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： 人类多能干细胞为研究正常和非正常的造血干细胞提供了一个有吸引力的实验平台。 人类神经网络的异常发育。在体外，诱导多能干细胞（iPSC）具有 已被用于研究早期发育机制和突触发生的初始阶段， 电路形成iPSC还为研究人类神经回路提供了诱人但尚未实现的潜力 体外我们在体外模拟人类皮层回路发育的努力表明， 分化可以分为5步进展，包括：1）在细胞中形成图案， 神经外胚层和早期神经发生-3周后明显; 2）成神经细胞迁移， 初始分化为区域特异性神经元亚型-6周后明显; 3）发育 自发电活动和早期突触发生-2-3个月后明显; 4）初始 星形胶质细胞的出现和内部剧烈和同步振荡爆发的形成 大的集合体-在3-5个月内明显; 5）大的超同步神经元消退 合奏成较小的，谨慎地发射子合奏-偶尔观察到超过6 个月在体内观察到的少突胶质细胞祖细胞和轴突髓鞘化的出现还没有 被观察到或报告。尽管令人欣慰的是， 在iPSC模型中，程序在时间上是完整的，延长的时间轴使研究具有挑战性 晚期发育机制或成熟电路功能。 该项目的最终目标是开发方法，以加速网络的形成， 具有成熟突触的高度互联的人类神经元。同步振荡神经元 活动似乎是发育中的神经系统的基本的和强制性的过渡性质。 在视网膜、大脑皮层和脊髓等不同结构中的年轻神经元经历周期性变化 高连通性和强大的神经元活动，随后进行提炼，以产生特定的 突触连接和调节动作电位活动。人神经元体外发育 可能需要获得这些相同的特性才能成为功能性神经元 网络.我们的初步工作表明，这些专属性是由 在发育的不同时间和/或从不同区域产生的细胞类型的相互作用 大脑发育。在这个建议的实验集中在新的方法，概括这些 相互作用，以加速同步振荡爆发的获得，并促进进一步的 iPSC衍生的人类神经网络的成熟。