Gaining insight into psychiatric disease by engineering piece by piece the human brain in vitro.

摘要 一个关键的挑战是理解开发、组装、 人类神经系统的功能和功能障碍是无法直接获得完整的， 用于通过成像、记录和刺激进行详细研究的功能性人脑组织。 我的实验室一直在开发定向分化特定区域大脑的方法 有机化合物，我们已经证明它们可以两两结合来研究细胞与细胞之间的相互作用 以及在被称为大脑集合体的准备过程中形成电路。然而，目前的体外脑 从干细胞衍生的模型不能捕捉神经调节输入，这限制了更广泛的 在神经科学和疾病建模方面的应用。在这里，我们建议开发一种人体3D 包括神经调节投射的细胞平台。更具体地说，我们将派生 来自多能干细胞的区域化的脑器官类似于中缝核 脑干和含有5-羟色胺能神经元，然后将它们与皮质组装 有机化合物。使用最先进的实时成像、转录、药理学、病毒跟踪和 电生理学方法，我们计划研究5-羟色胺能传入大脑皮层并使用 这一平台研究了一种严重遗传形式的神经元串扰缺陷 神经发育疾病。

ABSTRACT A critical challenge in understanding the intricate programs underlying development, assembly, function, and dysfunction of the human nervous system is the lack of direct access to intact, functioning human brain tissue for detailed investigation by imaging, recording, and stimulation. My laboratory has been developing methods for directed differentiation of region-specific brain organoids and we have shown that these can combined two by two to study cell-cell interactions and circuit formation in preparations called brain assembloids. However, current in vitro brain models derived from stem cells do not capture neuromodulatory input, which restrict broader applications in neuroscience and modeling of disease. Here, we propose to develop a human 3D cellular platform that includes neuromodulatory projections. More specifically, we will derive from pluripotent stem cells regionalized brain organoids resembling the nucleus raphe in the brainstem and containing serotonergic neurons, and subsequently assemble them with cortical organoids. Using state-of-the-art live imaging, transcriptomics, pharmacology, viral tracing and electrophysiological methods, we plan to study serotonergic input into the cerebral cortex and use this platform to investigate defects in neuronal cross-talk in a severe genetic form of neurodevelopmental disease.