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。精神分裂症患者少突胶质细胞的研究脱髓鞘疾病一直是 与行为改变有关最近，几个髓鞘相关的表达水平， 已经证明，与精神分裂症患者相比， 对照磁转移成像（MTI）也显示了髓磷脂含量的一致减少， 精神分裂的大脑扩散张量成像（DTI），测量白色物质束的方向性， 显示精神分裂症患者大脑的各向异性降低，表明白色 这种疾病中的物质束连贯性和方向性。这些数据共同构成了一个强有力的理由， 少突胶质细胞功能障碍前扣带皮层在 动机，注意力和行为，以及作为边缘系统的组成部分，影响和记忆。它有 通过对死后细胞结构变化和功能变化的研究， 成像显示精神分裂症患者的这一区域代谢低下。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 在精神分裂症患者死后大脑的扣带皮层中， 相关小鼠突变体（如Quaking小鼠）以及转基因小鼠的成像分析 如MAG、RPTPf1、CNF1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， 空间细胞分布和细胞结构边界，以及单细胞形态，通过细胞内 装载荧光染料或基于基因枪的DiOlistics技术。我们也在评估 在体内9.4 T条件下使用高场磁共振显微镜观察白色物质完整性的潜在变化 相关的小鼠模型。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，以调查髓鞘缺陷， 影响，并确定神经元的分子，发育和形态学特征， 其改变可能是精神分裂症的发病机制和临床表现的基础的回路。 神经元回路的分子、发育和形态学特征，其改变是 可能是精神分裂症的发病机制和临床表现的基础。