长链非编码RNA 9130221H12Rik调控GSK-3α在衰老小鼠模式分离功能障碍中的作用及机理研究

认知衰退严重危害老龄人群的身心健康，模式分离功能障碍被认为是认知衰退的早期表现，但其机制不明。已知糖原合酶激酶3α（GSK-3α）下调可诱发心脏等器官衰老，申请人发现GSK-3α在衰老小鼠海马中下降，GSK-3α敲除小鼠出现模式分离障碍；同时，在GSK-3α的基因组反义链上存在长链非编码RNA 9130221H12Rik，其可以正向调控GSK-3α的表达，并且在衰老时呈现与GSK-3α同向改变；干扰9130221H12Rik的表达可以诱发小鼠出现模式分离功能障碍，提示9130221H12Rik调控GSK-3α参与衰老时模式分离功能障碍。本项目拟综合利用生物信息学、分子生物学、电生理、分子成像及行为学等手段，明确9130221H12Rik调控GSK-3α在衰老模式分离障碍中的作用及机理，并探索通过干预该通路改善衰老动物认知衰退的可能性，为开发老龄人群预防或减缓认知功能减退的策略提供实验依据。

The deficit in pattern separation was recognized as an early manifestation in cognitive failure, which severely affects the mental and physical health in aged people. It is known that the downregulation of GSK-3α induces the senescence of heart and other organs. We found that the level of GSK-3α is decreased in aged hippocampus and the GSK-3α knockout mice display the impairment of pattern separation. Meanwhile, we found a long non-coding RNA, named as 9130221H12Rik, located in the reverse chain of genomic loci of GSK-3α. It can positively regulate the expression of GSK-3α and display the similar change during aging. Interference of 9130221H12Rik expression induces the pattern separation deficits in mice, suggesting the involvement of 9130221H12Rik and GSK-3α in the pattern separation impairment during aging. Here, we will use bioinformatics, molecular biological, electrophysiological, molecular imaging and behavioral approaches to explore the detailed roles and mechanisms of 9130221H12Rik/GSK-3α in the impairments of pattern separation and evaluate the possibility for the amelioration of cognitive failure by manipulating this pathway in aged mice, which will provide the experimental evidences for the prevention or attenuation of cognitive failure in aged people.