Structure and Function of Neonatal Social Communication in Genetic Mouse Models of Autism

自闭症遗传小鼠模型中新生儿社交沟通的结构和功能

• 批准号: 10005276
• 负责人: Noboru Hiroi
• 金额: $ 34.01万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-21 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10005276
• 关键词: 22q11.2; Address; Adult; Age-Months; Attenuated; Behavior; Behavioral; Brain; Caring; Chromosomal Duplication; Copy Number Polymorphism; Copying Processes; Early Intervention; Environmental Risk Factor; Epigenetic Process; Exhibits; Gene Expression; Gene Expression Regulation; Genes; Genetic; Genetic Diseases; Genetic Risk; Goals; Housing; Human; Individual; Measures; Methods; Methylation; Modeling; Modification; Mothers; Mus; Neonatal; Outcome; Positioning Attribute; Risk Factors; Role; Severities; Structure; Symptoms; Testing; Therapeutic Intervention; Work; autism spectrum disorder; base; behavioral phenotyping; early experience; gene environment interaction; genetic risk factor; genetic variant; improved; innovation; maternal separation; mouse model; neonatal period; neonate; novel; pup; social communication; synergism; tool; vocalization

A critical step to improving our understanding of autism spectrum disorder (ASD) is to identify underlying genetic and environmental risk factors. A number of rare copy number variants (CNVs) have emerged as robust genetic risk factors for ASD. However, not all individuals exhibit ASD and the severity of ASD symptoms varies among carriers of a CNV. Given that early therapeutic intervention attenuates symptoms, it is reasonable to assume that early environmental factors also influence ASD symptoms later. However, manipulation of the interplay between genetic and early environmental factors to identify mechanisms is difficult in humans. Our team is uniquely positioned to experimentally address this issue. First, we have identified atypical pup vocal call sequences of a genetic mouse model of ASD. To do so, our team applied a set of sophisticated statistical tools. Second, our team developed innovative experimental tools and demonstrated that such atypical pup call sequences induce less maternal approach. This observation shows that neonatal vocalization is a means of social communication with mothers and suggests that it influences the level of maternal care. Third, we found that enriched housing, an environmental manipulation known to reverse the detrimental behavioral effects of maternal separation in mice, alters the expression and methylation of a CNV-encoded gene in mouse brains. Capitalizing on these innovative methods and observations, we propose to test our central hypothesis that CNVs disturb neonatal social communication with the mother and this early experience exacerbates ASD-like behaviors via epigenetically modified expression of CNV- encoded genes. We will use mouse models of paternal 15q11-13 duplication, 15q13.3 hemizygosity and 22q11.2 hemizygosity, as they represent three robust genetic risk factors for ASD. Use of multiple models will allow us to determine common, as well as distinct roles of neonatal social communication in CNV-associated ASD. We propose to achieve the following three Aims: Aim 1: Determine if CNVs result in atypical vocalization structure during the neonatal period and if it is correlated with ASD-like behaviors at 2 months of age; Aim 2: Determine the impact of atypical neonatal vocalization on maternal care; Aim 3: Measure the effect of altered maternal care on the severity of ASD-like behaviors and CNV gene expression and epigenetic modification. The outcomes of this project will reveal the interplay between genetic factors and neonatal social communication with mothers resulting in the ultimate severity of ASD-like behaviors through epigenetic mechanisms. The project has high translational value because it could provide a novel mechanistic base to understand the gene-environment interaction underlying ASD.

提高我们对自闭症谱系障碍（ASD）的理解的关键步骤是识别基础 遗传和环境风险因素。许多稀有拷贝数变体（CNV）已出现为 ASD强大的遗传危险因素。但是，并非所有人都表现出ASD和ASD症状的严重程度 CNV的载体之间有所不同。鉴于早期的治疗干预措施减轻了症状，这是 合理地假设早期的环境因素在以后也会影响ASD症状。然而， 操纵遗传和早期环境因素之间识别机制的相互作用的是 在人类中很难。我们的团队是独特的，可以实验解决这个问题。首先，我们有 确定了ASD遗传小鼠模型的非典型幼犬声音呼叫序列。为此，我们的团队应用了 一组复杂的统计工具。其次，我们的团队开发了创新的实验工具和 证明这种非典型幼犬呼叫序列会引起较少的母体方法。该观察结果表明 新生儿发声是与母亲的社会交流的手段，并建议它影响 孕产妇护理水平。第三，我们发现富集的住房，一种已知会逆转的环境操纵 母体分离在小鼠中的有害行为影响，改变了A的表达和甲基化 小鼠大脑中的CNV编码基因。利用这些创新的方法和观察，我们建议 为了测试我们的中心假设，即CNV扰乱了与母亲的新生儿社会交流以及 这种早期的经历通过CNV-的表观遗传修饰的表达加剧了ASD样行为 编码基因。我们将使用父亲15q11-13复制的小鼠模型，15q13.3半合子和 22Q11.2半合子，因为它们代表了ASD的三个强大的遗传危险因素。使用多种模型将 允许我们确定在CNV相关的新生儿社会交流的共同点以及不同的作用 ASD。我们建议实现以下三个目标：目标1：确定CNV是否导致非典型发声 在新生儿期间的结构，如果它与2个月大时的ASD样行为相关；目标2： 确定非典型新生儿发声对孕产妇护理的影响；目标3：衡量改变的效果 对ASD样行为的严重程度以及CNV基因表达和表观遗传修饰的严重程度的母体护理。 该项目的结果将揭示遗传因素与新生儿社会之间的相互作用 与母亲的沟通，导致通过表观遗传学的类似ASD的行为的最终严重程度 机制。该项目具有很高的翻译价值，因为它可以为 了解ASD的基因环境相互作用。