丰富物理环境减轻社会隔离所致脑衰老HPA-NLRP3-细胞焦亡级联反应的机制研究

Social isolation (SI) threatens the physical and mental health in the elderly, and it is of great significance to explore effective methods to reduce the harmful consequences. Our recent studies found that the enriched physical environment could alleviate the cognitive and social dsyfunction of the elderly mice. This project will systematically verify the hypothesis that "enriched physical environment can reduce the HPA-NOD-like receptor protein 3 (NLRP3) inflammasome-pyroptosis cascade reaction through miRNA epigenetic regulation, thus protecting the brain function of aged mice exposure to SI. We will first determine whether the enriched physical environment could alleviate the cognitive dysfunction, social and emotional abnormal behavior, HPA axis activation, and NLRP3 signal pathway activation, inflammatory cytokine production and neural cell pyroptosis in the hippocampus, prefrontal cortex and amygdala of aged SI mice. We will illuminate the epigenetic mechanisms of enriched physical environment alleviating neuroinflammation in aged SI mice using miRNA sequencing combined with bioinformatics analysis and miRNA knockdown technology. Finally, we will determine whether the knockout of NLRP3 gene could reduce the pyroptosis of nervous cells and damage of brain function caused by SI. The findings are expected to deepen the understanding of the molecular mechanism about the influence of social factors and physical life style on brain function during the process of ageing, thus providing new insights into the establishment of effective non-drug therapy strategy to prevent and treat brain aging-related diseases.

社会隔离(SI)威胁老龄人身心健康，探索有效的方法以减少其有害后果具有重要意义。我们近期研究发现丰富物理环境减轻SI老龄鼠的认知和社会交往功能减退。本项目将系统验证“丰富物理环境通过miRNA表观遗传调控减轻HPA-神经炎性小体3(NLRP3)-细胞焦亡级联反应进而保护SI老龄鼠脑功能”这一科学假设。我们将首先明确丰富物理环境是否减轻SI老龄鼠认知功能障碍、社会和情绪行为异常、 HPA轴活化、海马、前额叶皮质、杏仁核内NLRP3信号激活、炎症因子产生和神经细胞焦亡；并应用miRNA测序结合生物信息学分析和miRNA敲减等技术阐明丰富物理缓解SI老龄鼠神经炎症反应的表观遗传学机制；最后研究NLRP3基因敲除是否减轻了SI所致的神经细胞焦亡和脑功能损害。预期研究结果将深化对社会和物理生活方式影响衰老进程中脑功能的分子机制认识，并为建立有效的非药物治疗策略防治脑衰老及其相关疾病提供新思路。

老年人群的社会隔离是老龄化社会中最大的健康风险之一，探索有效的方法以减少甚至消除其有害后果，具有重要意义。本研究项目针对此科学问题进行了研究。证实了社会隔离加剧了老衰老进程，并发现前额叶皮质髓鞘化损害是关键病理损害。筛选并发现前额叶皮质miR124在社会隔离损害社会交往能力方面发挥调控作用。利用NLRP3基因敲除鼠，揭示NLRP3介导的神经炎症是社会隔离加剧脑衰老的关键病理机制。项目执行过程中还成功构建了合作饮水行为学范式，为研究小鼠合作行为提供模式动物。目前已发表论文2篇，其中1篇为《国际神经精神药理学杂志》，另一篇为预印本期刊。2篇论文已整理成文。以上研究成果，本项目均为第一标注。