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

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.

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。

衰老过程伴随着多种认知功能的减退，包括模式分离能力的减退。模式分离是动物提取相似的环境或线索间微妙差异的基础。然而，衰老过程中模式分离受损的潜在机制尚不清楚。在这项研究中，我们报道了基底外侧杏仁核中糖原合成酶激酶3α (GSK-3α)的缺失诱导5月龄SAMP8鼠的模式分离能力的减退。我们观察到GSK-3α的缺失与老年小鼠和老年食蟹猴(食蟹猕猴)的杏仁核程序性坏死密切相关。此外，GSK-3α的敲低导致野生型小鼠程序性坏死的激活和模式分离受损，而 BLA 中 GSK-3α的过表达阻止了老年小鼠程序性坏死的激活和模式分离缺陷。我们进一步观察到 GSK-3α 缺失导致 mTORC1信号的激活以促进 RIPK3依赖性程序性坏死，非编码RNA GSK-3α-AS（ 9130221H12Rik）调节小鼠GSK-3α的转录抑制。此外，我们发现社会隔离加速了4月龄的 SAMP8小鼠的程序性坏死和模式分离能力的减退。总的来说，我们的研究不仅揭示了老年人模式分离功能障碍的分子机制，而且确定了一个关键的风险因素和可能的干预策略。