MicroRNA调控的大脑成体神经发生和焦虑抑郁症状关系的分子机制

Anxiety and depression disorders cause significant distress and functional impairments in patients. In China, 3-5% people suffer from depressive disorders, affecting 30 million patients. Moreover, about 40 million American adults are affected by anxiety disorders in a given year. Anxiety disorders and depression share a high level of comorbidity. Thus, antidepressants are also used for the treatment of anxiety disorders. But not all patients show recovery after treatments. The target molecules responding to antidepressants are poorly understood. In recent years, adult neurogenesis in the hippocampus, and its functions in anxiety and depression disorders become a hot research topic. However, little is known about the molecular mechanisms. In our preliminary studies, we have generated microRNA conditional knockout mice, and found that the adult hippocampal neurogenesis is significantly reduced. These mice showed anxiety-like behaviors. This proposal is built on these preliminary data. In this proposal, we will determine miRNA functions in adult hippocampal neurogenesis, and reveal response of this miRNA to antidepressant treatments in the adult hippocampus. We will next elucidate the therapeuticeffect of antidepressants in anxiety- and depression-related disorders in miRNA knockout mice, and finally determine the molecular mechanisms of this miRNA regulation. In this application, we will determine a new mechanism that controls adult neurogenesis, and anxiety- and depression-related behaviors by noncoding miRNAs. We have already generated miRNA mouse models in my lab to ensure the success of proposed experiments. This proposal will yield significant insights into developing new therapeutic tools for depression and anxiety disorders using miRNAs.

焦虑和抑郁症给患者带来了巨大的精神痛苦和躯体不适。在中国，抑郁症发病率为3%~5%，抑郁症患者3000万人。由于抑郁和焦虑的共病症状，临床常用抗抑郁药物治疗焦虑。可是现有的抗抑郁药对部分病人施治无效。抗抑郁药与其作用靶标在分子水平的应答机制仍不明了。近几年成年大脑海马区神经发生与焦虑和抑郁症相关性研究成为新热点，但分子机制几乎是空白。我们在前期工作中建立了非编码微型RNA（miRNA）条件性敲除小鼠模型，发现此条件性敲除小鼠海马区成体神经发生减少，小鼠显示焦虑相关行为。本课题申请建立在我们前期工作基础上。我们将阐述此miRNA在大脑海马区成体神经发生中的功能，揭示此miRNA对抗抑郁药物的应答反应，阐释抗抑郁药物对miRNA条件性敲除和过表达小鼠抑郁和焦虑症状的疗效及作用分子机制。本课题将阐明大脑成体神经发生与抑郁和焦虑症状关系的一个分子机理，并为开发抗抑郁药物新靶标提供理论基础。

焦虑症和抑郁症在中国的发病率很高，越来越成为影响人们正常生活和工作的重要情绪性疾病，也是导致自杀性行为的主要原因。目前焦虑症和抑郁症的诊断主要依据量表，缺乏客观的生物指标。本项目研究了非编码miRNA在成年大脑海马区神经生成中的功能，以及对焦虑症和抑郁症行为的调节作用。我们发现miR-17-92对成年神经干细胞发育起促进作用，在成年大脑敲除miR-17-92引起小鼠焦虑和抑郁性行为。我们还发现，给miR-17-92条件性基因敲除小鼠服用抗抑郁药物，可以使海马区神经生成恢复正常。我们的研究结果指出，miR-17-92对抗抑郁药应答，可以作为焦虑症和抑郁症的重要早期诊断指标。本项目的研究成果为进一步开发miR-17-92作为焦虑症和抑郁症的新的早期诊断和治疗靶点，提供了科学依据。