Neuronal activity-dependent intracellular calcium signaling regulates oligodendrocyte maturation

项目摘要/摘要 髓鞘形成对大脑中的信息传递和电路功能是必不可少的。新的少突胶质细胞 在一生中不断产生，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。成熟少突胶质细胞分化为 少突胶质前体细胞(OPC)，一群可移动的、增殖的前体细胞，可使CNS和 会持续一生。OPC从神经元接收直接突触，并被假设它们 整合神经元放电信息以调节其分化和髓鞘形成。重要的研究已经 旨在了解调控细胞成熟的细胞内信号通路 少突胶质细胞系细胞(少突胶质细胞)，但神经活动的分子机制- 依赖的髓鞘形成是未知的。此外，关于激发-转录偶联的研究还很少。 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。细胞内钙离子活性依赖的变化驱动多种过程 神经元与突触可塑性和学习有关，但钙动力学在OPC中的作用尚未得到证实 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 在学习后从细胞内储存物中释放，以控制其分化。目标1在体内使用快速时间 错位成像结合病毒表达神经毒素和全息光遗传刺激进行检测 神经元放电的操作如何调节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，以评估活性依赖的钙释放 从细胞内存储驱动少突胶质细胞发生。这些研究的结果将提供基本的见解 进入控制髓鞘可塑性的神经元-少突胶质细胞相互作用，并可能发现新的治疗方法 脱髓鞘疾病的治疗目标。

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.