小胶质细胞来源BDNF在术后认知功能障碍中的功能与机制研究

Postoperative cognitive dysfunction (POCD) is a commom clinical syndrome for noncardiac surgery. In addition to influencing daily activities of patients, POCD is associated with increased mortality after the surgery. However, effective interventions to reduce POCD have not been developed. In current study, we found that surgery itself can induce POCD, enriched environment training after surgery can promote functional recovery. Our results showed that surgery reduced the number of cells positively stained for Ki67 and BrdU in neuronal progenitor population and DCX which stand for newborn neuron in SGZ region, indicating that surgery could suppress neurogenesis in mice. Enriched environment promote functional recovery of POCD by increasing the expression level of BDNF and neurogenesis. A preliminary data show that synthesis and secretion of BDNF in microglia may reduce after surgery, suggesting microglia involved in POCD. PKC signaling pathway may play an important role in this process. In current project, we will use mouse, microglia primary culture, and neurosphere-microglia co-culture systerm as a model to in-depth study how microglia mediate POCD through BDNF synthesis and secretion in vitro and in vivo. By carring out this project, we will finally figure out microglia can be servered as potential targetable cell in POCD and their molecular mechanisms , suggesting the potential therapeutic targets for clinical diagnosis and treatment of postoperative cognitive dysfunction. These interventions are urgently needed to improve patient’s outcome after surgery.

术后认知功能障碍（POCD）是患者麻醉手术后常见的严重并发症，典型特征表现为记忆力和智力的下降。POCD确切的发病机制尚不明确，临床有效干预缺乏。前期研究发现手术应激本身能诱导小鼠POCD，丰富环境训练能促进POCD的功能性恢复。术后海马SGZ区神经前体细胞Ki67和BrdU阳性染色的细胞数目显著减少，DCX标记新生神经元也减少，提示手术可能抑制neurogenesis，丰富环境通过增加脑源性生长因子BDNF表达促进neurogenesis和POCD功能恢复。初步机制研究发现小胶质细胞合成分泌BDNF减少可能是POCD主要因素，PKC信号通路可能在其中扮演重要角色，本项目应用小鼠和体外细胞培养模型，深入研究手术导致POCD的机制，小胶质细胞来源BDNF在其中扮演的角色，可望阐明小胶质细胞可作为POCD治疗靶点，发现潜在的治疗分子靶标，有望为临床诊断和治疗提供新策略和方法。

术后认知功能障碍（postoperative cognitive dysfunction, POCD）是患者手术麻醉后常见的并发症，手术应激导致的中枢神经系统炎症反应被认为是重要的危险因素，但目前有效的临床干预措施缺乏。我们前期研究发现丰富环境（enriched environment, EE）训练通过促进神经元新生（neurogenesis）改善术后认知功能，其中脑源性神经营养因子（BDNF）在neurogenesis过程中发挥重要功能。. 已有研究表明BDNF可以由神经元和（或）小胶质细胞分泌，明确术后认知功能障碍模型中BDNF表达变化的靶细胞，有助于深入理解疾病的发生与发展，找到潜在的干预措施。小胶质细胞为中枢神经系统固有免疫细胞，负责维持大脑生理功能。鉴于手术炎症与认知功能的联系，小胶质细胞可能为关键靶细胞。因此，本研究拟探讨小胶质细胞来源BDNF在丰富环境训练干预术后认知功能障碍中的作用与机制，以期为临床治疗术后认知功能障碍提供新的靶点。通过我们的研究发现，通过丰富环境训练增加的BDNF来源于小胶质细胞，手术应激引起TNF-α表达增高，通过激活的PKC-δ信号通路抑制小胶质细胞分泌BDNF；应用PKC-δ的特异性抑制剂rottlerin，可以抑制TNF-α通过PKC-δ信号通路减少小胶质细胞分泌BDNF的作用；给予腹腔内注射C8-ceramide 可以改善小鼠术后学习记忆功能。. 临床可以模拟丰富环境实施改善术后认知功能下降；以小胶质细胞为作用靶点，C8-ceramide有望成为治疗POCD的新型药物，但具体机制还需进一步研究。