Robust Regeneration of CNS Axons through a Track Depleted of CNS Glia (original) (raw)
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Axon-glial relations during regeneration of axons in the adult rat anterior medullary velum
1998
The anterior medullary velum (AMV) of adult Wistar rats was lesioned in the midsagittal plane, transecting all decussating axons including those of the central projection of the IVth nerve. At selected times up to 200 days after transection, the degenerative and regenerative responses of axons and glia were analyzed using transmission and scanning electron microscopy and immunohistochemistry. In particular, both the capacity of oligodendrocytes to remyelinate regenerated fibers and the stability of the CNS/PNS junctional zone of the IVth nerve rootlet were documented. Transected central AMV axons exhibited four patterns of fiber regeneration in which fibers grew: rostrocaudally in the reactive paralesion neuropil (Group 1); randomly within the AMV (Group 2); into the ipsilateral IVth nerve rootlet, after turning at the lesion edge and growing recurrently through the old degenerated contralateral central trochlear nerve trajectory (Group 3); and ectopically through paralesion tears in the ependyma onto the surface of the IVth ventricle (Group 4). Group 1-3 axons regenerated unperturbed through degenerating central myelin, reactive astrocytes, oligodendrocytes, microglia, and large accumulations of hematogenous macrophages. Only Group 3 axons survived long term in significant numbers, and all became myelinated by oligodendrocytes, ultimately establishing thin sheaths with relatively normal nodal gaps and intersegmental myelin sheath lengths. Schwann cells at the CNS/PNS junction of the IVth nerve rootlet did not invade the CNS, but astrocyte processes grew across the junction into the PNS portion of the IVth nerve. The basal lamina of the junctional glia limitans remained stable throughout the experimental period.
Concepts and Methods for the Study of Axonal Regeneration in the CNS
Neuron, 2012
Progress in the field of axonal regeneration research has been like the process of axonal growth itself: there is steady progress toward reaching the target, but there are episodes of mistargeting, misguidance along false routes, and connections that must later be withdrawn. This primer will address issues in the study of axonal growth after central nervous system injury in an attempt to provide guidance toward the goal of progress in the field. We address definitions of axonal growth, sprouting and regeneration after injury, and the research tools to assess growth.
Journal of Experimental Biology
Tissue transplantation methods, previously used to study neural development, myelination and inherited disorders of myelin can be applied also to the investigation of repair and regeneration in the mammalian CNS. The elongation of axons from injured peripheral nerve of CNS has been studied in adult mice and rats by observing the growth of axons into PNS or CNS tissue grafts. Following spinal cord injury and also after transplantation of optic nerves into the PNS there is axonal sprouting but these neuronal processes fail to elongate more than a few mm into the surrounding glia. On the other hand if segments of a peripheral nerve are grafted into the transected spinal cord, axons arising from spinal neurons and dorsal root ganglia become associated with the transplanted Schwann cells and elongate along the graft, approximately 1 cm. Recently the elongation of axons from spinal and medullary neurones was studied using a new experimental model which employed PNS grafts as 'bridges&...
Facilitatory and inhibitory effects of glial cells and extracellular matrix in axonal regeneration
Current Opinion in Neurobiology, 1991
Recent studies have shown that Schwann ceils stimulate nerve regeneration by producing nerve growth factor in response to macrophage activation as well as by mediating growth through cell-surface and extracellular matrix adhesion molecules. Neurons sprouting in the central .' nervous system, however, encounter a hostile environment including mature oligodendrocytes with contact inhibitors of growth cone motility, * masses of proliferating astrocytes with surface properties that may block _ .:,,: ,,., regeneration, and an extracellular environment relatively rich in chondroitin ,* .; ' =,,_ ' sulfate and tenascin forming a matrix less permissive for regeneratiow;' ,, than that found in the peripheral nervous system. In addition, as neurons mature, integrins and cell adhesion molecules are reduced in number (transcriptionally) or in efficacy (post-translationally). Current Opinion in Neurobiology 1991, 1:407413 The effects of glial cells and extracellular matrix in axonal regeneration Carbonetto
Experimental Neurology, 2012
Several pharmacological approaches to promote neural repair and recovery after CNS injury have been identified. Blockade of either astrocyte-derived chondroitin sulfate proteoglycans (CSPGs) or oligodendrocyte-derived NogoReceptor (NgR1) ligands reduces extrinsic inhibition of axonal growth, though combined blockade of these distinct pathways has not been tested. The intrinsic growth potential of adult mammalian neurons can be promoted by several pathways, including pre-conditioning injury for dorsal root ganglion (DRG) neurons and macrophage activation for retinal ganglion cells (RGCs). Singly, pharmacological interventions have restricted efficacy without foreign cells, mechanical scaffolds or viral gene therapy. Here, we examined combinations of pharmacological approaches and assessed the degree of axonal regeneration. After mouse optic nerve crush injury, NgR1−/− neurons regenerate RGC axons as extensively as do zymosan-injected, macrophage-activated WT mice. Synergistic enhancement of regeneration is achieved by combining these interventions in zymosaninjected NgR1−/− mice. In rats with a spinal dorsal column crush injury, a preconditioning peripheral sciatic nerve axotomy, or NgR1(310)ecto-Fc decoy protein treatment or ChondroitinaseABC (ChABC) treatment independently support similar degrees of regeneration by ascending primary afferent fibers into the vicinity of the injury site. Treatment with two of these three interventions does not significantly enhance the degree of axonal regeneration. In contrast, triple therapy combining NgR1 decoy, ChABC and preconditioning, allows axons to regenerate millimeters past the spinal cord injury site. The benefit of a pre-conditioning injury is most robust, but a peripheral nerve injury coincident with, or 3 days after, spinal cord injury also synergizes with NgR1 decoy and ChABC. Thus, maximal axonal regeneration and neural repair are achieved by combining independently effective pharmacological approaches.
Regrowth and connectivity of injured central nervous system axons in adult rodents
Acta neurobiologiae experimentalis
The capacity of injured nerve cells to regrow and form terminal connections in the CNS of adult mammals was investigated in axotomized retinal ganglion cells (RGCs) of rodents whose optic nerves were substituted by an autologous segment of peripheral nerve. While many RGCs died after axotomy approximately 20% of the surviving RGCs regenerated axons several cm in length. Some of the regenerated RGC axons entered the superior colliculus where they arborized and formed well differentiated synapses that transynaptically excited or inhibited tectal neurons.
Influences of the Glial Environment on the Elongation of Axons After Injury
SUMMARY Tissue transplantation methods, previously used to study neural develop- ment, myelination and inherited disorders of myelin can be applied also to the investigation of repair and regeneration in the mammalian CNS. The elon- gation of axons from injured peripheral nerve or CNS has been studied in adult mice and rats by observing the growth of axons into PNS or CNS tissue grafts. Following spinal cord injury and also after transplantation of optic nerves into the PNS there is axonal sprouting but these neuronal processes fail to elongate more than a few mm into the surrounding glia. On the other hand if segments of a peripheral nerve are grafted into the transected spinal cord, axons arising from spinal neurons and dorsal root ganglia become associated with the transplanted Schwann cells and elongate along the graft, approxi- mately 1 cm. Recently the elongation of axons from spinal and medullary neurones was studied using a new experimental model which employed PNS grafts as...