Combined treatment promotes the long-range axon regeneration to right brain targets

Axons in the peripheral nervous system (PNS) can regenerate after injury. However, the adult mammalian central nervous system (CNS) loses the intrinsic regrowth ability. No robust axon regeneration occurs spontaneously after nerve injury, which was clear observed by Ramon y Cajal in the early 20^th century (1,2). Due to lack of regenerative potentials, the injured axons permanently lose their connections from their targets, e.g. in the optic nerve damage and spinal cord injury. Later, pioneer studies found peripheral nerve segments can bridge the injured axons in the rodent retina (3), medulla and spinal cord (4). The transected axons are able to regrow along the peripheral nerve “bridge”. In 2005, Dong Feng Chen Lab at Harvard Medical School found the elevation of calcium signaling by Bcl-2 overexpression triggered the axon regeneration of the retina (5). In addition, Zhigang He’s lab at Harvard Medical School demonstrated modulating the PTEN/mTOR signaling pathway promoted axon regeneration in the adult CNS (6). Therefore, manipulating the cellular signaling pathways overcomes intrinsic barriers that limit the regeneration capacity of the CNS. Besides, researchers found transcorneal electrical stimulation could enhance axon regeneration (7) and accelerate the speed of axon growth (8). It implies enhancing neuronal activity of RGCs would promote regrowth of axons in vivo. By these treatments, the regenerated axons went through the injury site for several millimeters, which shed lights on rebuilding the injured neural connection. However, there are at least three obstacles in the way to clinical interventions. (I) The regenerated axons can only regenerate for millimeters, far from reaching the brain; (II) how to guide confine regenerated axons to find the right targets; (III) how do regenerated axons re-establish functional connections with downstream neurons. Therefore, there is still a giant gap to the effective therapeutic interventions. In a recent milestone study, researchers from Stanford combined mTOR signaling modulation and visual stimulation to achieve the synergic effects in axon regeneration. The combined treatment promoted injured axons to regenerate along the retinofugal pathway, reinnervate the right targets and partially restore the visual function (Figure 1) (9).