The roles of anesthetics and neuroimmune interactions in postoperative cognitive dysfunction

项目摘要 术后认知功能障碍(POCD)是老年患者大手术后的常见症状。作为 老年外科患者人口增长，了解其发病机制势在必行 潜在的POCD并制定治疗策略。越来越多的证据表明，全身麻醉药 在手术中使用极端年龄的药物可能会对神经产生长期的有害影响 系统。事实上，我们对大脑皮层回路的研究揭示了全身麻醉的各种不良影响。 手术后对大脑发育和老化的影响，包括突触蛋白的变化，树突状细胞的异常 脊柱可塑性和神经功能，以及神经认知能力受损。这些麻醉剂- 诱导的神经元可塑性和功能改变可能在POCD的发展中起重要作用， 尤其是在年迈的个体中。除了麻醉药外，免疫细胞和信号通路也被激活 手术后还可能对大脑功能产生深远影响，并导致POCD。在体内使用 神经结构和功能的纵向成像，我们将首先确定全身麻醉是如何导致 神经回路的长期变化和手术后神经认知恢复的延迟。组合在一起 通过包括骨髓嵌合体、体内细胞耗尽和过继细胞转移在内的免疫学工具， 我们将进一步确定POCD神经回路功能障碍的神经免疫机制。我们会 也操纵神经传递和免疫信号通路，以促进术后认知 恢复。总而言之，我们提议的实验可能会揭示麻醉和 在POCD中免疫激活，并有助于治疗的发展。

Project Summary Postoperative cognitive dysfunction (POCD) is common in elderly patients after major surgery. As the population of geriatric surgical patients grows, it is imperative to understand the pathogenic mechanisms underlying POCD and develop treatment strategies. Accumulating evidence suggests that general anesthetics administered during surgery at the extremes of age could have long-lasting detrimental effects on the nervous system. Indeed, our studies of cortical circuits have revealed various undesired effects of general anesthesia on both developing and aging brains after surgery, including changes in synaptic protein, abnormal dendritic spine plasticity and neuronal function, as well as impaired neurocognitive performance. These anesthesia- induced changes in neuronal plasticity and function could have an important role in the development of POCD, particularly in aging individuals. In addition to anesthetic drugs, immune cells and signaling pathways activated after surgery may also have profound impacts on brain functions and contribute to POCD. Using in vivo longitudinal imaging of neuronal structure and function, we will first determine how general anesthesia leads to long-lasting changes in neuronal circuits and the delayed neurocognitive recovery after surgery. Combined with an immunological toolset including bone marrow chimera, in vivo cell depletion and adoptive cell transfer, we will further determine the neuroimmune mechanisms mediating neural circuit dysfunction in POCD. We will also manipulate neurotransmission and immune signaling pathways to facilitate postoperative cognitive recovery. Together, our proposed experiments will likely reveal the important functions of anesthesia and immune activation in POCD and help the development of therapeutic treatment.