权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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

基本信息

批准号：
8988069
负责人：
Sabina Berretta
金额：
$ 50.43万
依托单位：
MCLEAN HOSPITAL
依托单位国家：
美国
项目类别：
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/8988069
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 Human Image Impairment Indium Investigation Lasers Life Measures Medial Dorsal Nucleus Microdissection Microscopy Modeling Molecular Muscle fasciculation Myelin Neuroglia Neurons Nucleolar Fibrillar Material Oligodendroglia Pathology Pathway interactions Pattern Perception Play Population Post-Translational Protein Processing Prefrontal Cortex Proteins Proteomics Quantitative Microscopy Ranvier&apos 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 public health relevance relating to nervous system surface coating white matter

项目摘要

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.