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.

项目总结/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 最近的研究表明，阻止新的基因的产生， 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（OPCs）是一群能动的增殖性前体细胞，其平铺CNS， 持续一生。OPCs从神经元直接接受突触，并且已经假设它们 整合神经元放电信息以调节其分化和髓鞘形成。重要的研究表明， 目的是了解调节细胞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），但神经元活动的分子机制- 依赖性髓鞘形成是未知的。此外，很少有人知道的兴奋-转录耦合 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。细胞内钙离子的活性依赖性变化驱动了许多过程， 神经元的突触可塑性和学习，但在OPCs的钙动力学的影响还没有得到证实。 仔细研究。在这里，我将测试的假设，神经元活动的变化调节OPC钙 从细胞内储存释放以控制它们在学习后的分化。Aim 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来测试 如何操纵神经元放电调节OPC钙信号。Aim 2结合体外分子 生物化学与纵向成像和行为分析，以评估是否活动依赖性钙释放 从细胞内储存驱动少突发育。这些研究的结果将提供重要的见解 神经元-少突胶质细胞的相互作用，控制髓鞘的可塑性，并可能发现新的治疗 用于治疗脱髓鞘疾病的靶点。