术后认知功能障碍（Post-operative cognitive dysfunction, POCD）严重降低生活质量并与死亡率增加有关联。我们前期研究表明，神经炎症是POCD一个重要的病生机制。小鼠在颈动脉暴露术后出现远期POCD、海马脑源性神经营养因子（brain-derived neurotrophic factor, BDNF）降低及神经细胞生成减少。但手术如何激活神经炎症，并抑制神经细胞生成，目前并不明确。预实验发现手术增加了小鼠海马中toll样受体（TLR）2和4的表达，抑制TLR2/4可减低手术引起的促炎症细胞因子增加。因此本课题假设：TLR2/4介导神经炎症，通过抑制BDNF表达，减少脑细胞发生，从而引起远期POCD。我们将以药物抑制剂为工具，使用免疫组织化学，分子生物学和行为学等方法进行验证，以深入探讨不同年龄远期POCD的发病机制，找出有效的治疗靶点。

Post-operative cognitive dysfunction (POCD) decreases quality of life and is associated with increased death. Our previous studies have identified that neuroinflammation is a critical neuropathophysiological process for POCD. Moreover, our studies have shown that delayed POCD induced by right carotid artery exploration in mice is associated with reduction of brain-derived neurotrophic factor (BDNF) production and brain cell genesis in the hippocampus of mice. However，how surgery activates neuroinflammation and then inhibits neurogenesis is still undetermined. Our preliminary study showed that the surgery increased toll-like receptor (TLR) 2 and 4, proteins that are involved in innate immune and inflammatory response, in the hippocampus of mice. Inhibition of TLR2 and TLR4 reduced surgery-induced proinflammatory cytokine production. Therefore, we hypothesize that TLR-mediated neuroinflammation contributes to the delayed POCD by inhibiting neurotrophic factors including BDNF and the downstream brain cell genesis. Pharmacological agents targeting TLR2 or TLR4 will be used. These studies will reveal the mechanisms of delayed POCD and identify potential therapeutic targets for attenuating POCD. The parallel comparison of the surgical effects between young and elderly mice may reveal the mechanisms for the higher incidence of delayed POCD in elderly patients.

神经炎症是是术后认知功能障碍（POCD）的 重要病生机制，但其具体机制尚不清楚。本研究通过对出后7天大的SD鼠实施右颈动脉暴露术，诱导术后认知障碍。发现手术能介导神经炎症的发生，IL-1β、IL-6升高，进而导致神经营养因子（GDNF）的表达降低，海马新生脑细胞形成减少。进一步研究发现，在术前30分钟和术后6小时使用抗炎药吡咯烷二硫代氨基甲酸盐（PDTC），能够降低手术引起的炎症反应以及改善术后认知功能的损伤。单纯脑室内注射GDNF抗体能引起学习记忆功能损伤，而单纯脑室内注射GDNF抗体的热灭活形式则不能引起这种改变。同时，我们发现脑室内注射GDNF能减轻手术引起的认知功能损伤。其他相关研究发现，术后P2X7受体、caspase-1前体、IL-1β表达升高，认知功能损伤。P2X7受体抑制剂（BBG）能逆转认知功能减退。本研究提示：在新生大鼠中，手术能够介导神经炎症的发生，进而降低GDNF的表达，减少脑细胞发生，参与POCD的形成。其中，GDNF 表达降低在术后认知功能损伤中有非常重要的影响。另外，P2X7/caspase 1/IL-1β通路也可以影响术后神经炎症的发生。P2X7受体抑制剂和一些降低炎症反应的药物如PDTC可能对POCD有治疗作用。