Axonal Ultrastructure of Temporal White Matter in Autism

描述（由申请人提供）：自闭症谱系障碍（ASD）患者的神经连接和通信能力明显下降。在2岁时，ASD的白色物质体积比正常发育的儿童大约大10%，灰质大5%。结构和功能的差异在颞叶的“社会脑”区域最为明显，包括上级颞沟、梭状回和杏仁核。虽然灰质体积的差异在成年期通常无法检测到，但白色物质异常在整个生命周期中仍然很明显。事实上，超过40个扩散张量成像研究（DTI）报告普遍的白色物质轴突异常，最近的一项研究特别涉及下纵束的中颞部分。然而，导致连接颞叶区域的纤维束异常的潜在细胞机制在很大程度上仍然未知和未探索。本研究的目的是：1）使用电子显微镜（EM）研究ASD脑组织中异常颞叶白色物质发育的轴突超微结构的潜在异常; 2）将这些发现与先前收集的相同大脑颞叶细胞和分子数据相关联。已经出现了一种假说，认为ASD患者具有过多的表面/放射状白色物质，其连接局部脑区域，但缺乏深层、长距离轴突深层白色物质。这一理论可以通过使用EM测量离神经元区域一定距离处的有髓鞘轴突厚度和密度来检验。最近的一项额叶EM研究发现，前扣带皮质下方的白色物质中长距离轴突数量减少，而短距离轴突数量过多且密度较高。然而，这种现象还有待探讨颞叶白色物质区域。本研究的目的是利用电镜检查轴索超微结构和神经连接的白色物质异常的颞叶，包括下纵束，在人的大脑中的ASD相对于典型的发展。我们将使用以前为颞叶神经病理学研究准备的脑组织切片。我们的实验室已经开发出一种新的方法来研究轴突超微结构利用EM固定冷冻人脑组织样品。因此，我们第一次能够在同一脑内相邻组织切片中探索白色物质异常与ASD细胞发病机制的关系。这项创新的研究将使我们能够在神经元（灰质）和轴突（白色物质）连接中创建ASD病理学的全面图片，以阐明颞叶异常生长的细胞基础，识别ASD中的神经病理学表型，并指导靶向生物干预的发展。

DESCRIPTION (provided by applicant): Abnormalities in neural connectivity and communication are evident in people with autism spectrum disorders (ASD). At 2 years of age, ASD white matter volume is approximately 10% larger and gray matter is 5% larger than in typically developing children. Structural and functional differences are most pronounced in "social brain" regions of the temporal lobe, including the superior temporal sulcus, fusiform gyrus, and amygdala. Although gray matter volume differences are often not detectable in adulthood, white matter abnormalities continue to be apparent throughout lifespan. In fact, over 40 diffusion tensor imaging studies (DTI) report prevalent white matter axonal abnormalities, and a recent study implicates specifically the mid-temporal portion of the inferior longitudinal fasciculus. However, the underlying cellular mechanisms that contribute to abnormalities in fiber tracts connecting temporal lobe regions remain largely unknown and unexplored. The goal of this research is to 1) investigate potential abnormalities in axonal ultrastructure that underlie aberrant temporal lobe white matter development in ASD brain tissue using electron microscopy (EM) and 2) correlate these findings with previously collected temporal lobe cellular and molecular data carried out on the same brains. A hypothesis has emerged suggesting that people with ASD have excess superficial/radiate white matter, which connects local brain regions, but a deficiency in deep, long distance axonal deep white matter. This theory can be tested by measuring myelinated axon thickness and density at certain distances from neuronal regions using EM. One recent frontal lobe EM study found a decrease in the number of long distance axons and an excessive number and higher density of short-range axons in white matter underlying anterior cingulate cortex. However, this phenomenon has yet to be explored in temporal lobe white matter regions. The goal of this study is to utilize EM to examine the axonal ultrastructure and neural connectivity underlying white matter abnormalities in temporal lobe, including the inferior longitudinal fasciculus, in the brains of people with ASD relative to typical development. We will use banked brain tissue sections previously prepared for studies of temporal lobe neuropathology. Our laboratory has developed a novel method to investigate axonal ultrastructure utilizing EM with fixed-frozen human brain tissue samples. Therefore, for the first time, we are able to explore the relationship of white matter abnormalities and cellular pathogenesis of ASD in adjacent histological sections within the same brain. This innovative study will allow us to create a comprehensive picture of ASD pathology in both neuronal (gray matter) and axonal (white matter) connectivity to elucidate the cellular basis for aberrant growth of the temporal lobe, identify neuropathological phenotypes in ASD, and guide development of targeted biological interventions.