α-RGCs. Then the authors used OPN4-GFP mice to label the intrinsically photosensitive RGCs (ipRGCs) ⁽¹⁵⁾, which are critical for non-image-forming vision ⁽¹⁶⁾. In normal mice, ipRGCs mainly innervate SCN, vLGN, intergeniculate leaffet (IGL) and SCN, while they do not innervate MTN (16,17). After the combined treatment, the regenerating axons of ipRGCs reached their natural target including IGL, and avoided the wrong targets such as MTN. Therefore, Lim et al. revealed the regenerated RGC axons found the right path and reinnervated their right targets by the combined treatment.
The anatomical reconnection is necessary for the restoration of visual function, but not sufffcient. The functional recovery also critically relies on the number of reconnected axons and the electrical signal conduction ⁽¹⁸⁾. Therefore, the author reasoned whether the rebuilt retinofugal pathway would support visual functions. To address this question, the authors performed four behavioral tests with four different brain regions of visual function: the optomotor test for the oculomotor brainstem, the pupillary light reffex (PLR) for the OPN shell, the visual cliff test for retinogeniculo-cortical pathway, and the looming avoidance response for the retino-collicular pathway. In optomotor and looming response test, the visual behaviors of ONC mice with combined treatment were signiffcantly improved compared to untreated animals. The results indicated the reinnervation of injured RGC axons could rebuild the impaired visual function. Surprisingly, the combined treated mice showed no signiffcant difference in the PLR and visual cliff tests, despite that the regenerated axons were found in OPN and LGN. Three reasons may explain the failure of PLR and visual cliff function recovery. First, lots of RGCs die after optic nerve injury ^(10,19). The regenerated axons can only arise from surviving RGCs, while the RGC degeneration largely limits the number of regenerated axons. Second, despite some long-distance regenerated axons were found in brain targets, not all the regenerated axons could regenerate such a long distance to their targets. As a result, the number of synaptic reconnection is not sufficient to reach the functional recovery level. Third, axons propagate action potentials with myelin sheath, whereas regenerated axons are not myelinated ⁽¹⁸⁾. Consequently, the visual signal is difficult to be delivered to the brain. In summary, the enhancement of mTOR signaling and biased visual stimulation exhibit remarkable synergic effects on axon regeneration. By the combined treatment, axons regenerated a long distance, conffned right trajectories to their natural targets, and partially restored visual functions. 
Although the remarkable regeneration capacity was found under the combined treatment, there are still some open questions. First, why visual inputs from the uninjured eye largely inhibited the regeneration capacity of contralateral injured eye (Figure 1D,E). Probably, visual signals and/or molecular cues from the intact eye competitively suppress the axon outgrowth from the contralateral injured eye. Alternatively, the answer is simply behavioral: suturing the uninjured eye can force the animal to use the injured eye more frequently. Second, the regenerated axon number is not comparable to the intact eyes. It may partially due to the RGC degeneration induced by ONC ⁽¹⁰⁾. Neuroprotective interventions, e.g., manipulating microglial cells, would be applied to save more RGCs ⁽²⁰⁾. Third, the regenerated axons are not myelinated, which leads the poor conduction of electrical signals ⁽¹⁸⁾. Stimulating the remyelination of optic nerve ⁽²¹⁾ or pharmacologically enhance the conduction ⁽¹⁸⁾ would be helpful for functional recovery. In summary, this study sheds light on functional restoration of optic nerve damage and spinal cord injury.