Abstract: After injury of the central nervous system (CNS), neuronal circuits are known to remodel for functional recovery. In general, there are two strategies for the remodeling: axonal regeneration and sprouting (Figure 1A). Axonal regeneration is re-growth of injured neurons themselves, but axons hardly regenerate in the adult mammalian CNS (Silver and Miller, 2004). On the other hand, axonal sprouting is new growth from intact or spared neurons to the denervated target by forming axon collaterals, compensating for damaged circuits. This process is a more effective way for circuit remodeling, as it does not necessarily require long axonal elongation. A well-known example of axonal sprouting is the ectopic projections of the corticofugal projections after unilateral injury of the motor cortex (Figure 1B). Originally, layer 5 neurons in the cortex project ipsilaterally to the midbrain and hindbrain, and contralaterally to the spinal cord. After one side of the cortex is injured, axon sprouting from cortical neurons on the intact side restores connections to the denervated brainstem and spinal cord (Tsukahara, 1981a, b). The elaborate electrophysiological study revealed that ectopic contralateral projections are formed from the intact cortex to the denervated red nucleus in the midbrain, which is involved in the voluntary muscular movement (Tsukahara, 1981a, b). Subsequent studies have further shown that compensatory remodeling occurs in various parts of the CNS, and contributes to functional recovery (Schwab and Strittmatter, 2014). Despite its importance in the recovery, there has been limited progress toward understanding the molecular mechanism of spontaneous axonal sprouting; how the formation of axonal sprouting is coordinated after the injury. Recently, we have demonstrated that factors expressed in the denervated midbrain are involved in the remodeling process, and are produced by glial cells including astrocytes or microglia (Chang et al., 2022). In this perspective, we will briefly present our current understanding of the mechanisms of lesion-induced axonal sprouting of the corticofugal projections, and a view of how glial cells are involved in this process.