Genetic Regulation of Variability in Brain Oxytocin Receptors

脑催产素受体变异的遗传调控

• 批准号: 10361226
• 负责人: Larry J Young
• 金额: $ 43.46万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-05-24 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10361226
• 关键词: Affect; Alleles; Animal Model; Area; Attention; Autism Diagnosis; Behavior; Behavioral Genetics; Binding; Brain; Brain region; CRISPR/Cas technology; Cell Nucleus; ChIP-seq; Chromatin; Chromatin Structure; Cognition Disorders; Cues; Data; Detection; Emotions; Encyclopedia of DNA Elements; Enhancers; Eye; Face; Future; Gene Expression; Genes; Genetic; Genetic Polymorphism; Genetic Transcription; Genetic Variation; Genetic study; Goals; Human; Human Genetics; Immediate-Early Genes; Intranasal Administration; Lead; Learning; Life; Link; Linkage Disequilibrium; Mammals; Mental disorders; Microtus; Modeling; Molecular; Mus; Mutation; Nucleus Accumbens; Oxytocin; Oxytocin Receptor; Pair Bond; Partner in relationship; Pattern; Pharmacology; Phenotype; Play; Population Heterogeneity; Process; Psychopathology; RNA Interference; Receptor Gene; Regulation; Rewards; Role; SNP genotyping; Sampling; Sampling Studies; Sensory; Signal Transduction; Single Nucleotide Polymorphism; Social Behavior; Social Functioning; Social Values; Stimulus; Symptoms; System; Testing; Tissues; Translating; Untranslated RNA; Variant; autism spectrum disorder; behavioral phenotyping; brain behavior; brain tissue; chromatin immunoprecipitation; density; disorder risk; endophenotype; experience; gaze; genome editing; in vivo; individual variation; individuals with autism spectrum disorder; information processing; insight; molecular phenotype; neglect; prairie vole; precision medicine; prevent; resilience; response; reward processing; sex; social; social attachment; social cognition; social influence; trait; treatment strategy

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.

项目概要 催产素 (OT) 调节社会行为的许多方面，包括父母养育、社交信息 处理和社会依恋。 OT被认为可以通过增强显着性和影响社会行为 强化社会刺激的价值。人类鼻内施用 OT 会增加对社交线索的关注， 情绪检测和社会强化学习。鼻内 OT 增强社会功能的某些方面 OT 系统是自闭症谱系障碍 (ASD) 患者的主要药理学靶点 增强 ASD 患者的社会功能。非编码区的单核苷酸多态性（SNP） 人类 OT 受体基因 (OXTR) 与 ASD 的核心症状、大脑活动模式改变、 和 ASD 的诊断。然而，人类基因关联研究并没有提供关于如何 OXTR 的多态性会导致大脑功能或社会行为的变化。社会上实行一夫一妻制 草原田鼠是探索基因变异的精确分子机制的理想模式生物。 OXTR 基因可以导致大脑表型和下游社会行为的改变。 OXTR 信号传导 伏隔核（NAcc）在异亲养育和社会纽带形成中发挥着重要作用 草原田鼠。草原田鼠 NAcc 中 OXTR 的密度存在显着的个体差异，即 与社会行为的变化以及对早期社会忽视的恢复力有关。一组 14 个 SNP 草原田鼠 OXTR 基因 (Oxtr) 解释了 NAcc 中 OXTR 密度变异的 80%，但在 其他大脑区域。该提案的目标是利用草原田鼠来探索 Oxtr 的变异如何影响 分子过程和大脑表型是假设影响下游的机制的一部分 行为表型。由于与 NAcc OXTR 密度密切相关的 14 个 SNP 处于完美状态 迄今为止研究的样本中存在连锁不平衡，因此无法确定哪些 SNP 是 最有可能影响 Oxtr 表达。第一个目标将检查候选 SNP 的关联 通过 230 只遗传多样性草原田鼠的 NAcc OXTR 密度来确定相关性最强的 SNP NAcc 中的 OXTR 密度。第二个目标将审查候选 SNP 的影响力及其影响力 社会性互动期间协调大脑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 中 Oxtr 的监管环境 其他大脑区域，以进一步细化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发挥作用的 SNP。 为了确定那些对 NAcc 中 OXTR 密度影响最大的因素。的表征 最有可能影响 OXTR 表达的 SNP 的调控状态及其对大脑的影响 功能将提供重要的见解，指导未来人类遗传学研究的潜力 OXTR SNP 对大脑表型、社会认知和精神病理学的影响。