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

• 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
• 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

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 缩短的发育时期和类似的大脑组织使非人类灵长类动物成为理想的模型 用于研究自闭症谱系障碍（ASD）夸大的脑生长假设。具体来说， 研究表明，患有儿童的大脑发育轨迹显着陡峭，并且 与神经型对照相比，ASD与神经型对照相比，这种过度生长可能是由几个基因驱动的 神经发生和突触修剪。这样的基因是DUF1220，它已显示出影响大脑生长的 但是在非人类灵长类动物大脑的个体内变异性的背景下，仍然在很大程度上被研究 发展。在成年人中，DUF1220中的拷贝数变体增加与 脑大小和大脑大小病理学的个体变异。此外，在成年人中，DUF1220的增加 拷贝数与（1）一般智能，（2）数学能力和（3）增加的分数相关 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）测试 DUF1220拷贝数的种类是否增加与整体和区域大脑的生长有关 以及增加类似ASD的行为表型的严重程度。在AIM 1中，我们将量化副本编号 DUF1220中1q21区域的变体（来自血液），并在体内MRI和DTI中纵向扫描A 在6、12、18和24个月大时的42只猴子样本。我们将执行方差分析（方差分析） 每个进化枝（低/高）和性别（女性/男性）作为自变量和性变量，并以DUF1220的拷贝数为单位 大脑大小作为因变量（总体积，灰色和白色物质，表面积，皮质） 厚度，回旋和连通性）。我们还将检查DUF1220副本编号对 大脑措施的变化斜率（在6、12、18、24个月之间）。此外，我们将使用一个区域 量化包括社交大脑网络的大脑区域内灰质和白质的兴趣方法 并测试其与DUF1220拷贝数变体的关联。在AIM 2中，我们计划评估社会认知 每六个月使用针对ASD相关的三个认知测试，包括相互视线 和关注的关注以及社会动机测试。我们将使用方差分析来确定社会的差异 动机，相互视线和凝视在低和高的DUF1220复制号之间的关注 每个时间点（6、12、18和24个月）的六个进化枝中的任何一个。我们还将执行部分相关性 检查社交大脑网络中灰质与白质量之间的关系并得分 在社会认知测试中，DUF1220复制号作为协变量。这些发现将在一起：（1） 提供其他证据表明ASD非人类灵长类动物模型的实用性，（2）有助于阐明 与DUF1220相关的大脑规模和社会认知变化的发展时间框架，作为一种方式 确定潜在有效干预措施的关键时间点。