重性抑郁症(MDD)和双相抑郁症(BD-II)是发病率很高的遗传性精神疾病。由于它们临床症状相似，BD-II病人常误诊为MDD并发生用药错误，使得病情恶化。然而，由于精神疾病常由多基因的缺陷导致，两类抑郁症的致病机理仍旧很不清楚，使得神经病理和神经环路研究缺乏明确的目标。近年来，携带病人遗传信息的诱导多能干细胞(iPSC)模型被广泛用于复杂疾病的研究。我们将结合iPSC技术和小鼠模型，建立MDD和BD-II病人的iPSC模型和多种类型神经元分化模型，并结合转录组测序手段，将两种疾病进行对比分析，全面系统地进行细胞水平的表型缺陷鉴定，筛选出与致病可能相关的基因和通路，最后利用我们新近开发的脑内CRISPRi技术快速构建小鼠模型，进行动物行为分析以对可疑基因和通路进行深入验证。本研究将为抑郁症的在体神经病理和神经环路的研究提供理论依据和研究目标，并为遴选临床诊断标识物和开发新疗法提供理论依据。

Major depressive disorder (MDD) and type-II bipolar disorder (BD-II) are complex neuropsychiatric disorders characterized by depressive mood. However, BD-II patients also show hypomania while MDD patients not, so the two types of depressive disorders have highly variable courses and inconsistent responses to treatment. In clinical practice, BD is often misdiagnosed as MDD due to their similarities. However, accumulating evidence has suggested that there are significant differences between the two types of depression, especially when it comes to recommended treatments. Most patients suffering from BD are not benefited by antidepressants. In fact, there is a risk that antidepressants can exacerbate BD - triggering mania or hypomania, causing rapid cycling between mood states, or interfering with other mood stabilizing drugs. To date, there are no useful biological markers that reliably shown to distinguish between MDD and BD. The study of the neurobiology underlying these two severe polygenic psychiatric disorders has been hindered by the lack of access to the tissue of interest - neurons from patients and absence of animal models can faithfully recapitulate the phenotype of the two brain diseases. Therefore, developing an accurate and powerful biological model has been a challenge for research into these two brain disorders..At present, the induced pluripotent stem cell (iPSC) technology is instrumental in advancing the fields of disease modeling and cell transplantation. Many of these models succeeded in recapitulating the neuropathological phenotypes suffered by patients and animal models, indicating that the cells derived from patients retain the etiological and genetic information of pathological onset of disease. Hence, this approach has opened possibilities for study of complex polygenic psychiatric disorders, including MDD and BD. However, due to the innate limitation of iPSC model, mainly in that the cells cannot recapitulate the behavioral abnormalities of the disease, the findings based on iPSC should be further verified by animal models. .In the present study, we will establish iPSC models for sporadic and familial BD and MDD patients, and differentiate the iPSCs into multiple types of neurons to search for cell level deficiency of the diseases. With genomic analysis approaches, we will compare these two diseases to explore genes and signaling pathway involved in the disease phenotype. Finally, using our recently developed brain CRISPRi technique, we will establish acute gene knockdown animal models to perform behavioral tests, so that we can rapidly verify the role of the genes in the pathogenesis of the disorders.