White matter pathology in postmortem schizophrenia brain

 描述（由申请人提供）：精神分裂症（SZ）被认为是一种部分由于大脑区域内和之间的异常连接而导致的疾病。精神分裂症中存在的症状不仅与特定脑区和神经递质的异常有关，而且与通过纤维通路结构连接的脑区网络内部和之间的异常通信有关。SZ中大脑区域内和之间的这种异常连接被称为“连接障碍”。结构或功能连接性或两者耦合的异常可能是由于白色物质的紊乱，即连接大脑远端区域的轴突束。 影像学研究显示SZ患者脑内白色物质异常。对死后组织进行的研究显示了不同类型的病理学，其中可以进行更高分辨率的研究。在这个建议中，我们打算检查连接大脑异常区域的主要白色物质束，包括内囊、扣带回束和胼胝体。我们假设SZ的白色物质完整性异常，这可能是异常连接的基础，包括髓鞘、神经胶质、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检查从SZ受试者或关闭APD和匹配的对照组的死后组织中，以确定哪些缺陷可能导致受损的网络活动，以接近这一假设。SA 1）使用蛋白质印迹，我们将测量蛋白质，包括：髓鞘碱性蛋白、少突胶质细胞的标志物、微管相关蛋白、神经丝和线粒体功能的标志物。SA 2）将使用组织学和免疫细胞化学来确认和进一步定位SA 1）中鉴定的变化。SA 3）使用电子显微镜（EM），我们将计数和测量轴突和髓鞘的横截面积，并测量神经胶质细胞的结构完整性。 在这里，我们提出了一个低风险，高通量的研究，以确定 死后SZ脑中主要白色物质通路的结构性连接障碍的基础。这项研究是新颖的，因为它将联合收割机不同的技术和研究几个白色物质轨道在同一个大脑。此外，我们将使用电子显微镜，一种在死后人脑中很少使用的技术，来回答只能用电子显微镜回答的问题。这些研究的结果将使我们更全面地了解精神分裂症的白色物质病理，并有希望确定新的治疗机制的目标。

 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.