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: 10646397
• 负责人: Michael A Thornton
• 金额: $ 0.9万
• 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/10646397
• 关键词: Adult; Affect; Axon; Behavior; Behavioral; Behavioral Assay; Binding; Biochemical; Biochemistry; Brain; Calcium; Calcium Signaling; Cell Differentiation process; Cell Lineage; Cells; Central Nervous System; Collaborations; Complex; Corpus Callosum; Coupling; Cytosol; Demyelinating Diseases; Disease; Electric Stimulation; Endoplasmic Reticulum; Event; Frequencies; Future; G-Protein-Coupled Receptors; Gene Expression; Generations; Genes; Genetic Transcription; Glutamates; Goals; Holography; Human; ITPR1 gene; Image; Imaging Techniques; Immune Targeting; Immune system; In Vitro; Knockout Mice; Learning; Life; Life Experience; Link; Locomotion; Mediating; Memory; Metabolic; Molecular; Motor; Motor Cortex; Multiple Sclerosis; Mus; Myelin; 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.

项目概要/摘要 髓鞘形成对于大脑中的信息传递和电路功能至关重要。新的少突胶质细胞是 在整个生命过程中不断产生，最近的研究表明，阻止新的产生 少突胶质细胞破坏学习和记忆巩固。成熟的少突胶质细胞分化为 少突胶质细胞前体细胞 (OPC) 是一群能活动、增殖的前体细胞，分布于中枢神经系统和 终生持续。 OPC 接收来自神经元的直接突触，并且有人假设它们 整合神经元放电信息来调节其分化和髓鞘形成。重大研究已 旨在了解调节成熟的细胞内信号传导途径 少突胶质细胞谱系细胞（oligodendroglia），但神经元活动背后的分子机制- 依赖性髓鞘形成尚不清楚。此外，人们对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动力学和基因表达联系起来的事件 少突胶质细胞的变化。细胞内钙的活动依赖性变化驱动着细胞内的无数过程 与突触可塑性和学习相关的神经元，但 OPC 中钙动力学的影响尚未得到证实。 仔细研究过。在这里，我将检验神经元活动的变化调节 OPC 钙的假设 从细胞内储存中释放以控制它们在学习后的分化。目标1使用快速体内时间 延时成像结合神经毒素的病毒表达和全息光遗传学刺激进行测试 神经元放电操作如何调节 OPC 钙信号传导。目标 2 结合体外分子 通过纵向成像和行为分析进行生物化学评估是否存在活动依赖性钙释放 来自细胞内储存的物质驱动少突胶质细胞发生。这些研究的结果将提供重要的见解 研究控制髓磷脂可塑性的神经元-少突胶质细胞相互作用，并可能发现新的治疗方法 治疗脱髓鞘疾病的目标。