Institute of Physiology and Pathophysiology, Heidelberg University, Im Neuenheimer Feld 326, 69120, Heidelberg, Germany.
MEDISS Doctoral Program, INF 110, Heidelberg University, 69120, Heidelberg, Germany.
Sci Rep. 2024 Jun 22;14(1):14405. doi: 10.1038/s41598-024-64872-1.
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.
小胶质细胞是驻留于脑内的巨噬细胞，能获得不同的功能表型，这得益于细胞代谢的差异重编程。这些适应性改变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。在大脑中，这种现象可能非常重要，因为代谢必须精确调节以维持适当的神经元兴奋性和突触传递。然而，小胶质细胞是否能影响神经元的能量代谢，一直缺乏直接证据。通过结合分子谱分析、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脑能量代谢紊乱。我们的结果表明，表现出增强的一氧化氮释放和减少的 CX3CR1 表达的促炎小胶质细胞短暂增加组织中乳酸/葡萄糖的比率，这依赖于小胶质细胞中的转录重编程，而不是神经元。在这种情况下，神经元网络活动，如伽马振荡（30-70 Hz），可以通过线粒体中增加的 ATP 产生来提供燃料，这反映在耗氧量的增加上。在失调的炎症中，高能量需求和低葡萄糖可用性可以是神经元代谢适应性的边界条件，这可以通过单神经元能量代谢的动力学建模来揭示。总的来说，这些发现表明代谢灵活性可保护神经元网络功能免受局部底物可用性在适度神经炎症期间的改变。
