A1型星形胶质细胞介导线粒体能量代谢失衡导致POD的作用及机制

术后谵妄（POD）是老年患者术后发生主要神经系统并发症，认知障碍带来沉重社会经济负担。老年患者围术期普遍存在睡眠碎片化（SF）现象，我们前期研究显示：SF引起老年小鼠海马区IL-1α,TNF-α增加和术后认知下降，但机制未明。预实验发现：SF后呈现海马区A1型星形胶质细胞活化和线粒体代谢功能受损。因此提出假说：SF促进中枢IL-1α,TNF-α、C1q分泌增加，激活A1型星形胶质细胞活化，触发线粒体能量代谢和氧化应激失衡，导致POD发生。本研究首先明确抑制A1型星形胶质细胞活化与认知的相关性；其次采用转录组学探索SF激活哪些脑区A1型星形胶质细胞活化；再次采用Il1a-/-;Tnf-/-;C1q-/- KO小鼠和特异性工具药，揭示A1星形胶质细胞活化对线粒体能量代谢和氧化应激的影响；系统阐明A1型星形胶质细胞活化通过线粒体能量代谢失衡导致POD发生机制，为POD的防治提供新思路和新策略。

Postoperative delirium (POD) is a major neurological complication that occurs in elderly patients after surgery, and cognitive impairment brings a heavy social and economic burden. Sleep fragmentation (SF) is common in elderly patients during the perioperative period. Our previous studies showed that SF caused an increase in IL-1α and TNF-α in the hippocampus of old mice and a decrease in postoperative cognition, but the mechanism was not clear. Preliminary experiments found that SF can lead to the activation of A1 astrocytes in the hippocampus and impaired mitochondrial metabolic function. Therefore, it is hypothesized that SF promotes increased secretion of central IL-1α, TNF-α, and C1q, activates A1-type astrocyte activation, and triggers mitochondrial energy metabolism and oxidative stress imbalance, leading to POD. In this study, First, the inhibition of A1-type astrocyte activation and cognitive correlation were identified. Secondly, transcriptomics was used to explore which brain regions A1-type astrocytes were activated by SF. Il1a-/-; Tnf-/- ; C1q-/-conditional gene knockout mice and specific tool drugs, revealing the effect of A1 astrocyte activation on mitochondrial energy metabolism and oxidative stress; system clarifies A1 astrocyte activation through mitochondrial energy. The metabolic imbalance leads to the mechanism of POD, providing new ideas and new strategies for the prevention and treatment of POD.