Neuron-oligodendrocyte communication underlying myelin distribution in the neocortex

新皮质中髓磷脂分布的神经元-少突胶质细胞通讯

基本信息

批准号：
10664007
负责人：
Paola Arlotta
金额：
$ 42.25万
依托单位：
HARVARD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-15 至 2027-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10664007
关键词：
Action Potentials Adult Affect Axon Binding Brain CRISPR/Cas technology Candidate Disease Gene Cells Cellular biology Central Nervous System Cerebral cortex Classification Code Communication Complex Cues Cuprizone Data Demyelinations Development Developmental Biology Evolution Functional disorder Gap Junctions Genetic Goals Interneurons Investigation Knowledge Label Ligands Lipids Location Maps Mediating Membrane Membrane Proteins Modeling Molecular Molecular Profiling Monitor Morphology Multiple Sclerosis Myelin Myelin Sheath Natural regeneration Neocortex Neurons Oligodendroglia Parvalbumins Pathologic Pattern Population Positioning Attribute Process Protocols documentation Ranvier&apos s Nodes Regulation Reporting Repression Resolution Role Schizophrenia Signal Transduction Signaling Molecule Somatostatin Structure Surface Synapses Testing Therapeutic Thick Vasoactive Intestinal Peptide Work candidate identification cell type design experience experimental study in vivo evaluation in vivo two-photon imaging mRNA Differential Displays myelination neocortical nervous system disorder neural circuit neurotransmission receptor remyelination response transcriptome transcriptomics virtual

项目摘要

Summary: Over vertebrate evolution, the development of the myelin sheath has contributed to the expansion of the central nervous system and the emergence of complex brain function. Cumulative evidence indicates that the level of myelination and its positioning over the axon may be dependent on the class identity of myelinated neurons. A canonical example is the difference between L5 projection neurons, with extensive and uniform myelination, and the L2/3 callosal projection neurons, with lower and more diverse patterns of myelination, including “intermittent” profiles, where myelin tracts are separated by long unmyelinated regions rather than short nodes of Ranvier. Little is known about the mechanistic principles underlying cellular interaction between myelinating oligodendrocytes (OL) and axons of distinct neuronal classes in the CNS. Yet this knowledge is fundamental to understanding the cellular and developmental biology of myelination and regeneration. Focusing on the neocortex, we propose to answer fundamental questions regarding the mechanisms that control neuron-type specific myelination, and test hypotheses on how “attractive” and “repulsive” cues expressed by neuronal subtypes dynamically regulate their interactions with OLs. Here, we will 1) use molecular profiling of oligodendrocytes and cortical neuron subtypes across different cortical layers to map differences in their transcriptome, and use this data to generate a molecular interactome of candidates for genes mediating neuron- OL communication that may regulate neuron-subtype-specific myelination. We will 2) employ a screen to identify candidates able to induce or repress myelination (Aim 1). We will then 3) investigate membrane protein composition of myelinated and unmyelinated axonal segments of a specific neuronal class at subcellular resolution to understand the regulation of myelin positioning along the axon; and further 4) study whether long unmyelinated regions are differentially enriched for functionally-relevant structures such as synapses, gap junctions, and axonal branches (Aim 2). It has been reported that increased neuronal activity promotes myelination, which in turn stabilizes axon structure and neural circuit connectivity. Disrupted myelination can contribute to many debilitating neurological disorders, including multiple sclerosis and schizophrenia, and promoting oligodendrocyte differentiation and remyelination is an important therapeutic goal. We will investigate the molecular mechanisms that control cell-type specific adaptive remodeling of myelin and its regeneration after demyelination (Aim 3). In summary, the work proposed here aims to inform a conceptual framework for how different classes of neurons and oligodendrocytes interact to achieve differential myelination, mechanisms that will be critical in understanding the role of myelin in circuit function and dysfunction.

概括：在脊椎动物的进化过程中，髓鞘的发育有助于中枢神经系统的扩张。神经系统和复杂大脑功能的出现表明了其水平。髓鞘形成及其在轴突上的定位可能取决于有髓神经元 A 的类别身份。典型的例子是 L5 投射神经元之间的差异，具有广泛且均匀的髓鞘形成，以及 L2/3 胼胝体投射神经元，具有较低且更多样化的髓鞘形成模式，包括“间歇性” 剖面，其中髓磷脂束被长的无髓鞘区域而不是短的朗飞结节分开。人们对髓鞘形成之间的细胞相互作用的机制原理知之甚少。然而，这些知识是中枢神经系统中不同神经元类别的少突胶质细胞（OL）和轴突的基础。了解髓鞘形成和再生的细胞和发育生物学。新皮质，我们建议回答有关控制神经类型机制的基本问题特定的髓鞘形成，并测试关于神经元如何表达“吸引”和“排斥”线索的假设亚型动态调节它们与 OL 的相互作用。在这里，我们将 1) 使用 OL 的分子分析。不同皮质层的少突胶质细胞和皮质神经元亚型，以绘制它们的差异转录组，并使用这些数据生成介导神经元的候选基因的分子相互作用组可能调节神经元亚型特异性髓鞘形成的 OL 通讯我们将 2) 使用筛选来识别。能够诱导或抑制髓鞘形成的候选者（目标 1）然后我们将研究膜蛋白。亚细胞特定神经元类别的有髓和无髓轴突节段的组成分辨率以了解髓磷脂沿轴突定位的调节，并进一步研究 4) 是否长；无髓鞘区域的功能相关结构（例如突触、间隙）差异富集据报道，神经活动的增加会促进神经连接和轴突分支（目标 2）。髓鞘形成，进而稳定轴突结构和神经回路连接。导致许多使人衰弱的神经系统疾病，包括多发性硬化症和精神分裂症，以及促进少突胶质细胞分化和髓鞘再生是一个重要的治疗目标。控制髓磷脂细胞类型特异性适应性重塑及其再生的分子机制脱髓鞘（目标 3）总之，这里提出的工作旨在为如何脱髓鞘提供一个概念框架。不同类别的神经元和少突胶质细胞相互作用以实现不同的髓鞘形成，其机制对于理解髓磷脂在回路功能和功能障碍中的作用至关重要。