环状RNA在慢性应激诱发抑郁症中的作用及其调控机制

Depression has become one serious public health and social problem, since its increasing morbidity and high deformity year by year. Understanding the pathological mechanism of depression is one of the big open questions in neuroscience. Circular RNA (circRNA), acting as an important epigenetic regulatory molecule, has been attracted more and more attention in cancer, vascular diseases, neuronal differentiation, neurodegeneration and so on. Up to now, the functional significance of circRNA in the pathological processes of depression is still elusive. Based on our preliminary findings, using chronic mild stress (CMS) and social defeat (SD) mice model, combined with transcriptomic analysis, molecular biological methods, pharmacological methods and bioinformatic analysis, we aim to elucidate the changes of circRNA expression in the dorsal hippocampus of stress-induced depressed mice. Next, on the basis of lentivirus mediated overexpression and knockdown strategies, the functional significance of candidate circRNAs will be evaluated to determine the role of circRNA in stress-induced depression. Lastly, based on the “ceRNA-miRNA-target mRNA” and “circRNA-target protein” theories, we try to investigate the molecular mechanism of circRNA in stress-induced depression in vivo and in vitro. In a word, Research progress of the coming project will not only contribute to provide a new scientific basis for elucidating the epigenetic mechanism of pathology of depression, but also broaden new avenues to develop new therapeutic drugs based on circRNAs, for depression and even other stress-related disorders.

抑郁症发病率逐年攀升，致残率高，已成为非常严重的公共卫生和社会问题。阐明抑郁症的发生机制始终是神经科学领域的研究热点。作为一种新的重要调控分子，环状RNA（circRNA)与胚脑发育、神经元分化、衰老等密切相关，在抑郁症发病中的作用尚未明确。结合我们前期发现，本项目通过建立慢性应激小鼠抑郁模型结合体外细胞损伤模型，综合运用组学、生物信息学、分子生物学、行为学等方法，旨在：1）阐明应激诱发抑郁发生过程中海马区circRNA表达谱变化规律；2）基于慢病毒介导的过表达和敲低策略，对候选circRNA进行行为学功能评价，明确circRNA在应激致抑郁过程中的作用；3）以ceRNA-miRNA-mRNA、circRNA-靶蛋白互作为切入点，探讨circRNA调控抑郁行为的分子机制。项目的开展不仅为阐明抑郁症发病机制提供新的科学依据，也为开发基于circRNA的抑郁症及相关应激障碍疾病药物拓宽思路。

阐明抑郁症的发生机制始终是神经科学领域的研究热点。作为一种新的重要调控分子，环状RNA（circRNA)与胚脑发育、神经元分化、衰老等密切相关，在抑郁症发病中的作用尚未明确。结合我们前期发现，本项目通过建立慢性应激小鼠抑郁模型结合体外细胞损伤模型，综合运用组学、生物信息学、分子生物学、行为学等方法，旨在探讨circRNA在抑郁症发生发展中的作用及其调控机制。研究结果发现：1)circSYNDIG1能通过促进细胞增殖、增加神经元树突棘密度和突触相关蛋白的表达改善应激诱发的小鼠异常行为; 2) circSYNDIG1通过吸附miR-344-5p抑制了miR-344-5p对细胞增殖和树突棘密度的影响，从而缓解了应激诱发的小鼠异常行为; 3) circSYNDIG1通过miR-344-5p影响FTO的表达影响RNA m6A甲基化水平。综上，我们得出结论：小鼠海马脑区circSYNDIG1在慢性应激诱发的小鼠异常行为中发挥关键作用，其作用发挥可能与其增加海马神经元树突棘密度有关；从分子机制层面，circSYNDIG1可通过海绵吸附miR-344-5p，上调FTO的表达及其催化的RNA甲基化改善miR-344-5p诱发的小鼠异常行为。项目的开展不仅为阐明抑郁症发病机制提供新的科学依据，也为开发基于circSYNDIG1的抑郁症及相关应激障碍疾病药物拓宽思路。