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)的理解的关键一步是找出潜在的 遗传和环境风险因素。一些罕见的拷贝数变体(CNV)已经出现为 ASD的强大遗传风险因素。然而，并不是所有的个体都表现出ASD和ASD症状的严重性 在CNV的运营商中有所不同。鉴于早期治疗干预可以减轻症状，它是 有理由认为早期的环境因素也会影响以后的ASD症状。然而， 操纵遗传和早期环境因素之间的相互作用以确定机制 对人类来说很难。我们的团队处于独特的地位，可以试验性地解决这个问题。首先，我们有 鉴定ASD遗传性小鼠模型的非典型幼鼠发声序列。为此，我们的团队应用了一个 一套复杂的统计工具。第二，我们的团队开发了创新的实验工具和 证明了这种非典型的幼崽叫声序列诱导的母性方式较少。这一观察表明 新生儿发声是与母亲进行社会交流的一种方式，这表明它影响着 产妇保健水平。第三，我们发现，丰富的住房，这一已知的环境操纵逆转了 母体分离对小鼠的有害行为影响，改变了a基因的表达和甲基化 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 为了验证我们的中心假设，CNV干扰了新生儿与母亲的社交交流，并 这一早期经验通过表观遗传修饰CNV-1的表达加剧了ASD样行为。 编码的基因。我们将使用父本15q11-13重复、15q13.3半合子和 22q11.2半合子，因为它们代表了ASD的三个强大的遗传风险因素。使用多个型号将 使我们能够确定新生儿社交在CNV相关性中的共同和不同作用 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 新生儿时期的结构，以及它是否与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产妇护理的影响；目标3：测量改变的效果 产妇护理对ASD样行为和CNV基因表达和表观遗传修饰的严重程度。 这个项目的结果将揭示遗传因素和新生儿社会之间的相互作用。 与母亲的沟通通过表观遗传导致ASD样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背后的基因-环境相互作用。