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）理解的关键一步是识别潜在的