Neuronal activity-dependent intracellular calcium signaling regulates oligodendrocyte maturation

神经元活性依赖性细胞内钙信号传导调节少突胶质细胞成熟

• 批准号: 10451549
• 负责人: Michael A Thornton
• 金额: $ 3.45万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10451549
• 关键词: Adult; Affect; Axon; Behavior; Behavioral; Behavioral Assay; Binding; Biochemical; Biochemistry; Brain; Calcium; Calcium Signaling; Cell Differentiation process; Cell Lineage; Collaborations; Complex; Coupling; Cytosol; Demyelinating Diseases; Disease; Electric Stimulation; Endoplasmic Reticulum; Event; Frequencies; Future; G-Protein-Coupled Receptors; Gene Expression; Generations; Genes; Genetic Transcription; Germ Lines; Glutamates; Goals; Human; ITPR1 gene; Image; Imaging Techniques; Immune Targeting; Immune system; In Vitro; Knockout Mice; Learning; Life; Link; Locomotion; Mediating; Memory; Metabolic; Molecular; Motor; Motor Cortex; Multiple Sclerosis; Mus; Myelin; Neuraxis; Neurons; Neurotoxins; Oligodendroglia; Pattern; Performance; Persons; Play; Population; Process; Rattus; Receptor Activation; Research; Role; Second Messenger Systems; Signal Pathway; Signal Transduction; Sleep; Synapses; Synaptic plasticity; Techniques; Testing; Time; Viral; awake; cell motility; experience; experimental study; extracellular; in vivo; in vivo imaging; information processing; insight; knock-down; memory consolidation; memory recall; motor learning; multiple sclerosis treatment; myelination; neuronal circuitry; neuropsychiatric disorder; new therapeutic target; novel; oligodendrocyte lineage; oligodendrocyte precursor; optogenetics; precursor cell; remyelination; repaired; response; serial imaging; single-cell RNA sequencing; small hairpin RNA; treadmill; vesicular release

PROJECT SUMMARY/ABSTRACT Myelination is essential for information transfer and circuit function in the brain. New oligodendrocytes are continuously generated throughout life, and recent studies showed that blocking the generation of new oligodendrocytes disrupts learning and memory consolidation. Mature oligodendrocytes differentiate from oligodendrocyte precursor cells (OPCs), a population of motile, proliferative precursors that tiles the CNS and persists throughout life. OPCs receive direct synapses from neurons, and it has been hypothesized that they integrate neuronal firing information to regulate their differentiation and myelination. Significant research has been aimed at understanding the intracellular signaling pathways that regulate the maturation of oligodendrocyte lineage cells (oligodendroglia), yet molecular mechanisms underlying neuronal activity- dependent myelination are unknown. Furthermore, little is known about the excitation-transcription coupling events that link extracellular neuronal stimulation with intracellular signaling dynamics and gene expression changes in oligodendroglia. Activity-dependent changes in intracellular calcium drive myriad processes in neurons related to synaptic plasticity and learning, yet the effects of calcium dynamics in OPCs have not been carefully studied. Here, I will test the hypothesis that changes in neuronal activity modulate OPC calcium release from intracellular stores to control their differentiation following learning. Aim 1 uses fast in vivo time lapse imaging combined with viral expression of neurotoxins and holographic optogenetic stimulation to test how manipulations in neuronal firing modulate OPC calcium signaling. Aim 2 combines in vitro molecular biochemistry with longitudinal imaging and behavioral assays to assess if activity-dependent calcium release from intracellular stores drives oligodendrogenesis. Results from these studies will provide essential insights into the neuron-oligodendroglia interactions that govern myelin plasticity and may uncover novel therapeutic targets for the treatment of demyelinating diseases.

项目摘要/摘要 髓鞘化对于大脑中的信息传输和电路功能至关重要。新的少突胶质细胞是 一生不断产生，最近的研究表明，阻止了新的新产生 少突胶质细胞破坏学习和记忆巩固。成熟的少突胶质细胞与 少突胶质细胞前体细胞（OPC），一种运动群，增生性前体，瓷砖cns和cns和 一生持续。 OPC从神经元中获得直接的突触，并假设他们 整合神经元射击信息以调节其分化和髓鞘形成。重要的研究 旨在了解调节成熟的细胞内信号通路 少突胶质细胞谱系细胞（少突胶质细胞），但具有神经元活性的分子机制 依赖的髓鞘尚不清楚。此外，关于激发转录耦合知之甚少 将细胞外神经元刺激与细胞内信号传导动力学和基因表达联系起来的事件 少突胶质的变化。细胞内钙的活动依赖性变化驱动着无数过程 与突触可塑性和学习有关的神经元，但是钙动力学在OPC中的影响尚未 精心研究。在这里，我将测试神经元活性变化调节OPC钙的假设 从细胞内释放，以控制学习后的分化。 AIM 1在体内使用快速使用 衰减成像​​结合神经毒素的病毒表达和全息光遗传学刺激以测试 神经元发射中的操作如何调节OPC钙信号传导。 AIM 2结合了体外分子 具有纵向成像和行为测定的生物化学，以评估活动依赖性钙释放是否 从细胞内存储驱动少突胶质发生。这些研究的结果将提供基本见解 进入控制髓鞘可塑性并可能发现新型治疗的神经元 - 寡糖相互作用 治疗脱髓鞘疾病的靶标。