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.

抽象的缩短的发育周期和相似的大脑组织使非人类灵长类动物成为理想的模型获奖理由：研究自闭症谱系障碍（ASD）夸大的大脑生长假说。具体来说，研究表明，患有以下疾病的儿童的大脑发育轨迹明显更加陡峭且不同与神经典型对照相比，自闭症谱系障碍（ASD）的过度生长可能是由与神经发生和突触修剪。其中一个基因是 DUF1220，它已被证明会影响大脑生长，但在非人类灵长类动物大脑的个体内变异性方面仍然没有得到充分研究发展。在成年人中，DUF1220 拷贝数变异的增加与大脑大小和大脑大小病理学的个体差异。此外，在成年人中，DUF1220 增加拷贝数与以下方面的较高分数相关：(1) 一般智力、(2) 数学能力和 (3) 提高 ASD 症状严重程度。在这里，我们建议利用非人类灵长类动物模型（恒河猴）来测试物种内 DUF1220 拷贝数的增加是否与整体和区域大脑生长相关以及 ASD 样行为表型的严重程度增加。在目标 1 中，我们将量化拷贝数 1q21 区域（来自血液）中 DUF1220 的变异，并在体内纵向获取 MRI 和 DTI 扫描 42 只 6、12、18 和 24 个月大的猴子样本。我们将进行方差分析 (ANOVA) 以每个进化枝中的 DUF1220 拷贝数（低/高）和性别（女性/男性）作为自变量，大脑大小作为因变量（总体积、灰质和白质、表面积、皮质厚度、回转和连通性）。我们还将检查 DUF1220 拷贝数对我们的大脑测量值的变化斜率（跨越 6、12、18、24 个月）。此外，我们将使用一个区域- 兴趣法量化构成社交大脑网络的大脑区域内的灰质和白质并测试它们与 DUF1220 拷贝数变体的关联。在目标 2 中，我们计划评估社会认知每六个月使用三项与 ASD 相关的认知测试，包括相互注视目光跟随，以及社交动机测试。我们将使用方差分析来确定社交方面的差异低 DUF1220 拷贝数和高 DUF1220 拷贝数之间的动机、相互目光注视和注视追踪每个时间点（6、12、18 和 24 个月）的 6 个进化枝中的任何一个。我们还将执行偏相关检查社交大脑网络中灰质和白质体积之间的关系和分数在社会认知测试中，以 DUF1220 拷贝数作为协变量。这些发现共同将：(1) 提供非人类灵长类 ASD 模型的实用性的额外证据，并且 (2) 帮助阐明与 DUF1220 相关的大脑大小和社会认知变化的发育时间框架，作为确定潜在有效干预措施的关键时间点。