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)：丘脑连接中断在精神分裂症涉及的神经回路假说中占显著地位。与来自成像研究的有力证据表明这种干扰相反，对其潜在病理的调查远远落后。这里，我们关注内侧背核(MD)内的轴突通路和髓鞘细胞，MD是一个巨大的丘脑核团，通过大量的有髓轴突通路与额叶皮质相连，已知与精神分裂症有关。我们将我们的研究放在新出现的证据的背景下，证明硫酸软骨素蛋白多糖(CSPGs)在精神分裂症的病理生理学以及在大脑连通性和髓鞘形成的调节中所起的作用。我们已经证明，在精神分裂症患者的几个脑区，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网络(PNNS；围绕不同神经元群体的CSPG丰富的细胞外基质结构)中发生了显著变化。这些发现与神经连接的相关性在于CSPG及其与少突胶质前体细胞(OPC)的相互作用在轴突引导、神经束形成、髓鞘形成和脉冲传导中发挥着强大的作用。在人类MD中的初步结果显示，在SZ受试者的MD中，轴突被CSPG富含的“轴突外套”所包裹，并与表达CSPG的OPC密切相关，以及有髓纤维束的组织发生了变化。综上所述，这些因素支持一种假设，即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和髓鞘生物合成和调节相关的分子通路的失调有关。拟议的尸检将在来自健康对照组、精神分裂症和双相情感障碍受试者的MD样本上使用定量显微镜和蛋白质组学/糖组学相结合的方法来验证这一假设。具体目标1将阐明轴突外套的结构和组成，这是一种新的细胞外基质结构，显示在人类MD的轴突周围。《特殊目的2》将使用定量显微镜来检验这一假设，即在精神分裂症受试者的MD中，OPC和轴突外套中CSPG表达的变化与髓鞘形成中断和少突胶质细胞减少有关。特殊目标3将使用蛋白质组学和糖组学对MD进行分析，以检验与其生物合成和调节相关的CSPGs、髓鞘和与其生物合成和调节相关的分子通路在精神分裂症受试者的MD中受到破坏的假设，从而将显微镜研究置于与可能导致轴突外套和OPC中CSPGs异常的分子机制相关的聚焦假说的背景下。特定目标4将测试这一假设，即在精神分裂症患者中，CSPG/OPC/髓鞘异常与PNN在丘脑区域共存，即网状核，它特别丰富这些ECM细胞周围结构，并在门控前额叶皮质-丘脑连接中发挥关键作用。