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

摘要 缩短的发育周期和相似的大脑组织使非人灵长类成为理想的模型 用于研究自闭症谱系障碍(ASD)夸大的脑生长假说。具体来说， 研究表明，患有抑郁症的儿童的大脑发育轨迹明显更陡峭和不同 ASD与神经典型对照相比，这种过度生长可能是由几个与以下因素相关的基因驱动的 神经发生和突触修剪。其中一个这样的基因是DUF1220，它已经被证明影响大脑发育， 但在非人类灵长类动物大脑的个体内变异性的背景下，研究仍然很少 发展。在成年人中，DUF1220基因拷贝数增加的变异与 脑大小和脑大小病理的个体差异。此外，在成年人中，DUF1220的增加 文案数量与(1)一般智力、(2)数学能力和(3)增加的分数有关 ASD症状严重程度。在这里，我们建议使用非人类灵长类动物模型(恒河猴)来测试 种内DUF1220拷贝数增加是否与整体和局部脑发育有关 以及ASD样行为表型的严重性增加。在目标1中，我们将量化拷贝数量 DUF1220在1q21区域的变异(来自血液)，并在体内获得MRI和DTI纵向扫描 样本为42只6、12、18和24个月大的猴子。我们将执行方差分析(ANOVA) 以DUF1220拷贝数(低/高)和性别(女性/男性)为自变量 脑大小测量作为因变量(总体积、灰质和白质、表面积、皮质 厚度、回转和连通性)。我们还将研究DUF1220拷贝数对 我们大脑的变化斜率(跨越6个月、12个月、18个月、24个月)。此外，我们将使用一个区域- 用兴趣法量化组成社会脑网络的大脑区域内的灰质和白质 并检测它们与DUF1220拷贝数变异体的相关性。在目标2中，我们计划评估社会认知 每六个月使用三项认知测试，根据它们与ASD的相关性进行选择，包括相互凝视 和凝视跟踪，以及社交动机测试。我们将使用方差分析来确定社会差异 DUF1220拷贝数低的人和高拷贝数的人之间的动机、相互注视和注视 每个时间点(6个月、12个月、18个月和24个月)的六个分支中的任何一个。我们还将执行部分关联 检查社交大脑网络中灰质和白质体积与分数之间的关系 在社会认知测验上，以DUF1220拷贝数为协变量。总而言之，这些发现将：(1) 为ASD的非人类灵长类动物模型的实用性提供更多证据，以及(2)有助于阐明 大脑大小和社会认知变化的发育时间框架，与DUF1220有关，作为一种手段 确定潜在有效干预的关键时间点。

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.