中文摘要：

小胶质细胞是大脑驻留的巨噬细胞，可以获得不同的功能表型，这些表型得到了细胞代谢差异重编程的支持。这些适应包括糖酵解和线粒体代谢通量的重塑，可能会改变组织水平的能量底物可用性。这种现象可能与大脑高度相关，因为在大脑中，新陈代谢必须得到精确调节，以维持适当的神经元兴奋性和突触传递。然而，小胶质细胞可以影响神经元能量代谢的直接证据一直缺乏。结合分子分析、电生理学、氧微传感器记录和数学建模，我们研究了神经炎症期间小胶质细胞介导的大脑能量紊乱。我们的结果表明，促炎小胶质细胞表现出增强的一氧化氮释放和 CX3CR1 表达降低，短暂增加了组织乳酸/葡萄糖比率，这取决于小胶质细胞中的转录重编程，而不是神经元中的转录重编程。在这种情况下，神经网络活动，如伽马振荡（30-70 Hz）可以通过线粒体中ATP的产生增加来推动，这反映在耗氧量增加上。在失调的炎症期间，高能量需求和低葡萄糖可用性可能是神经元代谢适应性的边界条件，正如单神经元能量学的动力学模型所揭示的那样。总的来说，这些发现表明，在中度神经炎症期间，代谢灵活性可以保护神经元网络功能免受局部底物可用性的改变。。

英文摘要：

Microglia, brain-resident macrophages, can acquire distinct functional phenotypes, which are supported by differential reprogramming of cell metabolism. These adaptations include remodeling in glycolytic and mitochondrial metabolic fluxes, potentially altering energy substrate availability at the tissue level. This phenomenon may be highly relevant in the brain, where metabolism must be precisely regulated to maintain appropriate neuronal excitability and synaptic transmission. Direct evidence that microglia can impact on neuronal energy metabolism has been widely lacking, however. Combining molecular profiling, electrophysiology, oxygen microsensor recordings and mathematical modeling, we investigated microglia-mediated disturbances in brain energetics during neuroinflammation. Our results suggest that proinflammatory microglia showing enhanced nitric oxide release and decreased CX3CR1 expression transiently increase the tissue lactate/glucose ratio that depends on transcriptional reprogramming in microglia, not in neurons. In this condition, neuronal network activity such as gamma oscillations (30–70 Hz) can be fueled by increased ATP production in mitochondria, which is reflected by elevated oxygen consumption. During dysregulated inflammation, high energy demand and low glucose availability can be boundary conditions for neuronal metabolic fitness as revealed by kinetic modeling of single neuron energetics. Collectively, these findings indicate that metabolic flexibility protects neuronal network function against alterations in local substrate availability during moderate neuroinflammation.

论文信息：

论文题目：Metabolic flexibility ensures proper neuronal network function in moderate neuroinflammation

期刊名称：Scientific Reports

时间期卷：volume 14, Article number: 14405 (2024) pages685–700 (2024)

在线时间：2024年6月22日

研究亮点：

代谢灵活性确保了炎症期间神经元网络的正常功能。在体内平衡中，血液输入葡萄糖的消耗和脑细胞平行产生乳酸，从乳酸/葡萄糖比值低的血管周围空间到实质（该比率增加）产生温和的能量底物梯度。在炎症期间，小胶质细胞葡萄糖消耗和乳酸产生通过代谢重编程得到增强，这导致更高的乳酸/葡萄糖比率，加剧了血管周围空间和脑实质之间的能量底物梯度。在这种情况下，神经元网络活动可能会通过平行增加耗氧量来保持。炎症期间神经元能量适应性的边界是高能量需求伴随着极低的葡萄糖可用性。在炎症失调的生态位中可能会达到这些限制，其中反应性小胶质细胞的聚集可能发生在远离毛细血管的区域。

材料方法：

氯膦酸盐脂质体巨噬细胞清除剂Clodronateliposomes（liposoma，CP-005-005）加入培养基清除小胶质巨噬细胞，可以参考这篇文献。脑切片体外培养，文献浓度是100ug/ml。荷兰liposoma巨噬细胞清除剂Clodronate Liposomes的浓度是5mg/ml。仅仅体外实验才建议稀释，用无菌PBS稀释。