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

• 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
• 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' 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

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.

总结： 在脊椎动物的进化过程中，髓鞘的发育促进了中央神经的扩张 神经系统和复杂脑功能的出现。累积的证据表明， 髓鞘形成及其在轴突上的定位可能取决于有髓鞘神经元的类别身份。一 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，与 L2/3胼胝体投射神经元，具有较低和更多样化的髓鞘形成模式，包括“间歇性” 轮廓，其中髓鞘束被长的无髓鞘区域而不是短的Ranvier节点分开。 关于髓鞘形成和髓鞘形成之间的细胞相互作用的机制原理知之甚少。 少突胶质细胞（OL）和CNS中不同神经元类别的轴突。然而，这些知识是基础， 了解髓鞘形成和再生的细胞和发育生物学。围绕 新皮层，我们建议回答有关控制神经元类型的机制的基本问题， 特定的髓鞘形成，并测试假设如何“吸引”和“排斥”线索表达的神经元 亚型动态调节它们与OL的相互作用。在这里，我们将1）使用分子分析， 不同皮质层的少突胶质细胞和皮质神经元亚型，以绘制它们在不同皮质层中的差异。 转录组，并使用这些数据来产生候选基因的分子相互作用组，所述候选基因介导神经元- OL通信，可能调节神经元亚型特异性髓鞘形成。我们将使用屏幕来识别 能够诱导或抑制髓鞘形成的候选物（Aim 1）。然后我们将研究膜蛋白 特定神经元类别的有髓和无髓轴突节段的亚细胞组成 决议，以了解髓鞘定位的调节沿着轴突;并进一步4）研究是否长 无髓鞘区域差异富集功能相关的结构，如突触、间隙 连接和轴突分支（Aim 2）。据报道，增加的神经元活动促进 髓鞘形成，这反过来又稳定轴突结构和神经回路连接。髓鞘形成中断 导致许多神经系统疾病，包括多发性硬化症和精神分裂症， 促进少突胶质细胞分化和髓鞘再生是重要的治疗目标。我们将调查 控制髓鞘的细胞类型特异性适应性重塑及其再生的分子机制 脱髓鞘（Aim 3）。总之，这里提出的工作旨在为如何 不同种类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， 将是至关重要的了解髓鞘的作用，电路功能和功能障碍。