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）：丘脑连接的破坏在精神分裂症涉及的神经回路的假设中占据显着地位，与影像学研究中这种破坏的有力证据相反，对其潜在病理学的研究远远落后。中背核（MD）内的通路和髓鞘细胞，这是一个大的丘脑核，通过有髓鞘的巨大轴突通路与额叶皮层互连，已知参与其中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。细胞外基质在神经胶质细胞和神经周围网（PNNs；周围富含 CSPG 的细胞外基质结构）中发生显着改变。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、束颤和髓鞘形成中发挥的强大作用。人类 MD 包膜和脉冲传导的初步结果表明，轴突由富含 CSPG 的“轴突外套”组成，并与表达 CSPG 密切相关。 OPCs 以及 SZ 受试者 MD 中髓鞘纤维束组织的改变共同支持了以下假设：在精神分裂症受试者的 MD 中，OPCs 和轴突外套中 CSPG 表达的改变与白质/少突胶质细胞有关。与 CSPG 和髓磷脂生物合成和调节相关的分子途径的异常和失调。拟议的尸检研究将结合定量显微镜和方法来检验这一假设。对来自健康对照、精神分裂症和双相情感障碍受试者的 MD 样本进行蛋白质组学/糖组学分析，特定目标 1 将阐明轴突涂层的结构和组成，特定目标 2 将使用定量显微镜来阐明轴突涂层，这是一种新型细胞外基质结构。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 表达的改变与具体目标 3 将使用 MD 的蛋白质组学和糖组学分析来检验精神分裂症受试者的 MD 中 CSPG、髓磷脂及其生物合成和调节相关的分子途径受到破坏的假设，从而在精神分裂症患者中开展显微镜研究。与可能影响轴突外套和 OPC 中 CSPG 异常的分子机制相关的重点假设的背景将检验该假设。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，在门控前额皮质 - 丘脑连接中发挥着关键作用。