A 3Rs platform for glial research: From animal to human to in-silico models

被称为星形胶质细胞的被动非神经元脑细胞已经成为大脑机制的关键但严重不足的部分。肌萎缩细胞摄取释放的神经递质，维持细胞外空间的离子稳态，并产生调节神经回路活动的各种分子信号。然而，动物和人类星形胶质细胞在形态学和生理学上的差异威胁着神经科学和神经病学这一重要领域中动物制剂的利弊比。在这方面，星形胶质细胞和星形胶质细胞神经元网络的现实计算模型可以提供假设检验，机械生理学的见解，以及在动物实验中无法实现的物种间知识转移。探索这种模型应该在不损失知识的情况下最大限度地减少动物实验，但创建相应建模环境的方法才刚刚开始出现。因此，本项目的目标是一方面结合联合收割机实验方法学方法，另一方面结合开放式计算机模拟平台，将基于知识的神经胶质研究的重心从动物转移到人类组织制备和现实的计算模型。这将通过以下三个目标实现：（i）为有组织脑组织中人类星形胶质细胞的最新研究建立工作实验方案，使其成为动物脑组织研究策略的普遍可及、可行的替代方案，（ii）创建一个开放获取的计算平台，使星形胶质细胞的现实生物物理模型能够进行探索性研究，从而减少在动物中的类似目标的实验性试验，和（iii）产生适于动物和人类星形胶质细胞的功能比较的实验数据库，从而提供关于将动物数据潜在地难以置信地外推到人脑星形胶质细胞的指导。

Passive non-neuronal brain cells called astrocytes have emerged as a critical yet grossly understudied part of brain machinery. Atrocytes take up released neurotransmitters, maintain ionic homeostasis of the extracellular space, and generate a variety of molecular signlas that regulate neural circuit activity. However, the emerging difference between animal and human astroglia in their morphology and physiology threatens the harm-benefit ratio of animal preparations in this important field of neuroscience and neurology. In this respect, realistic computational models of astroglia and astroglia-neuronal networks could provide hypothesis testing, mechanistic physiological insights, and an inter-species knowledge transfer that are unattainable in animal experiments. Exploring such models ought to minimise animal experimentation with no loss of knowledge, yet the methodology to create the corresponding modelling environment is only beginning to emerge. Thus, the present project aims to combine an experimental methodological approach, on the one hand, and open-access computer-simulation platforms, on the other, that would shift the weight of knowledge-based glial research from animals to human tissue preparations and realistic computational models. This will be achieved through the three objectives: (i) to establish working experimental protocols for up-to-date studies of human astroglia in organised brain tissue, making them a commonly accessible, viable alternative to animal brain tissue research strategies, (ii) to create an open-access computational platform that enables exploratory investigation of realistic biophysical models of astroglia, thus reducing similarly aimed experimental trials in animals, and (iii) to generate an experimental data library adaptable for the functional comparison of animal and human astroglia, thus providing a guidance on potentially implausible extrapolation of animal data to human brain astroglia.