GABA Driven Depolarization in Early Human Cortical Development.

GABA 驱动早期人类皮质发育中的去极化。

• 批准号: 9317257
• 负责人: Theo D Palmer
• 金额: $ 27.48万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9317257
• 关键词: Action Potentials; Admixture; Appearance; Astrocytes; Axon; Behavior; Biological Neural Networks; Brain; Calcium; Cell Communication; Cell model; Cerebral cortex; Chloride Channels; Coculture Techniques; Data; Development; Event; Excitatory Synapse; Fire - disasters; Frequencies; Genetic study; Glutamates; Goals; Human; Immune; In Vitro; Interneurons; Light; Methods; Modeling; Monitor; N-Methylaspartate; Nervous system structure; Neuroectoderm; Neurons; Pattern; Periodicity; Phase; Pluripotent Stem Cells; Pregnancy; Property; Protocols documentation; Rattus; Receptor Activation; Reporter; Reporting; Reproducibility; Resolution; Retina; Role; Source; Spinal Cord; Structure; Synapses; Testing; Time; TimeLine; Work; calcium indicator; cell type; cytokine; experience; experimental study; gamma-Aminobutyric Acid; hippocampal pyramidal neuron; human pluripotent stem cell; in vivo; induced pluripotent stem cell; inhibitory neuron; member; migration; model development; nervous system disorder; neural circuit; neuroblast; neurodevelopment; neurogenesis; novel; oligodendrocyte myelination; oligodendrocyte progenitor; optogenetics; postsynaptic; programs; synaptogenesis

Project Summary: Human pluripotent stem cells provide an attractive experimental platform for studying the normal and abnormal development of human neural networks. In vitro, induced pluripotent stem cells (iPSC) have been used to study early developmental mechanisms and the initial stages of synaptogenesis and circuit formation. iPSC also offer the tantalizing but unrealized potential to study human neural circuits in vitro. Our efforts to model the development of human cortical circuits in vitro indicate that differentiation can be segmented into a 5-step progression involving: 1) patterning of the neuroectoderm and early neurogenesis - robustly evident after 3 weeks; 2) neuroblast migration and initial differentiation into regionally-specific neuronal subtypes - evident after 6 weeks; 3) development of spontaneous electrical activity and early synaptogenesis – evident after 2-3 months; 4) initial appearance of astrocytes and the formation of vigorous and synchronous oscillatory bursting within large ensembles – evident within 3-5 months; 5) resolution of large hypersynchronous neuronal ensembles into smaller, discreetly firing sub-ensembles – occasionally observed after more than 6 months. Appearance of oligodendrocyte progenitors and myelination of axons seen in vivo has not yet been observed or reported. Although it is comforting to confirm that human-specific developmental programs are temporally intact in iPSC models, the protracted timeline makes it challenging to study late developmental mechanisms or mature circuit function. The ultimate goal of this project is to develop methods to accelerate the formation of networks of highly interconnected human neurons with mature synapses. Synchronized and oscillatory neuronal activity appears to be a fundamental and obligate transitional property of developing nervous systems. Young neurons in structures as diverse as retina, cerebral cortex and spinal cord experience periods of high connectivity and robust neuronal activity that are subsequently refined to produce specific synaptic connections and regulated action potential activity. Human neurons developing in vitro presumably require the acquisition of these same properties in order to become functional neuronal networks. Our preliminary work suggests that these obligate properties are acquired by the interactions of cell types generated at different times in development and/or from different regions of the developing brain. Experiments in this proposal focus on novel methods that recapitulate these interactions to accelerate the acquisition of synchronous oscillatory bursting and promote the further maturation of iPSC-derived human neural networks.

项目摘要： 人多能干细胞为研究正常和 人类神经网络的异常发展。体外，诱导多能干细胞（IPSC）具有 用于研究早期发育机制和突触发生的初始阶段和 电路形成。 IPSC还提供了研究人类神经回路的诱人但未实现的潜力 体外。我们为在体外模拟人类皮质回路开发的努力表明 分化可以分为5步的进展，涉及：1） 神经外胚层和早期神经发生 - 3周后强烈的证据； 2）神经细胞迁移和 最初分化为区域特异性神经元亚型 - 6周后的证据； 3）发展 赞助电活动和早期突触发生 - 2-3个月后的证据； 4）初始 星形胶质细胞的出现以及剧烈和同步振荡的形成 大型合奏 - 3-5个月内的证据； 5）分辨出大型超同步神经元 合奏成较小的，谨慎的触发子谐波 - 偶尔在超过6之后观察到 月份。在体内尚未看到少突胶质细胞祖细胞和轴突的髓鞘形成 尽管很舒服地确认人类特定的发展 程序在IPSC模型中暂时完整，旷日持久的时间表使学习挑战 最新的发展机制或成熟电路功能。 该项目的最终目标是开发加速网络的形成方法 高度相互连接的人神经元与成熟的突触。同步和振荡的神经元 活动似乎是发展神经系统的基本和义务过渡性。 像视网膜，大脑皮层和脊髓经历的潜水员结构中的年轻神经元 高连通性和强大的神经元活性，随后被改进以产生特定 突触连接和调节动作潜在活动。人类神经元在体外发展 大概需要获得这些相同特性才能成为功能性神经元 网络。我们的初步工作表明，这些义务属性是由 在开发和/或来自不同地区产生的细胞类型的相互作用 发育中的大脑。该提案中的实验重点是概括这些方法的新方法 相互作用以加速同步振荡爆发并进一步促进同步振荡的相互作用 IPSC衍生的人类神经网络的成熟。