The roles of anesthetics and neuroimmune interactions in postoperative cognitive dysfunction

麻醉药和神经免疫相互作用在术后认知功能障碍中的作用

• 批准号: 10615008
• 负责人: Guang Yang
• 金额: $ 40.5万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10615008
• 关键词: Adoptive Cell Transfers; Age; Aging; Anesthesia procedures; Anesthetics; Animal Model; Bone Marrow; Brain; Cells; Chimera organism; Dendritic Spines; Development; Elderly; Functional disorder; General Anesthesia; General anesthetic drugs; Immune; Immune signaling; Immunologics; Impaired cognition; Individual; Innate Immune System; Mediating; Nervous System; Neurocognitive; Neurocognitive Deficit; Neuroimmune; Neuroimmunomodulation; Neuronal Plasticity; Neurons; Operative Surgical Procedures; Pathogenicity; Patients; Performance; Population; Postoperative Period; Proteins; Role; Signal Pathway; Structure; Synapses; aging brain; cognitive recovery; experimental study; immune activation; in vivo; insight; neural circuit; neuronal circuitry; neurotransmission; novel therapeutic intervention; older patient; post-operative cognitive dysfunction; postoperative recovery; serial imaging; therapeutic development; treatment strategy

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.

项目摘要 大手术后老年患者常见术后认知功能障碍（POCD）。作为 老年外科手术患者的种群成长，必须了解致病机制 基础POCD并制定治疗策略。积累的证据表明一般麻醉药 在年龄极端的手术期间进行给药可能会对神经产生持久的有害影响 系统。确实，我们对皮质回路的研究揭示了全身麻醉的各种不希望的影响 手术后的发育和衰老大脑，包括突触蛋白的变化，树突异常 脊柱可塑性和神经元功能以及神经认知性能受损。这些麻醉 - 诱导的神经元可塑性和功能的变化可能在POCD的发展中起重要作用 特别是在老年人中。除了麻醉药物外，免疫细胞和信号通路激活了 手术后，还可能对脑功能产生深远的影响，并有助于POCD。使用体内 神经元结构和功能的纵向成像，我们将首先确定全身麻醉如何导致 神经元回路的长期变化和手术后神经认知恢复的延迟。合并 具有免疫学工具集，包括骨髓嵌合体，体内细胞耗竭和收养细胞转移， 我们将进一步确定介导POCD中神经回路功能障碍的神经免疫机制。我们将 还要操纵神经传递和免疫信号传导途径，以促进术后认知 恢复。总之，我们提出的实验可能会揭示麻醉的重要功能和 POCD中的免疫激活并有助于发展治疗。