Axon plasticity in the mammalian central nervous system after injury

Abstract

It is widely recognized that severed axons in the adult central nervous system (CNS) have limited capacity to regenerate. However, mounting evidence from studies of CNS injury response and repair is challenging the prevalent view that the adult mammalian CNS is incapable of structural reorganization to adapt to an altered environment. Animal studies demonstrate the potential to achieve significant anatomical repair and functional recovery following CNS injury by manipulating axon growth regulators alone or in combination with activity-dependent strategies. With a growing understanding of the cellular and molecular mechanisms regulating axon plasticity, and the availability of new experimental tools to map detour circuits of functional importance, directing circuit rewiring to promote functional recovery may be achieved.

Figure 1. Representative neuron-intrinsic regulators of post-axotomy cell survival and/or axon regeneration

Response to axotomy and its regulators are compared between retinal ganglion cells (RGCs) and corticospinal neurons. RGCs undergo significant cell death following axotomy, rendering cell survival a prerequisite for axon regeneration. It is debatable whether axon injury compromises survival of corticospinal neurons, as indicated by dotted grey line. Neuron-intrinsic regulators of post-axotomy cell survival and axon regeneration validated in vivo are shown.

Figure 2. Circuit rewiring in the corticospinal tract (CST) and phrenic system after injury

(A) Left, In the intact CST (blue lines), axons of corticospinal neurons whose cell bodies reside in the motor cortex (blue circles) decussate at the medullary pyramids, descend contralaterally mainly in the dorsal and dorsolateral columns of the spinal cord, and synapse directly or indirectly on motor neurons (green) to control voluntary movements. For illustration purpose, only direct synapses are shown, which are more prevalent in primates than in rodents. Right, In the injured CST with unilateral lesion rostral to decussation, pyramidotomy (bold red line) results in contralateral denervation. Spontaneous compensatory sprouting from intact axons (orange) has been shown to re-establish detour connections with motor neurons through spinal interneurons (purple). (B) Left, In the intact phrenic system that controls respiration, medullary neurons in the rostral ventral respiratory group RVRG (blue circles) descend bilaterally through the bulbospinal tract (blue lines) to the phrenic nuclei (light green ovals) that project axons (dark green) to control the diaphragm. Bulbospinal axons also form “silent” connections (dotted blue lines) with the contralateral phrenic nuclei. Right, Spinal cord hemisection (long bold red line) paralyzes the ipsilateral hemidiaphragm. In the crossed phrenic phenomenon (CPP), subsequent lesion of the contralateral phrenic nerve (phrenicotomy – short bold red line) induces activation of the latent phrenic pathway (orange) to restore respiratory function of the hemidiaphram paralyzed by spinal cord injury. In addition, sprouting of the crossed phrenic pathway (dotted orange lines) may occur [115].

Figure 3. Shaping and mapping functional relay circuits

Illustrated is a proposed approach to guide the formation of adaptive sprouting and map the resultant relay circuit by combining post-injury rehabilitation, retrograde trans-synaptic labeling, tissue clearing, and three-dimensional imaging of cleared brain and spinal cord. (A) In an uninjured animal, retrograde trans-synaptic tracing with fluorescent label from spinal motor neurons (green) –as can be achieved by injection of viral tracer into the muscle of interest (brown)– followed by tissue clearing to reveal proper connection of spinal motor neurons to corticospinal neurons (blue) in the corresponding motor cortex. Rodent spinal interneurons are not shown. (B) In a spinally injured animal (red “X”), spontaneous sprouting occurs but is undirected, leading to nonfunctional or maladaptive connections (indicated by blue arrow) that may change cortical motor representation and worsen motor function among other adverse effects. (C) In a spinally injured animal subjected to post-injury rehabilitation (exercise and/or electrochemical stimulation), spontaneous sprouting occurs and training strengthens adaptive circuits (indicated by blue arrow) exemplified by the establishment of relay connections to motor neurons through spinal interneurons (purple) to enhance functional recovery. Retrograde transneuronal tracing and tissue clearing allow subsequent visualization of such functional relay network. Furthermore, molecular interventions may enhance the sprouting response that in combination with rehabilitation could increase formation of new functional connections (not shown).