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Genetic determinants of early brain development in an animal model of autism spectrum disorder (ASD)

自闭症谱系障碍（ASD）动物模型早期大脑发育的遗传决定因素

基本信息

批准号：
10215682
负责人：
WILLIAM D HOPKINS
金额：
$ 24.3万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-01 至 2023-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10215682
关键词：
1q21 Adult Affect Age-Months Analysis of Variance Animal Model Area Behavior Blood Brain Brain region Child Cognition Cognitive Communication impairment Copy Number Polymorphism Development Diagnosis Evolution Eye Female Genes Genetic Genetic Determinism Growth Human Individual Infant Intelligence Interdisciplinary Study Light Link Literature Location Macaca Macaca mulatta Magnetic Resonance Imaging Measures Modeling Monkeys Motivation Neurobiology Neurologic Pathology Phenotype Phylogenetic Analysis Physiology Play Primates Reporting Research Research Personnel Role Salvelinus Sampling Scanning Severities Study models Surface Symptoms Tertiary Protein Structure Testing Thick Time adult with autism spectrum disorder autism spectrum disorder autistic children behavioral phenotyping brain size cognitive testing communication behavior effective intervention gaze gray matter in vivo individual variation interest male mathematical ability nerve stem cell neurogenesis nonhuman primate repetitive behavior season of birth sex social social cognition social communication social deficits synaptic pruning trait white matter

项目摘要

Abstract The shortened developmental period and similar brain organization make nonhuman primates an ideal model for studying the exaggerated brain growth hypothesis of autism spectrum disorder (ASD). Specifically, research indicates that the brain development trajectory is significantly steeper and different in children with ASD compared to neurotypical controls, and this overgrowth is likely driven by several genes associated with neurogenesis and synaptic pruning. One such gene is DUF1220, which has been shown to affect brain growth, but remains largely understudied in the context of intra-individual variability in nonhuman primate brain development. In adult humans, increased copy number variants in DUF1220 are positively correlated with individual variation in brain size and brain size pathology. Further, in adult humans, increases in DUF1220 copy number is associated with higher scores on (1) general intelligence, (2) math ability, and (3) increases in ASD symptom severity. Here, we propose utilizing a nonhuman primate model (rhesus monkeys) to test whether intra-species increases in DUF1220 copy number is associated with whole and regional brain growth as well as increased severity of ASD-like behavioral phenotypes. In aim 1, we will quantify copy number variants in DUF1220 in the 1q21 region (from blood) and acquire in vivo MRI and DTI scans longitudinally in a sample of 42 monkeys at 6, 12, 18, and 24 months of age. we will perform analyses of variance (ANOVAs) with DUF1220 copy number in each clade (low/high) and sex (female/male) as the independent variables and the brain size measures as the dependent variables (total volume, gray and white matter, surface area, cortical thickness, gyrification, and connectivity). We will also examine the effect of DUF1220 copy number on the slope of change for our brain measures (across 6, 12, 18, 24 months). In addition, we will use a region-of- interest approach to quantify gray and white matter within brain regions comprising the social brain network and test for their association with DUF1220 copy number variants. In aim 2, we plan to assess social cognition every six months using three cognitive tests selected for their relevance to ASD, including mutual eye gaze and gaze following, and a social motivation test. We will use ANOVAs to determine the differences in social motivation, mutual eye gaze, and gaze following between those with low and high DUF1220 copy numbers in any of the six clades at each time point (6, 12, 18, and 24 months). We will also perform partial correlations to examine the relationship between gray matter and white matter volumes in the social brain network and scores on the social cognition tests, with DUF1220 copy number as a covariate. Together these findings will: (1) provide additional evidence of the utility of nonhuman primate models of ASD, and (2) help elucidate the developmental time frame for changes in brain size and social cognition, in relation to DUF1220, as a means of identifying key time points for potential effective interventions.

摘要