Mechanisms of Post-Anesthetic CNS Dysfunction in Aging

描述（由申请人提供）： “健康”衰老与CNS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改变。这些变化使老年人的大脑更加“脆弱”，并可能导致与年龄相关的认知功能障碍。老年患者经常需要手术和麻醉，但可能因此遭受长期的认知障碍。然而，涉及的机制是未知的，麻醉剂的作用是不清楚的。使用一个完善的行为模型，我们已经证明，一个简单的全身麻醉剂异氟烷-一氧化二氮产生长期的记忆障碍，为一个既定的空间任务，在老年大鼠和异氟烷单独破坏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磷酸化减少、突触可塑性树突标记物减少以及年轻成年大鼠神经发生增加有关，但老年大鼠无变化或减少。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，麻醉诱导的记忆处理变化可能解释了这种损害。本研究的目的是探讨麻醉相关认知功能障碍的发生机制及其神经生物学基础，采用选择性麻醉剂和非麻醉剂对GABA和多巴胺能神经递质进行调控，结合行为学和神经化学方法，系统研究麻醉后长时间的空间记忆改变与胆碱能神经传递改变之间的关系，突触可塑性和神经发生。从这个分析中，我们希望能够推断麻醉后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，或麻醉状态。我们将通过检查麻醉药理学、年龄和学习记忆介质或标记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的认知障碍，增强对麻醉对记忆影响的理解，并可能导致减轻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.