Mechanisms of Post-Anesthetic CNS Dysfunction in Aging

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、突触可塑性和海马神经发生的变化。这些变化使衰老的大脑更加“脆弱”，并可能解释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，但可能会因此遭受长期的认知障碍。然而，其中涉及的机制尚不清楚，麻醉剂的作用也不清楚。利用已建立的行为模型，我们已经证明了简单的全身麻醉剂和异氟醚-一氧化二氮在老年大鼠已建立的空间任务中会产生长期的记忆障碍，并且单用异氟醚就会扰乱年轻和老年大鼠学习新任务的能力。此外，这些变化与参与记忆的核蛋白的磷酸化减少、突触可塑性的树突标记减少以及年轻成年大鼠神经发生的增加有关，但在老年大鼠中没有变化或减少。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，麻醉剂引起的记忆处理的变化可能解释了这种损害。本提案的目的是描述麻醉相关认知损害的机制，并确定其神经生物学基础。我们将使用选择性麻醉剂和非麻醉剂来操纵GABA和谷氨酸能张力，并结合行为测试和神经化学，系统地研究麻醉后长时间空间记忆变化与胆碱能神经传递、突触可塑性和神经发生的变化的关系。从这一分析中，我们希望能够推断麻醉后的损害是否是药物受体特性的函数，兴奋性和抑制性神经传递之间的不平衡，或者麻醉状态。我们将通过检查麻醉药理学、年龄以及学习和记忆的中介物或标志物之间的关系来研究麻醉后长期学习障碍的机制。因此，这些实验将阐明全身麻醉如何在衰老过程中产生持续性认知障碍，增强对麻醉对记忆影响的了解，并可能导致减少与麻醉和手术相关的认知发病率的方法。

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.