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

摘要： 妄想在老年外科患者中普遍存在，并与显著的发病率、死亡率和 成本。许多年长的外科患者术后患有精神错乱，尽管有许多因素是 可能涉及的镇静剂、全身麻醉药和麻醉深度都与此密切相关。 然而，术后神志不清的分子机制仍不清楚。一个 镇静和全身麻醉的共同特点是都会降低神经活动，后者会严重影响神经活动。 足以在脑电上引起昏迷和近乎电学上的沉默，特别是在老年患者。在临床前阶段 在模型中，阻断神经活动刺激神经元的动态平衡反应，这样在不到一个 额外的AMPA型神经递质受体被插入到受影响的突触后膜上 突触--一种称为突触伸缩的现象。这种伸缩是神经元增加的一种机制 它们的突触输入的强度对全球活动水平的下降做出反应，从而使 突触接触的强度使神经回路活动恢复到正常水平。突触伸缩需要肿瘤坏死因子α，一种 细胞因子最为人所知的是炎症介质，但也是一种强大的直接神经调节剂。我们 已经发现全身麻醉暴露会在年轻的大脑中引起一过性的肿瘤坏死因子α的诱导，而这 老年小鼠大脑中的诱导作用受到了损害。我们推测，老年人大脑中肿瘤坏死因子α的诱导受损 最终会导致突触伸缩受损，从麻醉中苏醒时神经活动减少 导致神志不清的临床症状。为了验证这一假设，我们将测量突触比例和神经 全身麻醉后幼龄和老年小鼠的脑活动。然后我们将使用CX717、 Ampakine，增强AMPA受体活性，人工增加老龄小鼠的神经活动 麻醉，然后确定麻醉期间增加老年小鼠的神经活动水平是否有所改善 注意力集中在精神错乱的动物模型上。这项研究具有临床意义，因为它考察了年龄- 神经动态平衡的基本属性的依赖变化，研究被破坏的神经电路作为 老年人麻醉后精神错乱的潜在机制，并提出了减少老年人这种发病率的方法。 老年外科病人。

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.