用新信息记忆的动物模型研究认知障碍病理机制和防治策略

Cognitive deficits are associated with neurological and psychiatric disorders. It is critically important to investigate the pathological characteristics and therapeutics of these cognitive disorders. The storage and retrieval of new information are essential for cognitive processes, so that establishing new animal model about memory formation is pivotal to elucidate the mechanisms of cognitions and cognitive deficits. The studies in our new mouse model of memory formation indicate that associative memory cells are recruited as well as new axon and synapse innervations are formed after associative learning, and that miRNA-324-5p and miRNA-133a play the critical roles in improving memory and cell processes. These molecular and cellular mechanisms in the memory of new information are the basis of cognitive processes and constitute the criteria to merit cognitive deficits in cellular level. Our objective in current proposal is to reveal the pathological characteristics and therapeutics of cognitive deficits in cell-specific manner, especially the cognitive deficits associated to neurological and psychiatric disorders by using our mouse model. Specific aims are to address how cognitive deficits are correlated with memory cell deficits in Alzheimer’s disease, how the cognitive deficits are correlated with memory cell deficits in major depression, and how miRNA-324-5p and miRNA-133a improve cognitive deficits, axon innervation and synapse formation. Our study is expected to provide new data for the pathological characteristics and therapeutics of cognitive deficits.

神经精神疾病伴有认知障碍，研究认知障碍的病理与防治具有重要的科学和社会意义。新信息的储存与提取是认知的基础，建立新信息记忆的动物模型是研究认知障碍之关键。在我们新信息记忆小鼠模型的研究显示，与学习相关的大脑皮层建立了联合记忆细胞、轴突投射和突触联系，miRNA-324-5p和miRNA-133a改善记忆和细胞过程。这些新的记忆细胞和神经环路构成了认知的基础，为研究认知障碍的细胞机制提供研判标准。该项目的科学问题是认知障碍大脑皮层不同类型神经元病理特征与防治原则，阐明问题的策略是利用我们新建的动物模型研究神经精神疾病的认知障碍。研究内容包括：老年痴呆认知障碍与不同类型神经记忆细胞形成障碍的相关性及其机制；抑郁症认知障碍与不同类型记忆细胞形成障碍的相关性及其机制；miRNA-324-5p/miRNA-133a改善认知障碍，轴突投射和突触形成。该研究将为认知障碍的病理机制和防治策略增添新内容。

在利用新信息记忆动物模型研究认知障碍和防治策略项目的研究中，我们基于首创的联合学习记忆动物模型研究了联合记忆细胞及其环路形成的结构与功能特征，记忆细胞间交互投射与突触形成，以及新突触与不同类型联合记忆细胞形成的分子机制。我们还重点研究了表观遗传分子miRNA-324-5p/miRNA-133a改善记忆和联合记忆细胞形成，及其偶联轴突投射与新突触形成的靶基因和靶蛋白分子机理。我们同时建立了躯体应激和心理应激的恐惧记忆的动物模型，研究了躯体应激恐惧记忆与心理应激恐惧记忆的分子基础及其差异。这些分子机理被用于研究改善记忆衰退和认知障碍的防治策略。26篇研究成果已被发表在SCI收录国际期刊和一本专著由Springer-Nature出版。