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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要术后认知功能障碍（POCD）在大手术后的老年患者中很常见。作为老年外科患者数量不断增加，了解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在极端年龄的手术期间施用可能会对神经产生长期的有害影响系统。事实上，我们对皮质回路的研究揭示了全身麻醉的各种不良影响手术后大脑发育和老化的影响，包括突触蛋白的变化、异常树突脊柱可塑性和神经元功能，以及神经认知功能受损。这些麻醉—— 神经元可塑性和功能的诱导变化可能在 POCD 的发展中发挥重要作用，尤其是在老年人中。除了麻醉药物之外，免疫细胞和信号通路也被激活手术后也可能对大脑功能产生深远影响并导致 POCD。体内使用神经元结构和功能的纵向成像，我们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。组合具有免疫学工具集，包括骨髓嵌合体、体内细胞去除和过继细胞转移，我们将进一步确定介导 POCD 神经回路功能障碍的神经免疫机制。我们将还操纵神经传递和免疫信号通路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和麻醉的重要功能。 POCD 中的免疫激活并有助于治疗方法的开发。