Neural plasticity after peripheral nerve injury and regeneration

https://doi.org/10.1016/j.pneurobio.2007.06.005Get rights and content

Abstract

Injuries to the peripheral nerves result in partial or total loss of motor, sensory and autonomic functions conveyed by the lesioned nerves to the denervated segments of the body, due to the interruption of axons continuity, degeneration of nerve fibers distal to the lesion and eventual death of axotomized neurons. Injuries to the peripheral nervous system may thus result in considerable disability. After axotomy, neuronal phenotype switches from a transmitter to a regenerative state, inducing the down- and up-regulation of numerous cellular components as well as the synthesis de novo of some molecules normally not expressed in adult neurons. These changes in gene expression activate and regulate the pathways responsible for neuronal survival and axonal regeneration.

Functional deficits caused by nerve injuries can be compensated by three neural mechanisms: the reinnervation of denervated targets by regeneration of injured axons, the reinnervation by collateral branching of undamaged axons, and the remodeling of nervous system circuitry related to the lost functions. Plasticity of central connections may compensate functionally for the lack of specificity in target reinnervation; plasticity in human has, however, limited effects on disturbed sensory localization or fine motor control after injuries, and may even result in maladaptive changes, such as neuropathic pain, hyperreflexia and dystonia.

Recent research has uncovered that peripheral nerve injuries induce a concurrent cascade of events, at the systemic, cellular and molecular levels, initiated by the nerve injury and progressing throughout plastic changes at the spinal cord, brainstem relay nuclei, thalamus and brain cortex. Mechanisms for these changes are ubiquitous in central substrates and include neurochemical changes, functional alterations of excitatory and inhibitory connections, atrophy and degeneration of normal substrates, sprouting of new connections, and reorganization of somatosensory and motor maps. An important direction for ongoing research is the development of therapeutic strategies that enhance axonal regeneration, promote selective target reinnervation, but are also able to modulate central nervous system reorganization, amplifying those positive adaptive changes that help to improve functional recovery but also diminishing undesirable consequences.

Introduction

Injuries to the peripheral nerves result in partial or total loss of motor, sensory and autonomic functions conveyed by the lesioned nerves to the denervated segments of the body, due to the interruption of axons continuity, degeneration of nerve fibers distal to the lesion and eventual death of axotomized neurons. Injuries to the peripheral nervous system can result in substantial functional loss and decreased quality of life because of permanently impaired sensory and motor functions and secondary problems, such as neuropathic pain, and have major social consequences in terms of health care and long periods of sick-leave (Jaquet et al., 2001, Rosberg et al., 2005).

Functional deficits caused by nerve injuries can be compensated by three neural mechanisms: the reinnervation of denervated targets by regeneration of injured axons, the reinnervation by collateral branching of undamaged axons in the vicinity, and the remodeling of nervous system circuitry related to the lost functions. However, clinical and experimental evidences usually show that these mechanisms by themselves do not allow for a satisfactory functional recovery, especially after severe injuries (Sunderland, 1991, Kline and Hudson, 1995, Lundborg, 2000a). After peripheral nerve injuries, the capability of severed axons to regenerate and recover functional connections is dependent on the age of the subject, the nerve trunk affected, the site and type of lesion, the type and delay of surgical repair, and the distance over which axons must regrow to span the injury. Thus, if a nerve transection resulting in a gap between nerve stumps is left unrepaired or repaired with long grafts, the probability of effective reinnervation of muscle and sensory receptors is poor. It is generally considered that in humans, for nerve gaps of less than 2 cm neurological recovery is moderate, but for gaps longer than 4 cm recovery is minimal to non-existent (Reyes et al., 2005). On another hand, collateral reinnervation by undamaged axons is limited to temporal and spatial constraints, especially for large sensory and motor axons (Jackson and Diamond, 1984, Brown et al., 1980), and it is usually only helpful to recover protective pain sensibility and motor strength in partially denervated muscles.

The peripheral and central nervous systems are functionally integrated regarding the consequences of a nerve injury: a peripheral nerve lesion always results in profound and long-lasting central modifications and reorganization (Kaas, 1991, Wall et al., 2002, Kaas and Collins, 2003). Neuronal connections along the nervous system play an important role in regulating the expression of adequate neuronal characteristics, including morphology, dendritic and axonal arborization, membrane electrical properties and production of transmitters and metabolic molecules. The mechanisms of plasticity and reorganization of spinal and brain circuits linked with the axotomized peripheral neurons are complex; they may result in beneficial adaptative functional changes or contrarily cause maladaptive changes resulting in positive symptoms, such as pain, disesthesia, hyperreflexia and dystonia, that worsen the patient's clinical outcome. Nowadays, there are no repair techniques that can ensure the recovery of normal sensorimotor functions of an adult patient following severe nerve trauma, and it is generally considered that a plateau has been reached for the refinement of surgical repair techniques (Lundborg, 2000a, Lundborg, 2003). Therefore, new strategies that simultaneously potentiate axonal regeneration, promote selective target reinnervation and modulate central reorganization are needed. In this review, we focus on the developed plastic changes that follow peripheral nerve injuries and axonal regeneration, with structural, molecular and functional consequences at the level of the central nervous system (CNS), from the injured neuronal cell to the brain.

Section snippets

Cellular and molecular bases of peripheral nerve regeneration

After nerve injuries, axons distal to the lesion site are disconnected from the neuronal body and degenerate. The soma of axotomized neurons undergoes a series of phenotypic changes, known as neuronal reaction and chromatolysis. Whereas Wallerian degeneration serves to create a microenvironment distal to the injury site that is favorable for the axonal regrowth of surviving neurons, neuronal reaction represents the metabolic changes necessary for regeneration and axonal elongation. The

Neuronal survival and reaction

The success of nerve regeneration and functional reinnervation of targets depends at a first instance on the capacity of axotomized neurons to survive and shift towards a regenerative phenotype. One of the sequelae that follow transection of a peripheral nerve is the death of a number of axotomized neurons. The proportion of neuronal death among sensory neurons of the dorsal root ganglia (DRG) after sciatic nerve injury has been reported between 10 and 30%, affecting more small than large

Genotypic and phenotypic changes in axotomized neurons

Injury to neurons results in complex sequences of molecular responses that play an important role in the successful regenerative response and the eventual recovery of function. In the axotomized neurons, the rapid arrival of injury-induced signals is followed by the induction of transcription factors, adhesion molecules, growth-associated proteins and structural components needed for axonal regrowth.

Structural and synaptic plasticity of axotomized neurons

In parallel to the neuronal body reaction, there is a retraction of the dendritic tree and a reduction of the synapses received by axotomized neurons. Such morphological changes seem to account for a functional isolation of the injured, non-functional neurons from the remaining neural circuits (Sumner and Sunderland, 1973, Purves, 1975). These changes have been particularly studied in motoneurons but also in autonomic neurons. The dendritic diameter, membrane area and volume of axotomized

Facilitation of spinal reflexes after nerve injury

Marked plastic changes in the connections and function of spinal reflexes occur after nerve injuries in parallel to peripheral axonal regeneration and target reinnervation. Such changes may play important effects on movement control and sensory processing, if they remain permanent especially when reinnervation is incomplete or defective (Valero-Cabré and Navarro, 2001, Valero-Cabré and Navarro, 2002b).

Regarding motor spinal reflex restitution after nerve injury, Scott (1985) and Scott and

Remodeling of spinal cord circuitry

Peripheral regeneration following nerve section results in the mismatch of the connections between sensory receptors and afferent fibers with second-order neurons in the dorsal horn of the spinal cord and alters the somatotopy of the body representation at the spinal cord level. These alterations result in loss or decrease of tactile acuity and discrimination, and underlie in part positive symptoms such as dysesthesia and neuropathic pain. The lack of specificity in peripheral reinnervation

Plastic changes and reorganization at cortical and subcortical levels

Peripheral injuries resulting in the removal of sensory inputs from the body and the blockage of motor output activity cause a series of dysfunctions which have been classically attributed to changes in the finely organized cortical maps. Nevertheless, recent views indicate that peripheral injuries trigger alterations of neural substrates at multiple subcortical as well as cortical locations. Functional reorganization of sensory and motor systems following peripheral damage is an

Reshaping CNS plasticity

Along this review we have provided extensive evidence supporting the notion that peripheral nerve injury and its consequences – mainly sensory deafferentation and motor deefferentation – induce dramatic processes of reorganization in structures across the neuraxis. These changes consist in decreases of excitability, metabolism and surface extension of the disconnected central substrates with compensatory enhancement of neighboring representations (Fig. 5). Plastic reorganization occurring after

Acknowledgments

The authors research was supported by grants from the Ministerio de Ciencia y Tecnología (SAF2002-04016 and SAF2002-10159-E) and the Ministerio de Sanidad y Consumo (PI060201) of Spain, the European Commission (NEUROBOTICS project, IST-001917) and FEDER funds.

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