Neurons have a limited capacity to regenerate in the adult central nervous system (CNS). The inability of damaged axons to re-establish original circuits results in permanent functional impairment ...after spinal cord injury (SCI). Despite abortive regeneration of axotomized CNS neurons, limited spontaneous recovery of motor function emerges after partial SCI in humans and experimental rodent models of SCI. It is hypothesized that this spontaneous functional recovery is the result of the reorganization of descending motor pathways spared by the injury, suggesting that plasticity of intact circuits is a potent alternative conduit to enhance functional recovery after SCI. In support of this hypothesis, several studies have shown that after unilateral corticospinal tract (CST) lesion (unilateral pyramidotomy), the intact CST functionally sprouts into the denervated side of the spinal cord. Furthermore, pharmacologic and genetic methods that enhance the intrinsic growth capacity of adult neurons or block extracellular growth inhibitors are effective at significantly enhancing intact CST reorganization and recovery of motor function. Owing to its importance in controlling fine motor behavior in primates, the CST is the most widely studied descending motor pathway; however, additional studies in rodents have shown that plasticity within other spared descending motor pathways, including the rubrospinal tract, raphespinal tract, and reticulospinal tract, can also result in restoration of function after incomplete SCI. Identifying the molecular mechanisms that drive plasticity within intact circuits is crucial in developing novel, potent, and specific therapeutics to restore function after SCI. In this review we discuss the evidence supporting a focus on exploring the capacity of intact motor circuits to functionally repair the damaged CNS after SCI.
Axotomized neurons within the damaged CNS are thought to be prevented from functional regeneration by inhibitory molecules such as chondroitin sulfate proteoglycans (CSPGs) and myelin-associated ...inhibitors. Here, we provide a transgenic test of the role of CSPGs in limiting regeneration, using the gfap promotor to express a CSPG-degrading enzyme chondroitinase ABC (ChABC) in astrocytes. Corticospinal axons extend within the lesion site, but not caudal to it, after dorsal hemisection in the transgenic mice. The presence of the gfap-ChABC transgene yields no significant improvement in motor function recovery in this model. In contrast, functionally significant sensory axon regeneration is observed after dorsal rhizotomy in transgenic mice. These transgenic studies confirm a local efficacy for reduced CSPG to enhance CNS axon growth after traumatic injury. CSPGs appear to function in a spatially distinct role from myelin inhibitors, implying that combination-based therapy will be especially advantageous for CNS injuries.
Experience rearranges anatomical connectivity in the brain, but such plasticity is suppressed in adulthood. We examined the turnover of dendritic spines and axonal varicosities in the somatosensory ...cortex of mice lacking Nogo Receptor 1 (NgR1). Through adolescence, the anatomy and plasticity of ngr1 null mice are indistinguishable from control, but suppression of turnover after age 26 days fails to occur in ngr1−/− mice. Adolescent anatomical plasticity can be restored to 1-year-old mice by conditional deletion of ngr1. Suppression of anatomical dynamics by NgR1 is cell autonomous and is phenocopied by deletion of Nogo-A ligand. Whisker removal deprives the somatosensory cortex of experience-dependent input and reduces dendritic spine turnover in adult ngr1−/− mice to control levels, while an acutely enriched environment increases dendritic spine dynamics in control mice to the level of ngr1−/− mice in a standard environment. Thus, NgR1 determines the low set point for synaptic turnover in adult cerebral cortex.
► Turnover of synaptic anatomy is accelerated in the brain of mice lacking NgR1 ► Deletion of NgR1 in adult mice restores juvenile levels of anatomical plasticity ► NgR1 functions cell-autonomously to limit anatomical plasticity in vivo ► NgR1 expression limits the anatomical response to somatosensory input
Experience rearranges connectivity, but anatomical plasticity is restricted in adults. Akbik et al. demonstrate that Nogo Receptor 1 is required continuously and cell-autonomously to limit adult dendritic spine turnover. NgR1 determines the low set point for synaptic turnover in adult cerebral cortex.
Recovery of neurological function after traumatic injury of the adult mammalian central nervous system is limited by lack of axonal growth. Myelin-derived inhibitors contribute to axonal growth ...restriction, with ephrinB3 being a developmentally important axonal guidance cue whose expression in mature oligodendrocytes suggests a role in regeneration. Here we explored the in vivo regeneration role of ephrinB3 using mice lacking a functional ephrinB3 gene. We confirm that ephrinB3 accounts for a substantial portion of detergent-resistant myelin-derived inhibition in vitro. To assess in vivo regeneration, we crushed the optic nerve and examined retinal ganglion fibers extending past the crush site. Significantly increased axonal regeneration is detected in ephrinB3–/– mice. Studies of spinal cord injury in ephrinB3–/– mice must take into account altered spinal cord development and an abnormal hopping gait before injury. In a near-total thoracic transection model, ephrinB3–/– mice show greater spasticity than wild-type mice for 2 mo, with slightly greater hindlimb function at later time points, but no evidence for axonal regeneration. After a dorsal hemisection injury, increased corticospinal and raphespinal growth in the caudal spinal cord are detected by 6 wk. This increased axonal growth is accompanied by improved locomotor performance measured in the open field and by kinematic analysis. Thus, ephrinB3 contributes to myelin-derived axonal growth inhibition and limits recovery from adult CNS trauma.
Loss of function after neurological injury frequently occurs through the interruption of axonal connectivity, rather than through cell loss. Functional deficits persist because a multitude of ...inhibitory factors in degenerating myelin and astroglial scar prevent axonal growth in the adult brain and spinal cord. Given the high clinical significance of achieving functional recovery through axonal growth, substantial research effort has been, and will be, devoted toward this desirable goal. Unfortunately, the labels commonly used in the literature to categorize post-injury axonal anatomy might hinder advancement. In this article, we present an argument for the importance of developing precise terms that describe axonal growth in terms of the inciting event, the distance of axonal extension and the timing of axonal growth. The phenotypes produced by molecular interventions that overcome astroglial scar or myelin-associated inhibitors are reframed and discussed in this context.
Traumatic spinal cord injury results in persistent disability due to disconnection of surviving neural elements. Neural stem cell transplantation has been proposed as a therapeutic option, but ...optimal cell type and mechanistic aspects remain poorly defined. Here, we describe robust engraftment into lesioned immunodeficient mice of human neuroepithelial stem cells derived from the developing spinal cord and maintained in self-renewing adherent conditions for long periods. Extensive elongation of both graft and host axons occurs. Improved functional recovery after transplantation depends on neural relay function through the grafted neurons, requires the matching of neural identity to the anatomical site of injury, and is accompanied by expression of specific marker proteins. Thus, human neuroepithelial stem cells may provide an anatomically specific relay function for spinal cord injury recovery.
Axonal growth after traumatic spinal cord injury is limited by endogenous inhibitors, selective blockade of which promotes partial neurological recovery. The partial repair phenotypes suggest that ...compensatory pathways limit improvement. Gene expression profiles of mice deficient in
, which encodes a receptor for myelin-associated inhibitors of axonal regeneration such as Nogo, revealed that trauma increased the mRNA expression of
, which encodes the receptor for the opioid-related peptide nociceptin. Endogenous and overexpressed ORL1 coimmunoprecipitated with immature NgR1 protein, and ORL1 enhanced the O-linked glycosylation and surface expression of NgR1 in HEK293T and Neuro2A cells and primary neurons. ORL1 overexpression inhibited cortical neuron axon regeneration independently of NgR1. Furthermore, regeneration was inhibited by an ORL1 agonist and enhanced by the ORL1 antagonist J113397 through a ROCK-dependent mechanism. Mice treated with J113397 after dorsal hemisection of the mid-thoracic spinal cord recovered greater locomotor function and exhibited lumbar raphespinal axon sprouting. These effects were further enhanced by combined
deletion and ORL1 inhibition. Thus, ORL1 limits neural repair directly and indirectly by enhancing NgR1 maturation, and ORL1 antagonists enhance recovery from traumatic CNS injuries in wild-type and
null mice.
The hypothesis that Nogo-A (Reticulon 4A) and Nogo-66 receptor (NgR1) limit adult CNS axonal growth after injury is supported by both in vitro experiments and in vivo pharmacological studies. ...However, genetic assessment of the role of Nogo-A in corticospinal tract (CST) axons after spinal cord dorsal hemisection has yielded conflicting results. CST regeneration is detected in homozygous nogo-ab(trap/trap) mice, but not in nogo-ab(atg/atg) mice. CST regeneration is also present after pharmacological NgR blockade, but not in ngr1(-/-) mice. To assess the nogo-ab(atg) and ngr1-null alleles for other axon growth phenotypes, we created unilateral pyramidotomies and monitored the uninjured CST. There is robust pyramidotomy-induced growth of nogo-ab(atg/atg) and ngr1(-/-) CST axons into denervated cervical gray matter. This fiber growth correlates with recovery of fine motor skill in the affected forelimb. Thus nogo-ab and ngr1 play a modulated role in limiting CNS axonal growth across a spectrum of different tracts in various lesion models.
Objective:
Several interventions promote axonal growth and functional recovery when initiated shortly after central nervous system injury, including blockade of myelin‐derived inhibitors with soluble ...Nogo receptor (NgR1, RTN4R) decoy protein. We examined the efficacy of this intervention in the much more prevalent and refractory condition of chronic spinal cord injury.
Methods:
We eliminated the NgR1 pathway genetically in mice by conditional gene targeting starting 8 weeks after spinal hemisection injury and monitored locomotion in the open field and by video kinematics over the ensuing 4 months. In a separate pharmacological experiment, intrathecal NgR1 decoy protein administration was initiated 3 months after spinal cord contusion injury. Locomotion and raphespinal axon growth were assessed during 3 months of treatment between 4 and 6 months after contusion injury.
Results:
Conditional deletion of NgR1 in the chronic state results in gradual improvement of motor function accompanied by increased density of raphespinal axons in the caudal spinal cord. In chronic rat spinal contusion, NgR1 decoy treatment from 4 to 6 months after injury results in 29% (10 of 35) of rats recovering weight‐bearing status compared to 0% (0 of 29) of control rats (p < 0.05). Open field Basso, Beattie, and Bresnahan locomotor scores showed a significant improvement in the NgR‐treated group relative to the control group (p < 0.005, repeated measures analysis of variance). An increase in raphespinal axon density caudal to the injury is detected in NgR1 decoy‐treated animals by immunohistology and by positron emission tomography using a serotonin reuptake ligand.
Interpretation:
Antagonizing myelin‐derived inhibitors signaling with NgR1 decoy augments recovery from chronic spinal cord injury. ANN NEUROL 2011
Sensory axons in the adult spinal cord do not regenerate after injury. This is essentially because of inhibitory components in the damaged CNS, such as myelin-associated inhibitors and the glial ...scar. However, if the sciatic nerve is axotomized before injury of the dorsal column, injured axons can regenerate a short distance in the spinal cord. Here, we show that sciatic nerve transection results in time-dependent phosphorylation and activation of the transcription factor, signal transducer and activator of transcription 3 (STAT3), in dorsal root ganglion (DRG) neurons. This effect is specific to peripheral injuries and does not occur when the dorsal column is crushed. Sustained perineural infusion of the Janus kinase 2 (JAK2) inhibitor AG490 to the proximal nerve stump can block STAT3 phosphorylation after sciatic nerve transection and results in reduced growth-associated protein 43 upregulation and compromised neurite outgrowth in vitro. Importantly, in vivo perineural infusion of AG490 also significantly attenuates dorsal column axonal regeneration in the adult spinal cord after a preconditioning sciatic nerve transection. We conclude that STAT3 activation is necessary for increased growth ability of DRG neurons and improved axonal regeneration in the spinal cord after a conditioning injury.
PDF
