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（由申请人提供）：丘脑连通性的破坏在精神分裂症神经回路的假设中占突出地位。与来自成像研究的这种破坏的有力证据相反，对其潜在病理学的调查远远落后。在这里，我们专注于轴突通路和髓鞘细胞内的mediodorsal核（MD），一个大的丘脑核与额叶皮层通过大量的有髓鞘轴突通路互连，并已知参与精神分裂症。我们把我们的调查背景下的硫酸软骨素蛋白聚糖（CSPGs）在精神分裂症的病理生理学和脑连接和髓鞘形成的调节中的作用的新证据。我们已经表明，CSPGs的表达，细胞外基质的主要成分，显着改变神经胶质细胞和神经元周围的网络（PNNs; CSPG丰富的细胞外基质结构周围不同的神经元群体）在几个大脑区域的精神分裂症患者。这些发现与神经连接的相关性在于CSPG及其与少突胶质细胞祖细胞（OPC）的相互作用在轴突引导、成束、髓鞘形成和冲动传导中发挥的强大作用。人类MD的初步结果显示，轴突被富含CSPG的“轴突外套”包裹，并与表达CSPG的OPC密切相关，以及SZ受试者MD中有髓纤维束的组织改变。总之，这些考虑支持以下假设：在精神分裂症受试者的MD中，OPC和轴突被膜中CSPG表达的改变与白色物质/少突胶质细胞异常以及与CSPG和髓鞘生物合成和调节相关的分子途径的失调相关。拟议的尸检研究将使用定量显微镜和蛋白质组学/糖组学对来自健康对照、精神分裂症和双相情感障碍受试者的MD样本进行组合来检验这一假设。具体目标1将阐明轴突涂层的结构和组成，一种新的细胞外基质结构显示在人类MD轴突周围。具体目标2将使用定量显微镜来检验以下假设：在精神分裂症受试者的MD中，OPC和轴突涂层中CSPG表达的改变与髓鞘形成和少突胶质细胞减少的破坏相关。具体目标3将使用MD上的蛋白质组学和糖组学分析来检验以下假设：在精神分裂症受试者的MD中，CSPG、髓鞘和与其生物合成和调节相关的分子途径被破坏，从而在与可能影响轴突被膜和OPC中CSPG异常的分子机制相关的重点假设的背景下设置显微镜研究。具体目标4将检验以下假设：在精神分裂症中，CSPG/OPC/髓鞘异常与丘脑区域（即网状核）中的PNN减少共存，网状核特别富含这些ECM细胞周围结构，并在门控前额叶皮质-丘脑连接中起关键作用。