最大的因素。刻画人物形象 SNP的调节状态最有可能影响OXTR的表达及其对大脑的影响 功能将提供重要的见解，将指导未来的人类基因研究，研究潜在的 OXTR单核苷酸多态对脑表型、社会认知和精神病理的影响

Project Summary Oxytocin (OT) regulates many aspects of social behavior, including parental nurturing, social information processing, and social attachment. OT is thought to influence social behaviors by enhancing the salience and reinforcing value of social stimuli. Intranasal administration of OT in humans increases attention to social cues, emotion detection and socially reinforced learning. Intranasal OT enhances some aspects of social functioning in individuals with autism spectrum disorder (ASD), and the OT system is a leading pharmacological target for enhancing social function in ASD. Single nucleotide polymorphisms (SNPs) in noncoding regions of the human OT receptor gene (OXTR) are associated with core symptoms of ASD, altered brain activity patterns, and diagnosis of ASD. However, human gene association studies do not provide insights into how polymorphisms in OXTR lead to variation in brain function or social behavior. The socially monogamous prairie vole is an ideal model organism to explore the precise molecular mechanisms by which variation in the OXTR gene can lead to alterations in brain phenotype, and downstream social behaviors. OXTR signaling in the nucleus accumbans (NAcc) is critically involved in alloparental nurturing and social bond formation in prairie voles. There is remarkable individual variation in the density of OXTR in the NAcc of prairie voles that is associated with variation in social behavior and with resilience to early life social neglect. A set of 14 SNPs in the prairie vole OXTR gene (Oxtr) explains up to 80% of the variation in OXTR density in the NAcc, but not in other brain areas. The goal of this proposal is to use prairie voles to explore how variation in Oxtr influences molecular processes and brain phenotypes that are part of machinery hypothesized to affect downstream behavioral phenotypes. Since the 14 SNPs strongly associated with NAcc OXTR density were in perfect linkage disequilibrium in the samples studied thus far, it is not possible to determine which of those SNPs is most likely to be influencing Oxtr expression. The first Aim will examine the association of the candidate SNPs with NAcc OXTR density in 230 genetically diverse prairie voles to identify the SNPs most strongly associated with OXTR density in the NAcc. The second Aim will examine the influence of the candidate SNPs and their associated molecular phenotype on coordinated brain activity during sociosexual interactions. The third Aim will use chromatin immunoprecipitation (ChIP) to characterize the regulatory landscape of the Oxtr in NAcc and other brain regions in order to further refine the list of SNPs most likely to be influencing brain phenotype. Finally, the CRISPR/Cas9 genome editing system will be used to edit the SNPs most likely to be functional in order to identify those with the greatest influence on OXTR density in the NAcc. Characterization of the regulatory status of the SNP most likely to be influencing OXTR expression and the consequences on brain function will provide important insights that will guide future human genetic studies investigating the potential influence of OXTR SNPs on brain phenotype, social cognition and psychopathology.