Thalamic axonal pathways and extracellular matrix abnormalities in schizophrenia

精神分裂症的丘脑轴突通路和细胞外基质异常

• 批准号: 9135530
• 负责人: Sabina Berretta
• 金额: $ 45.57万
• 依托单位: MCLEAN HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9135530
• 关键词: Affect; Anabolism; Antibodies; Area; Autopsy; Axon; Bipolar Disorder; Brain; Brain region; CSPG4 gene; Cell Differentiation process; Cell Nucleus; Cells; Chondroitin Sulfate Proteoglycan; Cognition; Confocal Microscopy; Control Groups; Data; Disease; Electron Microscopy; Elements; Emotions; Extracellular Matrix; Fiber; Functional disorder; Health; Human; Image; Impairment; Indium; Investigation; Lasers; Life; Measures; Medial Dorsal Nucleus; Microdissection; Microscopy; Modeling; Molecular; Muscle fasciculation; Myelin; Neuroglia; Neurons; Oligodendroglia; Pathology; Pathway interactions; Pattern; Perception; Play; Population; Post-Translational Protein Processing; Prefrontal Cortex; Proteins; Proteomics; Quantitative Microscopy; Ranvier' s Nodes; Regulation; Role; Sampling; Scheme; Schizophrenia; Secretory Vesicles; Stem cells; Structure; Testing; Thalamic Nuclei; Thalamic structure; Ursidae Family; Work; aggrecan; axon guidance; brevican; cell type; frontal lobe; innovation; myelination; neural circuit; neurofilament; novel; oligodendrocyte myelination; phosphacan; relating to nervous system; surface coating; white matter

 DESCRIPTION (provided by applicant): Disruption of thalamic connectivity figures prominently in hypotheses on the neural circuitry involved in schizophrenia. In contrast to robust evidence for such disruption from imaging studies, investigations on its underlying pathology lag far behind. Here, we focus on axonal pathways and myelinating cells within the mediodorsal nucleus (MD), a large thalamic nucleus interconnected with the frontal cortex through massive myelinated axon pathways and known to be involved in schizophrenia. We place our investigations in the context of emerging evidence for a role of chondroitin sulfate proteoglycans (CSPGs) in the pathophysiology of schizophrenia and in the regulation of brain connectivity and myelination. We have shown that the expression of CSPGs, main components of the extracellular matrix, is markedly altered in glial cells and perineuronal nets (PNNs; CSPG-enriched extracellular matrix structures surrounding distinct neuronal populations) in several brain regions of subjects with schizophrenia. The relevance of these findings to neural connectivity resides in the powerful role that CSPGs, and their interactions with oligodendrocyte progenitor cells (OPCs), play in axon guidance, fasciculation, myelination and impulse conduction. Preliminary results in human MD show axons enveloped by CSPG-enriched `axonal coats' and intimately associated with CSPG-expressing OPCs, as well as altered organization of myelinated fiber bundles in the MD of SZ subjects. Together, these considerations support the hypothesis that, in the MD of subjects with schizophrenia, altered CSPG expression in OPCs and axonal coats is associated with white matter/oligodendrocyte abnormalities and dysregulation of molecular pathways related to CSPGs and myelin biosynthesis and regulation. The proposed postmortem investigations will test this hypothesis using a combination of quantitative microscopy and proteomics/glycomics on MD samples from healthy control, schizophrenic and bipolar disorder subjects. Specific Aim 1 will elucidate the structure and composition of axonal coats, a novel extracellular matrix structure shown to surround axons in the human MD. Specific Aim 2 will use quantitative microscopy to test the hypothesis that, in the MD of subjects with schizophrenia, altered CSPG expression in OPCs and axonal coats is associated with disruption of myelination and oligodendrocyte reductions. Specific Aim 3 will use proteomics and glycomics analyses on the MD to test the hypothesis that CSPGs, myelin and molecular pathways related to their biosynthesis and regulation are disrupted in the MD of subjects with schizophrenia, thus setting microscopy studies in the context of focused hypotheses related to molecular mechanisms potentially responsible for abnormalities affecting CSPGs in axonal coats and OPCs. Specific Aim 4 will test the hypothesis that, in schizophrenia, CSPG/OPC/myelin abnormalities coexist with PNN decreases in a thalamic region, i.e. the reticular nucleus, which is particularly enriched in these ECM pericellular structures and plays a key role in gating prefrontal cortex-thalamus connectivity.

 描述（由适用提供）：在精神分裂症涉及的神经回路上的假设中，丘脑连通性数字的破坏显着。与成像研究中这种破坏的强大证据相反，对其潜在病理的研究远远落后。在这里，我们关注培养基核（MD）内的轴突途径和髓鞘细胞，这是一种大型丘脑核与额叶皮层通过大规模的骨髓轴突途径相互联系，并已知与精神分裂症有关。我们将研究在精神分裂症的病理生理学以及调节脑连通性和髓鞘的调节中，在新兴证据的背景下进行了新的证据。我们已经表明，在神经胶质细胞和周围神经元网络（PNN；富含CSPG增强的细胞外基质结构）中，CSPG的表达明显改变，围绕不同神经元种群的细胞外基质结构）在患有精神分裂症的几个受试者的大脑区域中。这些发现与神经元的相关性在于CSPG的强大作用及其与少突胶质细胞祖细胞（OPC）的相互作用，在轴突指导，着迷，髓鞘形成和脉冲传导中发挥作用。人类MD的初步结果显示，由CSPG增强的“轴突涂层”包裹，并与表达CSPG表达OPC紧密相关，并改变了SZ受试者MD的骨髓纤维束的改变。总之，这些考虑支持以下假设：在精神分裂症的受试者的MD中，OPC和轴突涂层的CSPG表达改变了与白质/少突胶质细胞异常以及与CSPG和CSPG和髓磷脂生物合成和调节相关的分子途径的失调。拟议的验尸研究将使用来自健康对照，精神分裂症和双相情感障碍受试者的MD样品的定量显微镜和蛋白质组学/糖基质的组合来检验该假设。特定的目标1将阐明轴突外套的结构和组成，轴突涂层是一种新型的细胞外基质结构，显示了人类MD中轴突的周围。具体目标2将使用定量显微镜来检验以下假设：在精神分裂症的受试者的MD中，OPC和轴突外套中CSPG表达改变与髓鞘形成和少突胶质细胞减少有关。具体目标3将使用MD上的蛋白质组学和凝胶型分析来测试以下假设：CSPG，髓磷脂和分子途径与它们的生物合成和调节有关，在具有精神分裂症的受试者的MD中被破坏，从而破坏了精神分裂症的MD，从而在与分子义务的统计范围内构成了相关的显微镜研究，从而在与分子相关的情况下构成了与分子的构型相关的显微镜研究。和OPC。具体目标4将检验以下假设：在精神分裂症中，CSPG/OPC/髓磷脂异常与PNN降低，在丘脑区域，即网状核心，在这些ECM周期结构中尤其丰富，在这些ECM周围结构中尤其丰富，并且在frontal frontal frontal frontal frontal cortal corortex-thalamus thalamus connectivity中起着关键作用。