Oligodendroglial Interactions Group

少突胶质细胞相互作用组

• 批准号: 10922457
• 负责人: Tobias Merson
• 金额: $ 94.25万
• 依托单位: NATIONAL INSTITUTE OF MENTAL HEALTH
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10922457
• 关键词: AMPA Receptors; Ablation; Action Potentials; Adult; Affect; Anterior; Area; Astrocytes; Axon; Binding; Biochemical; Brain; CSPG4 gene; Cell Differentiation process; Cells; Central Nervous System; Classification; Communication; Complex; Corpus Callosum; Cuprizone; Data; Demyelinations; Development; Disease; Dorsal; Electrophysiology (science); Exhibits; Genetic; Glutamates; Goals; Health; Impairment; Individual; Injury; Knowledge; LIF gene; Ligands; Link; Major Depressive Disorder; Mediating; Mental Health; Molecular; Morphology; Multiple Sclerosis; Mus; Myelin; Myelin Sheath; National Institute of Mental Health; Natural regeneration; Nerve Degeneration; Neuroglia; Neurologic; Neuronal Plasticity; Neurons; Oligodendroglia; PDGFRA gene; Pathologic; Pattern; Pharmacogenetics; Play; Population; Process; Proliferating; Property; Prosencephalon; Publishing; Purinoceptor; Research; Resources; Rodent; Role; Schizophrenia; Signal Transduction; Speed; Structure; Synapses; System; Testing; Thinness; Transgenic Organisms; Ventricular; Viral; autism spectrum disorder; burden of illness; cell regeneration; cytokine; depressive symptoms; experience; functional outcomes; interest; migration; myelination; nerve stem cell; nervous system disorder; neural network; neurotransmitter release; novel; oligodendrocyte progenitor; postsynaptic; precursor cell; prevent; programs; psychologic; receptor; recombinase; regenerative; remyelination; repaired; response; stem; stem cells; subventricular zone; tool; vesicular release; white matter; working group

The capacity for oligodendrocytes to effect a change in brain function is explained by the dramatic increase in impulse propagation speed and efficiency that occurs when axons are myelinated. Critically, in most white matter tracts, myelination is selective, only appearing in a subpopulation of axons, and the precise structure of individual myelin internodes has a marked influence over action potential propagation. Yet the mechanisms that regulate which axons or axonal domains become myelinated and the functional connectivity between neurons and oligodendrocytes is poorly understood. Beyond ligand/receptor-mediated interactions, neuronal activity is an essential factor that dictates which axons become myelinated. The release of ATP from excited axons stimulates the differentiation of oligodendrocyte progenitor cells (OPCs) directly via purinergic receptors and indirectly by stimulating astrocytes to release the cytokine leukemia inhibitory factor, which promotes OPC differentiation. In addition, unmyelinated axons form synapses with OPCs, and vesicular release of the neurotransmitter glutamate binds AMPA receptors on OPCs to stimulate myelination. Blocking electrical activity during developmental myelination impairs the proliferation of OPCs and the final stages of oligodendrocyte differentiation. Further, studies in Dr. Mersons group and others have demonstrated that increasing the activity of subsets of axons results in their selective myelination, and conversely, decreasing their activity reduces their myelination. These data indicate that activity-dependent myelination of axons likely plays a vital role in defining the repertoire of myelinated and unmyelinated axons generated developmentally and during ongoing plasticity. However, we still need to understand how populations of axons that require synchronous activity are myelinated to a similar extent to ensure that signals are received at their post-synaptic targets with appropriate isochronicity. The Oligodendroglial Interactions Group is developing approaches to link structural relationships between neurons and glia to functional outcomes in terms of the function of specific neural networks. The research approach leans heavily on using existing and novel transgenic tools to manipulate and record the functional interplay between oligodendroglia and axonal targets. We are developing the capability to assess the extent to which oligodendrocytes communicate with one another in executing myelination of a standard set of axons. We are utilizing these resources to test that activity-dependent changes in myelin morphology tune axonal properties via persistent bidirectional signaling between oligodendrocytes and their target axons. Another critical area of interest for the Merson Group is the cellular and molecular mechanisms orchestrating myelin repair after a demyelinating injury. Demyelination is a common pathological consequence of several neurodegenerative and neurological conditions, including multiple sclerosis, a disease that carries a significant psychological toll. We have previously demonstrated that in addition to OPCs, neural precursor cells (NPCs) that derive from the ventricular-subventricular zone (V-SVZ) also contribute to remyelination following cuprizone-mediated demyelination of the corpus callosum in mice. We have been interested in developing approaches to probe the relative importance of OPCs and NPCs to the regenerative process, given that these two populations of progenitor cells regenerate myelin that exhibits vital structural differences. Specifically, we revealed that while OPCs regenerate thin myelin sheaths during remyelination, NPCs regenerate significantly thicker myelin and more akin to normal healthy myelin. To explore the functional differences between myelin regenerated from oligodendrogenesis cells of NPC versus OPC origin, we have been developing tools to genetically ablate OPCs from the adult CNS so that we can examine remyelination mediated by NPCs in the absence of OPCs. Approaches to ablate OPCs in the rodent CNS have been limited in the extent and duration of OPC depletion. In recently published work from the group (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10014347/), we demonstrate the development of a pharmacogenetic approach for conditional OPC ablation, eliminating >98% of OPCs throughout the brain. By combining recombinase-based transgenic and viral strategies for targeting OPCs and V-SVZ-derived neural precursor cells (NPCs), we found that new PDGFRA-expressing cells born in the V-SVZ repopulated the OPC-deficient brain starting 12 days after OPC ablation. Our data reveal that OPC depletion induces V-SVZ-derived NPCs to generate vast numbers of PDGFRA+/NG2+ cells with the capacity to proliferate and migrate extensively throughout the dorsal anterior forebrain. Further application of this approach to ablate OPCs will advance knowledge of the function of both OPCs and oligodendrogenic NPCs in health and disease.

少突胶质细胞实现大脑功能的变化的能力是通过脉冲传播速度和效率的急剧增加来解释的。至关重要的是，在大多数白质区域中，髓鞘形成是有选择性的，仅出现在轴突的亚群中，并且单个髓磷脂节节节的精确结构对动作电位传播具有显着影响。然而，调节哪些轴突或轴突结构域的机制已成为髓鞘，以及神经元和少突胶质细胞之间的功能连通性。除了配体/受体介导的相互作用之外，神经元活性是决定哪些轴突变为髓鞘的重要因素。从激发轴突中释放ATP刺激了直接通过嘌呤能受体的少突胶质细胞祖细胞（OPC）的分化，并通过刺激星形胶质细胞释放细胞因子白血病抑制因子，从而间接地释放，从而促进OPC分化。此外，不髓鞘的轴突与OPC形成突触，而神经递质谷氨酸的囊泡释放结合了OPC上的AMPA受体，以刺激髓鞘形成。在发育性髓鞘中阻断电活动会损害OPC的扩散和少突胶质细胞分化的最后阶段。此外，梅尔森（Mersons）组和其他人的研究表明，增加轴突子集的活性会导致其选择性髓鞘形成，相反，减少其活性会降低其髓鞘形成。这些数据表明，轴突的活性依赖性髓鞘化可能在定义髓鞘和无髓鞘轴突的曲目中起着至关重要的作用，从而在发育和持续的可塑性过程中产生。 但是，我们仍然需要了解如何在相似的程度上进行同步活动的轴突群体，以确保在其后突触后目标接收信号，并具有适当的等位置性。基于特定神经网络的功能，少突胶质相互作用组正在开发将神经元和神经胶质之间的结构关系与功能结果联系起来的方法。该研究方法在很大程度上使用现有和新颖的转基因工具来操纵和记录寡头胶质和轴突靶标之间的功能相互作用。我们正在开发能力，以评估少突胶质细胞在执行一组标准轴突时相互通信的程度。我们正在利用这些资源来测试通过少突胶质细胞及其靶轴突之间的持续双向信号传导，髓鞘形态调子轴突特性的活动依赖性变化。 默森组感兴趣的另一个关键领域是脱髓鞘损伤后修复髓磷脂修复的细胞和分子机制。脱髓鞘是几种神经退行性和神经系统疾病的常见病理后果，包括多发性硬化症，这种疾病会带来重大的心理伤害。我们先前已经证明，除了OPC，源自心室 - 侧面 - 牙周区域（V-SVZ）的神经前体细胞（NPC），在小鼠callosum callosum callosum脱髓鞘之后，也有助于再生。 鉴于这两个祖细胞再生髓磷脂群，我们对开发OPC和NPC对再生过程的相对重要性的方法感兴趣。具体而言，我们透露，虽然OPC在再生过程中再生薄髓鞘，但NPC会重新生成明显较厚的髓磷脂，并且更类似于正常健康的髓磷脂。为了探索NPC与OPC起源的少突胶质发生细胞再生的髓磷脂之间的功能差异，我们一直在开发从成年CNS遗传赋予OPC的工具，以便我们可以检查NPC在不存在OPC的情况下由NPC介导的remereelination。在OPC耗竭的程度和持续时间内，在啮齿动物中枢神经系统中消融OPC的方法受到限制。在该小组最近发表的工作（https://www.ncbi.nlm.nih.gov/pmc/articles/pmc10014347/）中，我们证明了有条件的OPC消融的药物遗传学方法的发展，消除了整个大脑中> 98％的OPC。通过结合靶向OPC和V-SVZ衍生的神经前体细胞（NPC）的基于重物组织酶的转基因和病毒策略，我们发现在OPC经过12天后，在V-SVZ中出生的新的表达PDGFRA的细胞重新填充了OPC缺陷型大脑。我们的数据表明，OPC耗竭诱导V-SVZ衍生的NPC生成大量的PDGFRA+/NG2+细胞，具有在整个背前前端广泛增殖和迁移的能力。这种方法将这种方法的进一步应用在消融OPC中将提高OPC和少突义基因在健康和疾病中的功能的知识。