Prior pathology in the basal forebrain cholinergic system predisposes to inflammation-induced working memory deficits: reconciling inflammatory and cholinergic hypotheses of delirium.
Prior pathology in the basal forebrain cholinergic system predisposes to inflammation-induced working memory deficits: reconciling inflammatory and cholinergic hypotheses of delirium.
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DOI：
10.1523/jneurosci.4673-11.2012
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发表时间：
2012-05-02
期刊：
影响因子：
--
通讯作者：
Cunningham C
中科院分区：
文献类型：
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作者：
Field RH;Gossen A;Cunningham C
精神错乱是一种严重的、严重的混乱状态，会导致长期的认知能力下降。增加的抗胆碱能药物和既往的痴呆，其中基底前脑胆碱能变性是一个突出的特征，都预示着精神错乱。因此，胆碱能活性低下被认为是精神错乱时认知功能障碍的重要因素，而急性全身炎症是这种功能障碍的主要触发因素。在这里，我们假设胆碱能功能下降会增加急性炎症诱导的认知障碍的易感性。我们使用小鼠p75-Saporin免疫毒素(MU-P75-SAP)选择性地损伤小鼠的基底前脑胆碱能系统，模拟早期痴呆相关的胆碱能丧失，并使用低剂量细菌脂多糖(LPS)叠加全身炎症。侧脑室注射u-p75-sap导致基底前脑胆碱能神经元耗竭，海马区神经支配减少，但在海马依赖的参考和工作记忆任务中的表现相对完好。然而，全身性脂多糖(100μg/kg)可引起损毁动物的急性和短暂性工作记忆障碍，而对未损毁的对照组无影响。在正常和受损动物中，中枢神经系统炎症反应相似，乙酰胆碱酯酶抑制剂多奈哌齐(1 mg/kg)对这项胆碱能依赖任务中的急性认知缺陷具有保护作用。因此，胆碱能耗竭容易在随后的全身炎症性损害时发展成急性认知缺陷。这些数据为检验急性全身性炎症和慢性胆碱能功能低下之间的相互作用提供了一个有用的模型，并对最近利凡斯明治疗败血症相关性痴呆的试验具有一定的指导意义。
Delirium is a profound, acute confusional state that leads to long-term cognitive decline. Increased anti-cholinergic medications and prior dementia, in which basal forebrain cholinergic degeneration is a prominent feature, both predict delirium. Thus, cholinergic hypoactivity is thought to be important in cognitive dysfunction during delirium and acute systemic inflammation is a major trigger for this dysfunction. Here, we hypothesize that decreased cholinergic function confers increased susceptibility to acute inflammation-induced cognitive deficits. We used the murine-p75-saporin immunotoxin (mu-p75-sap) to induce selective lesions of the basal forebrain cholinergic system in mice, mimicking early dementia-associated cholinergic loss, and superimposed systemic inflammation using low dose bacterial lipopolysaccharide (LPS). Intracerebroventricular injection of mu-p75-sap produced depletion of cholinergic neurons in the basal forebrain and decreased innervation of the hippocampus, but left performance on hippocampal-dependent reference and working memory tasks relatively intact. However, systemic LPS (100μg/kg) induced acute and transient working memory deficits in lesioned animals without effect in unlesioned controls. CNS inflammatory responses were similar in normal and lesioned animals and the acetylcholinesterase inhibitor, donepezil (1 mg/kg), protected against the acute cognitive deficits in this cholinergic-dependent task. Thus, cholinergic depletion predisposes to development of acute cognitive deficits upon subsequent systemic inflammatory insult. These data provide a useful model for examining interactions between acute systemic inflammation and chronic cholinergic hypofunction in delirium and have implications for the recent trial of rivastigmine in sepsis-associated delirium.