Oligodendrocytes and neuron pathology in cingulate cortex

扣带皮层少突胶质细胞和神经元病理学

• 批准号: 8080383
• 负责人: PATRICK R HOF
• 金额: $ 23.2万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-01 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8080383
• 关键词: 2' ,3' -Cyclic-Nucleotide Phosphodiesterases; Address; Affect; Anisotropy; Anterior; Architecture; Attention; Autopsy; Behavior; Behavioral; Brain; Brain imaging; Cell Count; Cellular Morphology; Characteristics; Clinical; Data; Demyelinating Diseases; Dendritic Spines; Development; Diffusion Magnetic Resonance Imaging; Disease; Fluorescent Dyes; Functional Imaging; Functional disorder; Funding; Gene Mutation; Gene Proteins; Genes; Gray unit of radiation dose; Human; Image; Image Analysis; Investigation; Knockout Mice; Label; Lead; Limbic System; Link; Magnetic Resonance; Magnetism; Measures; Medial; Memory; Methods; Microscopy; Modeling; Modification; Molecular; Morphology; Motivation; Mus; Mutant Strains Mice; Mutation; Myelin; Neurons; Oligodendroglia; Outcome; Pathogenesis; Pathology; Pathway interactions; Patients; Pattern; Phenotype; Play; Postmortem Changes; Prefrontal Cortex; Procedures; Pyramidal Cells; Quaking Mice; Quantitative Microscopy; Relative (related person); Resolution; Role; Schizophrenia; Spatial Distribution; Specimen; Techniques; Time; Time Study; Vertebral column; base; cingulate cortex; density; design; dysmyelination; endophenotype; gene gun; hippocampal pyramidal neuron; in vivo; indexing; mouse model; myelination; neuropathology; programs; protein expression; white matter

Project 1. Project 1. An investigation of oligodendroglia in schizophrenia. Demyelinating diseases have been known to be associated with behavioral changes. Recently, the expression levels of several myelin-related genes have been shown to be consistently decreased in postmortem schizophrenic brains compared to controls. Magnetic transfer imaging (MTI) has also shown consistent reduction in myelin content in schizophrenic brains. Diffusion tensor imaging (DTI), which measures the directionality of white matter tracts, has shown a decrease in anisotropy in the brains of schizophrenic patients, suggesting disruptions in white matter tract coherence and directionality in this disease. These data together make a strong case for oligodendrocyte dysfunction in schizophrenia. The anterior cingulate cortex plays a significant role in motivation, attention, and behavior and, as a component of the limbic system, in affect and memory. It has been clearly implicated in schizophrenia by studies of cytoarchitectural postmortem changes and functional imaging showing hypometabolism in this region in schizophrenia. In this project, we propose a quantitative analysis of possible relationships between oligodendrocytic pathology and abnormalities in cytoarchitecture in the cingulate cortex of postmortem brains from schizophrenic patients and neuropathologic and brain imaging analyses of relevant mice mutants such as the Quaking mouse, as well as genetically modified mice such as MAG, RPTPfi, CNPase, or MAGI knock-outs. Our analyses will use advanced microscopy quantitative approaches including the most rigorous stereologic methods for cell counting, estimators of spatial cellular distribution and cytoarchitectural boundaries, as well as single cell morphology by intracellular loading of fluorescent dyes or gene-gun-based DiOlistics techniques. We also are assessing progression of potential changes in white matter integrity using high field magnetic resonance microscopy in vivo at 9.4 T in the relevant mouse models. The combined analysis of human specimens and relevant mice models within the context of this program offers a superb opportunity to investigate myelin deficits that have a clinical impact and to determine the molecular, developmental, and morphologic characteristics of the neuronal circuits whose alteration is likely to underlie the pathogenesis and clinical manifestations of schizophrenia. the molecular, developmental, and morphologic characteristics of the neuronal circuits whose alteration is likely to underlie the pathogenesis and clinical manifestations of schizophrenia.

项目 1. 项目 1. 精神分裂症少突胶质细胞的调查。脱髓鞘疾病已 已知与行为改变有关。最近，一些与髓磷脂相关的表达水平 与其他人相比，精神分裂症患者死后大脑中的基因持续减少 控制。磁转移成像 (MTI) 也显示髓磷脂含量持续减少 精神分裂症的大脑。扩散张量成像（DTI），测量白质束的方向性， 研究表明，精神分裂症患者大脑的各向异性有所减少，这表明白细胞 这种疾病的物质通道的一致性和方向性。这些数据共同有力地证明了 精神分裂症中的少突胶质细胞功能障碍。前扣带皮层在以下方面发挥着重要作用 动机、注意力和行为，以及作为边缘系统组成部分的情感和记忆。它有 通过对死后细胞结构变化和功能的研究明确表明与精神分裂症有关 影像显示精神分裂症患者该区域代谢低下。在这个项目中，我们提出了一个定量的 分析少突胶质细胞病理学与细胞结构异常之间的可能关系 精神分裂症患者死后大脑的扣带皮层以及神经病理学和大脑 对相关小鼠突变体（例如 Quak 小鼠）以及转基因小鼠的成像分析 例如 MAG、RPTPfi、CNPase 或 MAGI 敲除。我们的分析将使用先进的显微镜 定量方法，包括最严格的细胞计数体视学方法、估计量 空间细胞分布和细胞结构边界，以及细胞内的单细胞形态 荧光染料的装载或基于基因枪的 DiOlistics 技术。我们还正在评估进展情况 使用 9.4 T 体内高场磁共振显微镜观察白质完整性的潜在变化 相关鼠标型号。人体标本和相关小鼠模型的联合分析 该计划的背景提供了一个极好的机会来研究具有临床意义的髓磷脂缺陷 影响并确定神经元的分子、发育和形态特征 其改变可能是精神分裂症发病机制和临床表现的基础。 神经元回路的分子、发育和形态学特征，其改变是 可能是精神分裂症发病机制和临床表现的基础。