Scopolamine causes delirium-like brain network dysfunction and reversible cognitive impairment without neuronal loss

Delirium is a severe acute neuropsychiatric syndrome that commonly occurs in the elderly and is considered an independent risk factor for later dementia. However, given its inherent complexity, few animal models of delirium have been established and the mechanism underlying the onset of delirium remains elusive. Here, we conducted a comparison of three mouse models of delirium induced by clinically relevant risk factors, including anesthesia with surgery (AS), systemic inflammation, and neurotransmission modulation. We found that both bacterial lipopolysaccharide (LPS) and cholinergic receptor antagonist scopolamine (Scop) induction reduced neuronal activities in the delirium-related brain network, with the latter presenting a similar pattern of reduction as found in delirium patients. Consistently, Scop injection resulted in reversible cognitive impairment with hyperactive behavior. No loss of cholinergic neurons was found with treatment, but hippocampal synaptic functions were affected. These findings provide further clues regarding the mechanism underlying delirium onset and demonstrate the successful application of the Scop injection model in mimicking delirium-like phenotypes in mice.谵妄是一种老年人高发的严重急性神经精神综合征，谵妄发病后数年，仍可作为独立风险因素影响痴呆发病。由于谵妄的复杂性，目前鲜有可用的动物模型，谵妄发生的机制研究受限。通过三种临床谵妄风险因素（包括手术麻醉、全身炎症和抗胆碱药），该文分别构建了三种谵妄小鼠模型，并对比了其神经行为学，病理表型和神经元活性特征。我们发现，细菌脂多糖和胆碱能受体拮抗剂东莨菪碱都会诱导谵妄相关大脑网络中的神经元活动减少，其中东莨菪碱表现出与谵妄患者相似的降低模式。东莨菪碱注射会导致亢进行为和可逆性认知障碍。东莨菪碱治疗并不损伤胆碱能神经元数量，而会显著地损伤海马突触功能。研究发现，小鼠的东莨菪碱注射模型很好地模拟了临床的谵妄表型，为谵妄发生的机制提供了线索。.