The study investigates the metabolic coupling between oligodendrocytes (OLs) and axons, focusing on how OLs detect axonal spiking and regulate metabolic coupling in the white matter. Key findings include: 1. **Ca²⁺ Signaling and Glycolysis in OLs**: Fast axonal spiking triggers Ca²⁺ signaling and glycolysis in OLs. This is mediated by increases in extracellular potassium (K⁺) concentrations and activation of Kir4.1 channels, which regulate metabolite supply to axons. 2. **Axonal Lactate Dynamics**: OLs detect axonal activity through K⁺ signaling and Kir4.1 channels. Pharmacological inhibition or OL-specific inactivation of Kir4.1 reduces the activity-induced axonal lactate surge. Mice lacking oligodendroglial Kir4.1 exhibit lower resting lactate levels and altered glucose metabolism in axons. 3. **Axonal Glucose Metabolism**: OLs regulate axonal glucose uptake and consumption. In Kir4.1 cKO mice, axonal glucose consumption is reduced, leading to decreased axonal lactate levels and glucose metabolism. These early deficits in axonal energy metabolism are associated with late-onset axonopathy. 4. **Proteomic Analysis**: Proteomics analysis reveals that loss of oligodendroglial Kir4.1 affects the abundance of metabolite transporters (MCT1 and GLUT1) in myelin, suggesting a role in adjusting the axon-OL metabolic unit. 5. **Discussion**: The study highlights the critical role of OLs in maintaining axonal health through metabolic coupling mediated by K⁺ signaling and Kir4.1 channels. Impaired K⁺ clearance and reduced axonal glucose metabolism contribute to axonal damage and late-onset axonopathy. Overall, the research provides insights into the mechanisms by which OLs detect and respond to axonal activity, and how these processes are essential for preserving axonal health and function.The study investigates the metabolic coupling between oligodendrocytes (OLs) and axons, focusing on how OLs detect axonal spiking and regulate metabolic coupling in the white matter. Key findings include: 1. **Ca²⁺ Signaling and Glycolysis in OLs**: Fast axonal spiking triggers Ca²⁺ signaling and glycolysis in OLs. This is mediated by increases in extracellular potassium (K⁺) concentrations and activation of Kir4.1 channels, which regulate metabolite supply to axons. 2. **Axonal Lactate Dynamics**: OLs detect axonal activity through K⁺ signaling and Kir4.1 channels. Pharmacological inhibition or OL-specific inactivation of Kir4.1 reduces the activity-induced axonal lactate surge. Mice lacking oligodendroglial Kir4.1 exhibit lower resting lactate levels and altered glucose metabolism in axons. 3. **Axonal Glucose Metabolism**: OLs regulate axonal glucose uptake and consumption. In Kir4.1 cKO mice, axonal glucose consumption is reduced, leading to decreased axonal lactate levels and glucose metabolism. These early deficits in axonal energy metabolism are associated with late-onset axonopathy. 4. **Proteomic Analysis**: Proteomics analysis reveals that loss of oligodendroglial Kir4.1 affects the abundance of metabolite transporters (MCT1 and GLUT1) in myelin, suggesting a role in adjusting the axon-OL metabolic unit. 5. **Discussion**: The study highlights the critical role of OLs in maintaining axonal health through metabolic coupling mediated by K⁺ signaling and Kir4.1 channels. Impaired K⁺ clearance and reduced axonal glucose metabolism contribute to axonal damage and late-onset axonopathy. Overall, the research provides insights into the mechanisms by which OLs detect and respond to axonal activity, and how these processes are essential for preserving axonal health and function.