Mechanisms of Post-Anesthetic CNS Dysfunction in Aging

老年麻醉后中枢神经系统功能障碍的机制

• 批准号: 6883148
• 负责人: GREGORY CROSBY
• 金额: $ 32.18万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-04-01 至 2007-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6883148
• 关键词: acetylcholine; aging; anesthesia complication; behavior test; central nervous system; cognition disorders; drug adverse effect; electroencephalography; gamma aminobutyrate; general anesthesia; glutamates; immunocytochemistry; isoflurane; laboratory rat; memory disorders; neural plasticity; neurobiology; neurochemistry; neurotransmitter transport; nitrous oxide; western blottings

DESCRIPTION (provided by applicant): "Healthy" aging is associated with widespread changes in the CNS that include alterations in neurotransmitter systems, synaptic plasticity, and hippocampal neurogenesis. These changes make the aged brain more "fragile" and may account for development of age-related cognitive dysfunction. Elderly patients frequently require surgery and anesthesia but may suffer prolonged cognitive impairment as a result. However, the mechanisms involved are unknown and the role of anesthetic agents is unclear. Using a well-established behavioral model, we have demonstrated that an uncomplicated general anesthetic with isoflurane-nitrous oxide produces long-lasting impairment in memory for an established spatial task in aged rats and isoflurane alone disrupts the ability of young and old rats to learn a new task. Moreover, these changes are associated with reduced phosphorylation of a nuclear protein involved in memory, a decrease in a dendritic marker of synaptic plasticity, and an increase in neurogenesis in young adult rats but no change or a decrease in aged rats. This suggests that general anesthesia could be a factor in human postoperative cognitive dysfunction and that anesthetic-induced changes in memory processing may explain the impairment. The objectives of this proposal are to characterize the mechanisms of anesthesia-related cognitive impairment and to define the neurobiological basis of it. We will use selective anesthetic and non-anesthetic agents to manipulate GABA and glutaminergic tone, in conjunction with behavioral testing and neurochemistry, to systematically investigate the relationship between prolonged post-anesthetic changes in spatial memory and alterations in cholinergic neurotransmission, synaptic plasticity, and neurogenesis. From this analysis, we expect to be able to draw inferences about whether post-anesthetic impairment is a function of the receptor characteristics of the agents, an imbalance between excitatory and inhibitory neurotransmission, or the state of anesthesia. We will investigate mechanisms of prolonged post-anesthetic learning impairment by examining relationships between anesthetic pharmacology, age, and mediators or makers of learning and memory. As such, these experiments will clarify how general anesthesia produces persistent cognitive impairment in aging, enhance understanding of anesthetic effects on memory, and potentially lead to methods to mitigate the cognitive morbidity associated with anesthesia and surgery.

描述（由申请人提供）： “健康”衰老与中枢神经系统的广泛变化有关，包括神经递质系统的改变，突触可塑性和海马神经发生。这些变化使老化的大脑更加“脆弱”，并可能解释了与年龄相关的认知功能障碍的发展。老年患者经常需要手术和麻醉，但结果可能会长期遭受认知障碍。但是，涉及的机制尚不清楚，麻醉剂的作用尚不清楚。使用良好的行为模型，我们证明了一种简单的一般麻醉与异氟硝基氧化物产生长期的记忆障碍，以实现老年大鼠的确定空间任务，而单独的异氟烷则破坏了年轻人和老鼠学习新任务的能力。此外，这些变化与涉及记忆的核蛋白的磷酸化降低有关，突触可塑性的树突状标记降低以及年轻大鼠的神经发生的增加，但没有变化或减少老年大鼠。这表明全身麻醉可能是人类术后认知功能障碍的一个因素，并且麻醉剂诱导的记忆处理变化可能解释了损害。该提案的目标是表征与麻醉相关的认知障碍的机制，并定义其神经生物学基础。我们将使用选择性麻醉和非动力学剂来操纵GABA和谷氨酰胺能张力，并结合行为测试和神经化学，以系统地研究长时间的动静后自动记忆变化与胆红素神经传播的变化之间的关系。从该分析中，我们希望能够推断出解除后的损伤是受体特征的函数，兴奋性和抑制性神经传递之间的不平衡还是麻醉状态。我们将通过研究麻醉药理学，年龄，介体或学习和记忆的介体或制造商之间的关系来研究长期的可理用后学习障碍的机制。因此，这些实验将阐明全身麻醉如何在衰老中产生持续的认知障碍，增强对麻醉对记忆作用的理解，并可能导致方法减轻与麻醉和手术相关的认知发病率。