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）：在有关精神分裂症的神经回路的假设中，丘脑连接性的破坏尤为突出。与影像学研究中证明这种破坏的有力证据相比，对其潜在病理学的研究却远远落后。在这里，我们重点关注中背核 (MD) 内的轴突通路和髓鞘细胞，这是一个大型丘脑核，通过大量有髓鞘轴突通路与额叶皮层互连，已知与精神分裂症有关。我们将我们的研究置于硫酸软骨素蛋白聚糖（CSPG）在精神分裂症病理生理学以及大脑连接和髓鞘形成调节中的作用的新证据的背景下。我们已经表明，在精神分裂症患者的几个大脑区域中，细胞外基质的主要成分 CSPG 的表达在神经胶质细胞和神经周围网（PNN；围绕不同神经元群体的富含 CSPG 的细胞外基质结构）中显着改变。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、束颤、髓鞘形成和脉冲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，并且 SZ 受试者的 MD 中有髓纤维束的组织发生了改变。总之，这些考虑因素支持这样的假设：在精神分裂症受试者的 MD 中，OPC 和轴突外套中 CSPG 表达的改变与白质/少突胶质细胞异常以及与 CSPG 和髓磷脂生物合成和调节相关的分子途径失调有关。拟议的尸检研究将结合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，轴突涂层是一种新型细胞外基质结构，在人类 MD 中显示围绕轴突。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 和轴突外套中 CSPG 表达的改变与髓鞘形成破坏和少突胶质细胞减少有关。具体目标 3 将使用 MD 的蛋白质组学和糖组学分析来检验以下假设：CSPG、髓磷脂以及与其生物合成和调节相关的分子途径在精神分裂症受试者的 MD 中受到破坏，从而将显微镜研究置于与可能导致影响轴突外套和 CSPG 异常的分子机制相关的集中假设的背景下进行显微镜研究。 原花青素。具体目标 4 将检验以下假设：在精神分裂症中，CSPG/OPC/髓磷脂异常与丘脑区域（即网状核）中的 PNN 减少共存，该区域在这些 ECM 细胞周结构中特别丰富，并在门控前额皮质 - 丘脑连接中发挥关键作用。