奥氮平是临床处方量排第一的抗精神病药物，其在孕期使用可能导致胚胎大脑发育异常。大脑皮质类器官是由干细胞定向诱导分化形成的大脑皮质结构，可一定程度上在体外模拟人类胚胎早期大脑的发育过程和结构特点。申请人前期建立了大脑皮质类器官模型，发现奥氮平对类器官分化过程中的神经上皮形成有重要影响。相比于对照组，奥氮平处理组的神经上皮组织形成的神经芽突明显增多。进一步RNA测序发现奥氮平组Nodal生长分化因子显著升高。由此我们提出了“Nodal生长分化因子可能通过相应的通路调节，参与奥氮平对大脑皮质类器官分化的促进作用”的科学假说。本课题拟在此基础上进一步探讨：奥氮平长时间处理对大脑皮质类器官分化、脑区形成和神经细胞的影响；奥氮平调控Nodal来促进大脑类器官分化的相关靶点和具体机制。本项目的完成将阐明奥氮平促进大脑皮质类器官分化的分子机制，为奥氮平用药提供新的实验依据和数据支持，具有重要的临床意义。

Olanzapine is the most frequently used antipsychotic, and concerns have been raised about a potential association with abnormal fetal brain development. The cerebral organoids—derived from human pluripotent stem cells (hPSCs)—undergoes early stage neural tube formation, followed by neuroepithelia differentiation, eventually developed into self-organized, brain-specific epithelial tissue. It offers a promising approach for investigating the mystery of human brain, which can mimic the endogenous development of human brain. We have previously generated human cerebral organoids using human-induced pluripotent stem cells and treated with different concentrations of olanzapine to study the influence. We found that the neural epithelium tissues formed in olanzapine group have more buds compared with control group. Further analysis demonstrated that Nodal is highly expressed in olanzapine-treated group. Therefore, we suppose that Nodal is closely participated in the promotion of cerebral organoids development by olanzapine treatment. We determine to establish the cerebral organoid model to investigate the effect of long treatment of olanzapine on early brain development. Then, we plan to explore the role of Nodal in regulating the development promotion effect of olanzapine, identify potential related targets, explicit molecular mechanisms and signaling pathways. Therefore, the implement of our project is helpful to provide new evidence for olanzapine use with a vital clinical significance.