Regeneration of Functional Neuronal Connections After Injury in the Central and Peripheral Nervous System

Abstract

During development both the peripheral nervous system and the central nervous system (CNS: brain and spinal cord) are very plastic and can adapt well to nerve fibre damage. In the mature organism, however, major differences exist in the molecular processes of nerve fibre regeneration in peripheral nerves and the CNS of higher animals and humans. Thus, spontaneous nerve fibre regeneration and functional recovery can occur only in the peripheral nervous system. In the adult CNS, specific molecules that suppress growth and block regeneration have been found. Some of the mechanisms blocking fibre regeneration can be experimentally influenced in animal models. They lead to nerve fibre regeneration and, importantly, to improved recovery after spinal cord injury or stroke. Several approaches are currently in the preclinical stage and some of them are being tested in human PhaseI/II clinical trials.

Key Concepts:

  • During development regeneration and functional recovery of the injured PNS and CNS take place.

  • Within the critical period of early postnatal life neuronal circuits are shaped by experience; the critical period is a time window with enhanced brain plasticity.

  • In the adult CNS spontaneous regeneration is strongly limited in contrast to the PNS where nerve fibres regenerate over long distances leading to functional recovery.

  • Axonal regeneration and plasticity in the mature CNS are restricted by growth inhibitory molecules found in particular in myelin, as well as inhibitory factors present in the glial scar and the extracellular matrix.

  • After acute CNS injury, secondary damage involving different cell types, secreted factors as well as ECM molecules at the site of primary damage leads to more tissue loss, eventually resulting in the formation of a glial scar.

  • After nerve axotomy or crush the distal nerve stump degenerates; this process is called Wallerian degeneration.

  • In the CNS, plasticity is defined as the functional adaptation of surviving tracts and anatomical areas of the CNS; this includes cellular and molecular modifications at the level of the synapse, and changes on the cellular level leading to the formation of new circuits through sprouting and anatomical reorganisation.

Keywords: PNS; CNS; regeneration; plasticity; spinal cord injury; paraplegia; stroke

Figure 1.

The nervous system consists of the central nervous system (CNS), including the brain and spinal cord (blue), and the peripheral nervous system (PNS), including sensory dorsal root ganglia and peripheral nerves. Crush or section of peripheral nerve fibres leads to spontaneous regrowth (red). In contrast, no regrowth of lesioned nerve fibres occurs after CNS injuries.

Figure 2.

Degeneration and regeneration of axons in the PNS. (a) Historical drawing of a sciatic nerve graft (bottom left) which was transplanted on the retinal stump of the optic nerve (a part of the CNS) (top right) of a rabbit. At the top, several regenerating nerve fibres crossed the scar and grew into the sciatic graft (Ramon y Cajal, ). (b) The peripheral sensory axons of transgenic mice were marked with yellow fluorescent protein. After transection (‘cut’) of the saphenous nerve, axons thickened and formed club‐like endings at the scar; due to this scar, only a few fibres regenerated into the distal stump (to the left). Nerve crush led to less scarring and extensive axon regeneration. From Pan YA, Misgeld T, Lichtman JW and Sanes JR (2003) Journal of Neuroscience23: 11479–11488. Copyright 2004, The Society for Neuroscience.

Figure 3.

Experimental evidence for the regenerative potential of PNS tissue and the limited capacity of the CNS for regeneration. (a) A. Aguayo first transplanted pieces of sciatic nerve into the spinal cord, leading to outgrowth of CNS nerve fibres into these explants. (b) Explants of rat sciatic (PNS) and optic nerves (CNS) were implanted as ‘bridges’ in a three‐compartment chamber culture system, leading from a centre chamber to two adjacent side chambers. Dissociated newborn rat sympathetic or sensory neurons were plated into the centre chamber and grown in the presence of nerve growth factor (NGF). Nerve fibres grew out of the sciatic nerve explants in the side chambers after 2–3 weeks. Besides their tendency to fasciculate, axons grew with high preference on Schwann cell membranes and the Schwann cell side of the basal lamina, a situation identical to in vivo regeneration. In contrast to the sciatic nerves, no axons could be found under any condition in the optic nerves. From Schwab and Thoenen .

Figure 4.

Analysis of the inhibitory activity of Nogo‐A on neurite outgrowth in a stripe assay. Stripes of Nogo‐A/laminin (light background) versus laminin‐only (dark) were compared. Left: Axons growing from chicken retina explants (from left to right) avoid Nogo/laminin stripes and show strong axon fasciculation. Right: At a 10× lower concentration of Nogo‐A fasciculation is less prominent and collaterals grow from the laminin‐only substrate into the Nogo/laminin stripes. From Oertle et al..

Figure 5.

Regeneration of the CNS can be induced with antibodies against the neurite growth inhibitor Nogo‐A after lesion. After spinal cord injury, rats were treated with Nogo‐A neutralising antibodies. In a reconstruction of anatomical sections, this treatment leads to enhanced sprouting of fibres rostral to the lesion, fibres crossing the injury sites on remaining tissue bridges and growing down the spinal cord over long distances (drawn in red). Spared fibres also show enhanced sprouting in the caudal spinal cord. Examples of micrographs are shown below.

Figure 6.

Schematic representation of the corticospinal reorganisation after spinal cord hemisection or motor cortex destruction, for example, after stroke. The intact tract (left) can compensate for some lost connections by sprouting and building new connections, also with nerve cell bodies lying on the contralateral side of the spinal cord.

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Further Reading

Edgerton VR, Tillakaratne NJ, Bigbee AJ et al. (2004) Plasticity of the spinal neural circuitry after injury. Annual Review in Neuroscience 27: 145–167.

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Schwab, Martin E, and Buchli, Anita D(Jun 2012) Regeneration of Functional Neuronal Connections After Injury in the Central and Peripheral Nervous System. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0003384.pub2]