Neuronal Redevelopment and the Regeneration of Neuromodulatory Axons in the Adult Mammalian Central Nervous System

Abstract

One reason that many central nervous system injuries, including those arising from traumatic brain injury, spinal cord injury, and stroke, have limited recovery of function is that neurons within the adult mammalian CNS lack the ability to regenerate their axons following trauma. This stands in contrast to neurons of the adult mammalian peripheral nervous system (PNS). New evidence, provided by single-cell expression profiling, suggests that, following injury, both mammalian central and peripheral neurons can revert to an embryonic-like growth state which is permissive for axon regeneration. This "redevelopment" strategy could both facilitate a damage response necessary to isolate and repair the acute damage from injury and provide the intracellular machinery necessary for axon regrowth. Interestingly, serotonin neurons of the rostral group of raphe nuclei, which project their axons into the forebrain, display a robust ability to regenerate their axons unaided, counter to the widely held view that CNS axons cannot regenerate without experimental intervention after injury. Furthermore, initial evidence suggests that norepinephrine neurons within the locus coeruleus possess similar regenerative abilities. Several morphological characteristics of serotonin axon regeneration in adult mammals, observable using longitudinal in vivo imaging, are distinct from the known characteristics of unaided peripheral nerve regeneration, or of the regeneration seen in the spinal cord and optic nerve that occurs with experimental intervention. These results suggest that there is an alternative CNS program for axon regeneration that likely differs from that displayed by the PNS.

Keywords: axon regeneration; glial scar; neuromodulatory neuron; neuronal injury and repair; redevelopment; serotonin; spinal cord injury.

FIGURE 1

Axon regeneration and collateral sprouting. A few different classes of response can occur following axon injury (A,B). First, the injured axon can regenerate (C–E). This regeneration can originate directly from the transected tip (C) or from the axon shaft (D,E). Regeneration from the axon shaft can occur close to the injured end (D) or from a region more remote to the injury site (E). The regenerating axon does not have to pass through the injured tissue, it can also navigate around the tissue as shown in (E). In addition to regeneration, axons that were spared from injury can sprout collaterals to reinnervate the denervated tissue and compensate for the damage (F,G). This is a distinct process from regeneration. These collaterals can originate anywhere on the intact axon. Finally, the axon can fail to regenerate (H,I). This can be observed through a complete failure to generate new growth (H) or new growth that fails to navigate distal to the site of injury (I). These three classes of response are not mutually exclusive, each one can occur simultaneously at the same injury site across the population of injured axons.

FIGURE 2

Progression of peripheral axon regeneration following injury. Following peripheral nerve injury (A,B), the distal portion of an injured peripheral axon undergoes Wallerian degeneration and is cleared by invading macrophages while the proximal end retracts a short distance from the site of injury (C). The proximal end of the injured axon will stabilize and form a growth cone that generates new neurites to sample the surrounding environment. These neurites can originate from the injured tip, as shown in blue, or from the axon shaft, as shown in green. Surviving axons can also undergo collateral sprouting, shown in purple, to help reinnervate distal tissues (D). Neurites that receive sufficient growth factor signaling stabilize and elongate while the others retract back to the main axon shaft (E). Occasionally two neurites from a single damaged axon can stabilize leading to growth from two branches. These new growths can navigate through the injured tissue or around the injured tissue to reestablish pre-injury synaptic connections (F).

FIGURE 3

Peripheral nerve injury induces the activation of nested transcription factor networks. Axonal injury leads to the unregulated flow of ions at the breach resulting in a propagating wave of depolarization and the opening of voltage gated Ca²⁺ channels. The rise in Ca²⁺ is further potentiated by Ca²⁺ induced Ca²⁺ release from internal stores (not shown). Ca²⁺ then activates adenylyl cyclase leading to a dramatic increase in cAMP production. This rise in cAMP promotes axon regeneration through two pathways, one initiated by PKA and the other through activation of IL-6. PKA leads to the activation of transcription factor hubs AP1 and CREB while the IL-6 pathway leads to the activation of STAT3. These three transcription factor hubs induce the expression of other regeneration associated genes (RAGs) including ATF3, another transcription factor hub crucial to the early injury and regeneration response.

FIGURE 4

Extrinsic inhibition of CNS axon regeneration. Oligodendrocytes express four membrane bound regeneration inhibitors: Sema4D, MAG, oMgp, and NogoA. Sema4D binds to the PlexinB1 receptor and the others bind to the Nogo-66 Receptor (NgR) complex expressed on the CNS axon. Each of these receptors signal growth cone collapse through the Rho/ROCK pathway. Invading meningeal cells in the glial scar secrete Sema3A molecules which associate with chondroitin sulfate proteoglycan (CSGP) glycosaminoglycan (GAG) side-chains and bind the PlexinA1 receptor to signal growth cone collapse through the activation of Ras. CSPG GAG chains, secreted by astrocytes and other cells, bind the PTPσ or the LAR receptor to signal growth cone collapse through the same Rho/ROCK pathway. Furthermore, the PTPσ and LAR receptors also signal back to the cell body to inhibit pro-regeneration signaling cascades.