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Reactive astrocytes are associated with neuroinflammation and cognitive decline in diverse neuropathologies; however, the underlying mechanisms are unclear. We used optogenetic and chemogenetic tools to identify the crucial roles of the hippocampal CA1 astrocytes in cognitive decline. Our results showed that repeated optogenetic stimulation of the hippocampal CA1 astrocytes induced cognitive impairment in mice and decreased synaptic long-term potentiation (LTP), which was accompanied by the appearance of inflammatory astrocytes. Mechanistic studies conducted using knockout animal models and hippocampal neuronal cultures showed that lipocalin-2 (LCN2), derived from reactive astrocytes, mediated neuroinflammation and induced cognitive impairment by decreasing the LTP through the reduction of neuronal NMDA receptors. Sustained chemogenetic stimulation of hippocampal astrocytes provided similar results. Conversely, these phenomena were attenuated by a metabolic inhibitor of astrocytes. Fiber photometry using GCaMP revealed a high level of hippocampal astrocyte activation in the neuroinflammation model. Our findings suggest that reactive astrocytes in the hippocampus are sufficient and required to induce cognitive decline through LCN2 release and synaptic modulation. This abnormal glial–neuron interaction may contribute to the pathogenesis of cognitive disturbances in neuroinflammation-associated brain conditions.

反应性星形胶质细胞与多种神经病理状态下的神经炎症（neuroinflammation）及认知衰退密切相关，但其潜在具体机制尚未阐明。本研究借助光遗传学（optogenetic）与化学遗传学（chemogenetic）工具，明确了海马CA1区星形胶质细胞在认知衰退进程中的关键作用。实验结果显示，对小鼠海马CA1区星形胶质细胞进行反复光遗传学刺激，可诱发小鼠认知功能障碍，降低突触长时程增强（LTP）水平，同时伴随炎症性星形胶质细胞的出现。通过基因敲除动物模型与海马神经元原代培养开展的机制研究表明，反应性星形胶质细胞分泌的脂质运载蛋白-2（LCN2）可通过降低神经元N-甲基-D-天冬氨酸（NMDA）受体的表达水平，抑制突触长时程增强，进而介导神经炎症并诱发认知功能障碍。对海马星形胶质细胞进行持续化学遗传学刺激，也得到了一致的实验结果。反之，使用星形胶质细胞代谢抑制剂可缓解上述现象。采用GCaMP标记的光纤光度成像技术检测发现，神经炎症模型小鼠的海马星形胶质细胞激活水平显著升高。本研究结果表明，海马区的反应性星形胶质细胞通过释放LCN2并调控突触功能，足以且必需参与认知衰退的诱发过程。这种异常的胶质-神经元相互作用，可能参与神经炎症相关脑部疾病中认知障碍的病理发生过程。