海马-内侧前额叶环路损伤与术后认知功能障碍的关系及其分子机制研究

Previous studies have explored the pathological mechanism of postoperative cognitive dysfunction (POCD) from the molecular and cellular levels. The molecular and cellular changes in brains could recover in a short time after surgery, which is inconsistent with the characteristics of POCD that can last for a long time. Our preliminary data found the damage of the linkage of medial prefrontal cortex (mPFC) to the dorsal hippocampus, and an increase of HDAC6 and AMPK activities in aged rats after surgery, but not in adult rats. Inhibiting HDAC6 and AMPK activities both improved POCD of aged rats. Inhibiting HDAC6 also improved the linkage of mPFC to the dorsal hippocampus by increasing ac-Tubulin level. In addition, HDAC6 could be pulled down by AMPK of co-immunoprecipitation. Based on the above information, we think, anesthesia and surgery could induce POCD by damaging the linkage between mPFC and hippocampus in an age-dependent manner. AMPK-HDAC6-ac-Tubulin signal plays an important role in the circuit damage. Here we will detect 1) the spatiotemporal and age characteristics of hippocampus- mPFC circuit damage after surgery, 2) the effects of hippocampus- mPFC circuit damage on learning and memory of aged rats after surgery, and 3) the roles of AMPK-HDAC6-ac-Tubulin signal in hippocampus- mPFC circuit damage. These results will supplement the deficiencies of the existing POCD pathological mechanism and provide new information for the development of the prevention and treatment methods of POCD.

以往研究从分子和细胞层面探索了术后认知功能障碍（POCD）的病理机制，但这些病理改变恢复较快，与POCD能持续较长时间的特性不一致。我们前期发现：老年大鼠术后内侧前额叶（mPFC）至背侧海马的联系损伤、HDAC6和AMPK活性上调，但成年大鼠无此改变；抑制HDAC6和AMPK活性都能改善老年大鼠POCD，其中抑制HDAC6能通过Tubulin增强mPFC至背侧海马的联系。此外，我们也发现HDAC6可与AMPK直接作用。据此我们推断：麻醉手术以年龄依赖方式损伤海马-mPFC环路，导致POCD；而AMPK-HDAC6-Tubulin通路是其分子机制。本项目拟检测：1）术后海马-mPFC环路损伤的时空特性和年龄特性，以及该环路损伤对学习记忆具体环节的影响；2）术后AMPK-HDAC6-Tubulin通路在海马-mPFC环路损伤中的作用。这些结果将为POCD防治方法的开发提供全新视角和依据。

本研究在探索“海马-内侧前额叶环路损伤与术后认知功能障碍的关系及其分子机制研究”的同时，也探索了：1）miR-124丢失在脑老化和脑退变中的作用和机制；2）脑靶向的miR-124纳米花对脑退变的调节作用及其机制；3）化疗期间补充益生菌对化疗脑损伤的预防及其机制；4）益生菌对恐惧消退的影响。.发现：1）麻醉手术损伤了mPFC-背侧海马之间的联系，该损伤具有年龄依赖特性；2）mPFC-背侧海马联系损伤影响了记忆巩固，是POCD的重要结构基础，而HDAC6是一个重要的调节分子；3）年龄依赖的miR-124丢失通过抑制RyR3表达引起了认知损伤，是脑老化和脑退变的重要机制；4）从尾静脉多次给予搭载miR-124和芦丁的DNA纳米花能增加AD转基因小鼠脑内miR-124水平，减轻其脑脆性；5）化疗期间补充益生菌能预防化疗脑损伤，紫苏醇是其重要介质；6）益生菌能加速小鼠恐惧消退，抑制其复发。.这些工作不仅阐明了POCD的新机制，而且为AD、化疗脑损伤、创伤性应激的防治提供了新方法。这些工作共发表SCI论文5篇，其中Q1区4篇，大于10分的3篇。