White matter pathology in postmortem schizophrenia brain

 描述(申请人提供)：精神分裂症(SZ)被认为是一种疾病，部分原因是大脑区域内和大脑区域之间的异常连接。精神分裂症的症状不仅与特定大脑区域和神经递质的异常有关，还与通过纤维路径在结构上连接的大脑区域网络内部和之间的异常通信有关。这种在SZ脑区内和脑区之间的异常连接被称为“连接障碍”。结构或功能连接的异常或两者的耦合可能是由于白质的障碍，即连接大脑远处区域的轴突束。成像研究显示，患有SZ的受试者大脑中的白质出现异常。对身体组织进行的研究，可以进行更高分辨率的研究，显示了不同类型的病理。在这项建议中，我们打算检查连接大脑SZ异常区域的主要白质束，包括内囊、扣带束和穹隆体部。我们推测SZ的白质完整性异常可能是连接异常的基础，包括髓鞘、胶质、线粒体和/或细胞骨架的异常。我们将使用蛋白质研究、组织学、免疫组织化学和电子显微镜对SZ患者死后组织进行蛋白质研究、组织学、免疫组织化学和电子显微镜检查，以确定哪些缺陷可能导致网络活动受损。用免疫印迹法检测髓鞘碱性蛋白、少突胶质细胞标志物、微管相关蛋白、神经丝和线粒体功能标志物。SA2)将使用组织学和免疫细胞化学来确认并进一步定位SA1)中发现的变化。用电子显微镜(EM)计数和测量轴突和髓鞘的横截面积，并测量胶质细胞的结构完整性。在这里，我们建议进行一项低风险、高吞吐量的研究，以确定 死后SZ脑主要白质通路结构连接障碍的基础。这项研究是新颖的，因为它将结合不同的技术，研究同一大脑中的几个白质轨迹。此外，我们将使用电子显微镜，这是一种在人脑中很少使用的技术，来回答那些只能用电子显微镜才能回答的问题。这些研究的结果将使我们能够更全面地了解精神分裂症的白质病理，并有望确定新的治疗机制的靶点。

 DESCRIPTION (provided by applicant): Schizophrenia (SZ) is thought to be a disorder due in part to abnormal connectivity within and between brain regions. The symptoms present in schizophrenia are not only related to abnormalities in specific brain regions and neurotransmitters, but also are related to aberrant communication within and between networks of brain regions that are structurally connected by fiber pathways. This abnormal connectivity within and between brain regions in SZ is termed "dysconnectivity". Abnormalities in structural or functional connectivity or the coupling of the two could be due to disorders of the white matter, ie the axon bundles connecting distant regions of the brain. Imaging studies have shown abnormalities in white matter in the brains of subjects with SZ. Studies conducted with postmortem tissue, where higher resolution studies can be performed, show different types of pathology. In this proposal we intend to examine major white matter tracts that connect areas of the brain that are abnormal is SZ, including the internal capsule, cingulum bundle, and corpus callosum. We hypothesize that there will be abnormalities in white matter integrity in SZ that could underlie abnormal connectivity, including anomalies in myelin, glia, mitochondria, and/or the cytoskeleton. We will approach this hypothesis using protein studies, histology, immunohistochemistry and electron microscopy in postmortem tissue from SZ subjects on or off APD and a matched comparison group to determine which deficits could result in impaired network activity. SA1) Using western blots we will measure proteins including: myelin basic protein, markers of oligodendrocytes, microtubule associated protein, neurofilament, and markers of mitochondrial function. SA2) will use histology and immunocytochemistry to confirm and further localize changes identified in SA1). SA3) Using electron microscopy (EM), we will count and measure the cross sectional area of axons and myelin sheaths and measure the structural integrity of glial cells. Here we propose a low risk, high throughput study to identify the underpinnings of structural dysconnectivity in major white matter pathways in postmortem SZ brain. The study is novel, as it will combine different techniques and study several white matter tracks in the same brains. In addition, we will use electron microscopy, a rarely used technique in postmortem human brain, to answer questions that can only be answered with electron microscopy. The results of these studies will allow us to more comprehensively understand the white matter pathology in schizophrenia, and hopefully to identify targets for new treatment mechanisms.