Axonal Ultrastructure of Temporal White Matter in Autism

自闭症颞白质轴突超微结构

基本信息

批准号：
8771308
负责人：
Cynthia Schumann
金额：
$ 7.78万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-08-01 至 2016-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8771308
关键词：
2 year old Adult Age-Years Amygdaloid structure Anterior Autistic Disorder Autopsy Axon Biological Brain Brain region Cessation of life Child Communication Data Databases Development Diffusion Magnetic Resonance Imaging Disease Electron Microscopy Fiber Freezing Fusiform gyrus Goals Growth Human Individual Inferior Intervention Laboratories Longevity Measures Methods Molecular Myelin Sheath Nerve Degeneration Neuroglia Neurons Pathogenesis Pathology Phenotype Relative (related person)Reporting Research Structure Structure of superior temporal sulcus Temporal Lobe Testing Thick Time Tissue Sample Tissues Toddler autism spectrum disorder base brain tissue cingulate cortex density frontal lobe gray matter innovation neurodevelopment neuroinflammation neuron development neuropathology novel public health relevance relating to nervous system social theories therapy development white matter

项目摘要

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.

描述（由申请人提供）：自闭症谱系障碍 (ASD) 患者的神经连接和交流异常明显。 2 岁时，自闭症谱系障碍 (ASD) 的白质体积比正常发育儿童大约大 10%，灰质体积大约大 5%。结构和功能差异在颞叶的“社交脑”区域最为明显，包括颞上沟、梭状回和杏仁核。尽管成年后通常无法检测到灰质体积差异，但白质异常在整个生命周期中仍然很明显。事实上，超过 40 项弥散张量成像研究 (DTI) 报告了普遍存在的白质轴突异常，最近的一项研究特别指出了下纵束的颞中部分。然而，导致连接颞叶区域的纤维束异常的潜在细胞机制仍然很大程度上未知和未经探索。本研究的目标是 1) 使用电子显微镜 (EM) 研究自闭症谱系障碍 (ASD) 脑组织中颞叶白质发育异常的轴突超微结构的潜在异常，2) 将这些发现与之前收集的颞叶细胞和分子数据相关联在同一个大脑上。一种假设表明，自闭症谱系障碍患者有过多的连接局部大脑区域的浅层/放射状白质，但深层、长距离轴突深层白质却缺乏。该理论可以通过使用 EM 测量距神经元区域一定距离处的有髓轴突厚度和密度来检验。最近的一项额叶电镜研究发现，前扣带皮层下面的白质中长距离轴突数量减少，短距离轴突数量过多且密度较高。然而，这种现象尚未在颞叶白质区域中得到探索。本研究的目的是利用电镜检查自闭症谱系障碍患者大脑颞叶白质异常（包括下纵束）相对于典型发育的轴突超微结构和神经连接。我们将使用之前为颞叶神经病理学研究准备的脑组织切片。我们的实验室开发了一种利用固定冷冻人脑组织样本的电镜研究轴突超微结构的新方法。因此，我们首次能够探索同一大脑内相邻组织切片中白质异常与自闭症谱系障碍细胞发病机制的关系。这项创新研究将使我们能够全面了解神经元（灰质）和轴突（白质）连接的 ASD 病理学，以阐明颞叶异常生长的细胞基础，识别 ASD 的神经病理表型，并指导发育有针对性的生物干预措施。