Age-dependent abnormalities in postanesthetic synaptic scaling as a potential mechanism for delirium

麻醉后突触缩放的年龄依赖性异常是谵妄的潜在机制

基本信息

批准号：
9345987
负责人：
Matthew Bach Friese
金额：
$ 12.82万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-08-15 至 2018-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9345987
关键词：
AMPA Receptors Affect Anesthesia procedures Anesthetics Animal Model Animals Attention Attenuated Behavior Behavioral Biological Assay Brain Characteristics Clinical Coma Data Defect Delirium Depressed mood Development Elderly Electroencephalography Employee Strikes Etiology Failure Fluorescence Microscopy General Anesthesia General anesthetic drugs Homeostasis Hour Human Immediate-Early Genes Impairment In Vitro Incidence Individual Inflammation Mediators Isoflurane Link Literature Measures Mental Depression Molecular Morbidity - disease rate Mus Nerve Block Neuroglia Neuromodulator Neurons Neurotransmitter Receptor Nootropic Agents Operative Surgical Procedures Patients Physiological Processes Postoperative Period Postsynaptic Membrane Pre-Clinical Model Property Receptor Signaling Recovery Research Risk Factors Sedation procedure Surface Symptoms Synapses Syndrome TNF gene Testing Time Up-Regulation Western Blotting Work age related aged brain dysfunction clinically significant cost cytokine experience high risk improved inattention mortality neural circuit older patient postoperative delirium receptor function relating to nervous system response sedative young adult

项目摘要

Abstract: Delirium is prevalent in geriatric surgical patients and is associated with significant morbidity, mortality, and cost. Many older surgical patients suffer from delirium postoperatively and, although numerous factors are likely involved, sedatives, general anesthetics, and depth of anesthesia have been strongly implicated. Nonetheless, the molecular mechanisms underlying the etiology of postoperative delirium remain unclear. A common feature of sedation and general anesthesia is that both decrease neural activity, the latter profoundly enough to induce coma and near-electrical silence on EEG, especially in the older patient. In preclinical models, blockade of neural activity stimulates a homeostatic response in neurons such that in less than an hour additional AMPA-type neurotransmitter receptors are inserted into the postsynaptic membrane of affected synapses—a phenomenon termed synaptic scaling. This scaling is a mechanism by which neurons increase the strength of their synaptic inputs in response to a decrease in global activity level, such that the increased strength of synaptic contacts restores neural circuit activity toward normal. Synaptic scaling requires TNFα, a cytokine best known as a mediator of inflammation, but one that is also a powerful direct neuromodulator. We have found that general anesthesia exposure causes transient TNFα induction in the young brain, and that this induction is impaired in the brains of old mice. We hypothesize that impaired induction of TNFα in old brain leads to impaired synaptic scaling and reduced neural activity upon emergence from anesthesia, ultimately leading to the clinical signs of delirium. To test this hypothesis, we will measure synaptic scaling and neural activity in the brains of young and old mice following general anesthesia. We will then use CX717, an ampakine that potentiates AMPA receptor activity, to artificially increase neural activity in aged mice during anesthesia, and then determine if increasing neural activity level in aged mice during anesthesia improves attention in an animal model for delirium. This research is clinically significant because it examines age- dependent changes in a fundamental property of neural homeostasis, investigates disrupted neural circuitry as a potential mechanism for postanesthetic delirium in seniors, and suggests ways to mitigate this morbidity in geriatric surgical patients.

抽象的：谵妄在老年手术患者中很常见，并且与显着的发病率、死亡率和死亡率相关。许多老年手术患者术后仍会出现谵妄，并且有许多因素影响。可能与镇静剂、全身麻醉剂和麻醉深度密切相关。然而，术后谵妄病因的分子机制仍不清楚。镇静和全身麻醉的共同特点是都会降低神经活动，后者会严重降低神经活动。足以引起脑电图昏迷和近电静默，尤其是在临床前的老年患者中。在模型中，神经活动的阻断会刺激神经元的稳态反应，从而在不到小时额外的 AMPA 型神经递质受体被插入受影响的突触后膜突触——一种称为突触缩放的现象。这种缩放是神经元增加的机制。他们的突触输入的强度响应全球活动水平的下降，从而增加突触接触的强度使神经回路活动恢复正常，突触缩放需要 TNFα，一种细胞因子最著名的是炎症介质，但它也是一种强大的直接神经调节剂。发现全身麻醉会导致年轻大脑中短暂的 TNFα 诱导，并且这老年小鼠大脑中的 TNFα 诱导受损我们一直在努力解决老年小鼠大脑中 TNFα 的诱导受损问题。最终导致麻醉苏醒后突触缩放受损和神经活动减少导致谵妄的临床症状为了检验这一假设，我们将测量突触缩放和神经元。然后我们将使用 CX717，一种全身麻醉后年轻和年老小鼠大脑的活动。 ampakine 可增强 AMPA 受体活性，人为地增加老年小鼠的神经活动麻醉，然后确定在麻醉期间增加老年小鼠的神经活动水平是否会改善这项研究具有临床意义，因为它检查了年龄。神经稳态基本特性的依赖性变化，研究破坏的神经回路老年人麻醉后谵妄的潜在机制，并提出了减轻这种发病率的方法老年外科患者。