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

• 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
• 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

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： 在老年手术患者中，del妄普遍存在，并且与显着的发病率，死亡率和 成本。许多年长的外科手术患者术后患有ir妄，尽管许多因素是 可能涉及的是，镇静剂，全身麻醉和麻醉深度已被强烈暗示。 尽管如此，术后del妄病因的分子机制仍不清楚。一个 镇静和全身麻醉的共同特征是均降低神经活动，后者深刻 足以引起脑电图，尤其是在老年患者中的昏迷和接近电的沉默。在临床前 模型，神经元活性的封锁刺激神经元的稳态反应，使得小于小于 小时额外的AMPA型神经递质接收器被插入受影响的突触后膜中 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 其突触输入的强度响应全球活动水平的降低，以至于增加 突触接触的强度恢复了正常的神经回路活性。突触缩放需要TNFα，A 细胞因子最著名的是炎症的介体，但它也是强大的直接神经调节剂。 已经发现，全身麻醉暴露会导致年轻大脑中的瞬时TNFα诱导，这是 老鼠的大脑中的诱导受损。我们假设旧大脑中TNFα中的受损 导致合成缩放率受损并减少麻醉出现后的神经活动，最终 导致del妄的临床体征。为了检验该假设，我们将测量突触缩放和中性 全身麻醉后，年轻小鼠和老鼠的大脑活动。然后，我们将使用CX717， 潜在的AMPA受体活性的安帕宁，以人为地增加老年小鼠的神经活动 麻醉，然后确定麻醉期间老年小鼠的神经活动水平是否会改善 在动物模型中的注意。这项研究具有临床意义，因为它会检查年龄 - 神经稳态的基本特性的依赖性变化，研究神经回路的干扰 老年人的后态del妄的潜在机制，并提出了减轻这种发病率的方法 老年手术患者。