Surviving anoxia: A tale of two white matter tracts

Successful axon function is vital to the overall performance of the central nervous system (CNS). White matter (WM) axons are dependent on constant supply of oxygen and glucose to transmit signals with high fidelity. The optic nerve is a pure WM tract composed of completely myelinated axons while corpus callosum (CC) slices contain both gray and WM portions of the brain with a mixture of myelinated and unmyelinated axons. Axon function in both WM tracts is resistant to anoxia with a subset of axons able to survive exclusively on energy generated by glycolysis. In mouse optic nerves (MONs), removal of glucose during anoxia causes complete loss of axon function, implicating glucose as the sole source of energy. In contrast, in rat optic nerve (RON), anoxia causes rapid and complete loss of function. Because RON is about twice the diameter of MON, glucose diffusion during anoxia is inadequate. Increasing bath glucose concentration restores the ability of RON axons to persist during anoxia. Although in 10 mM glucose, MONs and CC slices exhibit identical resistance to anoxia, 30 mM glucose unmasks the greater resistance of CC axons suggesting unmyelinated axons and/or the smallest axons with the thinnest myelin sheath are resistant to anoxia. These results reveal that CNS WM is remarkably tolerant of anoxia although there is regional variability in their ability to function and survive anoxia. To achieve optimal protection of the CNS in various neurological diseases, it is critical to understand the properties of regional energy metabolisms and injury mechanisms for successful therapeutic approaches.