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成为脑机制的一个关键但尚未得到充分研究的部分。萎缩细胞吸收释放的神经递质，维持细胞外空间的离子稳态，并产生多种调节神经回路活动的分子信号。然而，动物和人类星形胶质细胞在形态和生理上的差异威胁着动物制剂在神经科学和神经病学这一重要领域的损益比。在这方面，星形胶质细胞和星形胶质-神经元网络的现实计算模型可以提供假设检验、机械生理学见解和物种间知识转移，这些在动物实验中是无法实现的。探索这样的模型应该在不损失知识的情况下尽量减少动物实验，然而，创建相应的建模环境的方法才刚刚开始出现。因此，目前的项目旨在结合实验方法和开放的计算机模拟平台，这将把基于知识的神经胶质研究的权重从动物转移到人类组织准备和现实的计算模型上。这将通过以下三个目标来实现：(i)为有组织脑组织中人类星形胶质细胞的最新研究建立有效的实验协议，使其成为动物脑组织研究策略的普遍可及的可行替代方案；（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的探索性研究成为可能，从而减少类似目的的动物实验试验；（iii）生成一个适用于动物和人类星形胶质细胞功能比较的实验数据库，从而为可能不可信的动物数据外推到人类大脑星形胶质细胞提供指导。

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.