In the central nervous system, glycogen-derived bioenergetic resources in astrocytes help promote tissue survival in response to focal neuronal stress. However, our understanding of the extent to which these resources are mobilized and utilized during neurodegeneration, especially in nearby regions that are not actively degenerating, remains incomplete. Here we modeled neurodegeneration in glaucoma, the world’s leading cause of irreversible blindness, and measured how metabolites mobilize through astrocyte gap junctions composed of connexin 43 (Cx43). We elevated intraocular pressure in one eye and determined how astrocyte-derived metabolites in the contralateral optic projection responded. Remarkably, astrocyte networks expand and redistribute metabolites along distances even 10 mm in length, donating resources from the unstressed to the stressed projection in response to intraocular pressure elevation. While resource donation improves axon function and visual acuity in the directly stressed region, it renders the donating tissue susceptible to bioenergetic, structural, and physiological degradation. Intriguingly, when both projections are stressed in a WT animal, axon function and visual acuity equilibrate between the two projections even when each projection is stressed for a different length of time. This equilibration does not occur when Cx43 is not present. Thus, Cx43-mediated astrocyte metabolic networks serve as an endogenous mechanism used to mitigate bioenergetic stress and distribute the impact of neurodegenerative disease processes. Redistribution ultimately renders the donating optic nerve vulnerable to further metabolic stress, which could explain why local neurodegeneration does not remain confined, but eventually impacts healthy regions of the brain more broadly.

在中枢神经系统中，星形胶质细胞中糖原衍生的生物能量资源有助于促进组织响应局部神经元应激而存活。然而，我们对神经退行性变过程中这些资源的动员和利用程度的理解仍然不完整，特别是在附近没有积极退化的区域。在这里，我们模拟了青光眼（世界上导致不可逆失明的主要原因）的神经退行性疾病，并测量了代谢物如何通过由连接蛋白 43 (Cx43) 组成的星形胶质细胞间隙连接动员。我们升高了一只眼睛的眼压，并确定了对侧视神经投射中星形胶质细胞衍生的代谢物如何反应。值得注意的是，星形胶质细胞网络会沿着甚至 10 毫米长的距离扩展和重新分配代谢物，响应眼压升高，将资源从无应激投射到应激投射。虽然资源捐赠改善了直接受压区域的轴突功能和视力，但它使捐赠组织容易受到生物能、结构和生理退化的影响。有趣的是，当野生型动物的两个投射都受到压力时，即使每个投射受到不同长度的压力，轴突功能和视敏度在两个投射之间保持平衡。当 Cx43 不存在时，不会发生这种平衡。因此，Cx43 介导的星形胶质细胞代谢网络作为一种内源性机制，用于减轻生物能量应激并分散神经退行性疾病过程的影响。 重新分布最终使捐赠视神经容易受到进一步代谢应激的影响，这可以解释为什么局部神经变性不会受到限制，而是最终更广泛地影响大脑的健康区域。