奥地利科学院分子生物技术研究所Jürgen A. Knoblich课题组，利用空间排列的腹侧中脑-脊髓-皮质组合体对人类多巴胺能系统进行体外建模。相关论文于2023年12月5日在线发表在《自然—方法学》杂志上。

研究人员建立了一个人类体外模型，该模型再现了纹状体和皮层多巴胺能神经支配的关键环节。这些空间排列的腹侧中脑-纹状体-皮层类器官（MISCO）可用于研究多巴胺能神经元的成熟、神经支配和功能，对细胞治疗和成瘾研究具有重要意义。研究人员详细介绍了腹侧中脑、纹状体和皮层有机体的生长规程，并描述了它们如何在定制的包埋模具中以线性方式融合。研究人员报告了在MISCO中与纹状体和皮层组织形成功能性长程多巴胺能连接的情况，并表明注射的腹侧中脑模式祖细胞可以成熟并支配组织。

利用这些组装体，研究人员揭示了多巴胺能回路的扰动，并表明慢性可卡因治疗会导致持久的形态、功能和转录变化，这些变化在停药后仍会持续。因此，这个方法为研究人类多巴胺能细胞移植和回路重建以及药物对人类多巴胺能系统的影响开辟了新途径。

据悉，腹侧中脑多巴胺能神经元可投射到纹状体和皮层，参与运动控制和与奖赏相关的认知。在帕金森病中，黑质中脑多巴胺能神经元变性，导致典型的帕金森病运动相关障碍，而皮层中脑多巴胺能神经元的功能障碍则与成瘾和神经精神障碍有关。然而，由于缺乏适当的模型和人类材料，对人类多巴胺能系统的发育和选择性神经变性的研究一直受到限制。

附：英文原文

Title: In vitro modeling of the human dopaminergic system using spatially arranged ventral midbrain–striatum–cortex assembloids

Author: Reumann, Daniel, Krauditsch, Christian, Novatchkova, Maria, Sozzi, Edoardo, Wong, Sakurako Nagumo, Zabolocki, Michael, Priouret, Marthe, Doleschall, Balint, Ritzau-Reid, Kaja I., Piber, Marielle, Morassut, Ilaria, Fieseler, Charles, Fiorenzano, Alessandro, Stevens, Molly M., Zimmer, Manuel, Bardy, Cedric, Parmar, Malin, Knoblich, Jrgen A.

Issue&Volume: 2023-12-05

Abstract: Ventral midbrain dopaminergic neurons project to the striatum as well as the cortex and are involved in movement control and reward-related cognition. In Parkinson’s disease, nigrostriatal midbrain dopaminergic neurons degenerate and cause typical Parkinson’s disease motor-related impairments, while the dysfunction of mesocorticolimbic midbrain dopaminergic neurons is implicated in addiction and neuropsychiatric disorders. Study of the development and selective neurodegeneration of the human dopaminergic system, however, has been limited due to the lack of an appropriate model and access to human material. Here, we have developed a human in vitro model that recapitulates key aspects of dopaminergic innervation of the striatum and cortex. These spatially arranged ventral midbrain–striatum–cortical organoids (MISCOs) can be used to study dopaminergic neuron maturation, innervation and function with implications for cell therapy and addiction research. We detail protocols for growing ventral midbrain, striatal and cortical organoids and describe how they fuse in a linear manner when placed in custom embedding molds. We report the formation of functional long-range dopaminergic connections to striatal and cortical tissues in MISCOs, and show that injected, ventral midbrain-patterned progenitors can mature and innervate the tissue. Using these assembloids, we examine dopaminergic circuit perturbations and show that chronic cocaine treatment causes long-lasting morphological, functional and transcriptional changes that persist upon drug withdrawal. Thus, our method opens new avenues to investigate human dopaminergic cell transplantation and circuitry reconstruction as well as the effect of drugs on the human dopaminergic system.

DOI: 10.1038/s41592-023-02080-x

Source: https://www.nature.com/articles/s41592-023-02080-x