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Progress in Neurobiology 82 (2007) 163201

www.elsevier.com/locate/pneurobio

Neural plasticity after peripheral nerve injury and regeneration


X. Navarro a,b,*, Meritxell Vivo a, Antoni Valero-Cabre c,d
a

Group of Neuroplasticity and Regeneration, Institute of Neurosciences and Department of Cell Biology, Physiology and Immunology,
Universitat Auto`noma de Barcelona, E-08193 Bellaterra, Spain
b
Institut Guttmann, Badalona, Spain
c
Department of Anatomy and Neurobiology, School of Medicine, Boston University, Boston, MA 02118, USA
d
CNRS Unit 5105-ERT-Treat Vision, Department of Neurology, Fondation Ophtalmologique Rothschild, Paris, France
Received 3 October 2006; received in revised form 18 February 2007; accepted 14 June 2007

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.
# 2007 Elsevier Ltd. All rights reserved.
Keywords: Axonal regeneration; Peripheral nerve; Nerve injury; Neuroplasticity; Neurorehabilitation; Cortical reorganization; Spinal cord

Abbreviations: 5-HT, serotonin; ATF, activating transcription factor; BDNF, brain-derived neurotrophic factor; CCK, cholecystokinin; CGRP, calcitonin generelated peptide; ChAT, choline acetyltransferase; CMAK, calcium/calmodulin-dependent kinase; CNS, central nervous system; CNTF, ciliary neurotrophic factor;
CREB, cAMP responsive element binding protein; DRG, dorsal root ganglia; EPSP, excitatory postsynaptic potential; FGF, fibroblast growth factor; fMRI, functional
magnetic resonance imaging; GAP, growth-associated protein; GDNF, glial cell line-derived neurotrophic factor; IB4, isolectin B4; IEG, immediate early gene; IGF,
insulin-like growth factor; IL, interleukin; JNK, c-jun N-terminal kinase; LIF, leukemia inhibitory factor; LTP, long-term potentiation; LTD, long-term depression;
MAPK, mitogen-activated protein kinase; MN, motoneuron; NFkB, nuclear factor kappa B; NGF, nerve growth factor; NO, nitric oxide; NPY, neuropeptide Y; NT,
neurotrophin; PAS, paired associative stimulation; PET, positron emission tomography; PK, protein kinase; STAT, signal transducer and activator of transcription;
TMS, transcranial magnetic stimulation; TTX, tetrodotoxin; VIP, vasoactive intestinal polypeptide; VPM, ventral-posterior medial nucleus of the thalamus; VPL,
ventral-posterior lateral nucleus of the thalamus
* Corresponding author at: Faculty of Medicine, Universitat Auto`noma de Barcelona, E-08193 Bellaterra, Spain. Tel.: +34 935811966; fax: +34 935812986.
E-mail address: xavier.navarro@uab.es (X. Navarro).
0301-0082/$ see front matter # 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.pneurobio.2007.06.005

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X. Navarro et al. / Progress in Neurobiology 82 (2007) 163201

Contents
1.
2.
3.
4.

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7.

8.

9.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Cellular and molecular bases of peripheral nerve regeneration. . . . .
Neuronal survival and reaction . . . . . . . . . . . . . . . . . . . . . . . . . .
3.1. Neuronal reaction and chromatolysis . . . . . . . . . . . . . . . . .
Genotypic and phenotypic changes in axotomized neurons . . . . . . .
4.1. Axonal injury signaling . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.2. Activation of transcription factors and gene regulation . . . . .
4.3. Changes in neuropeptide expression . . . . . . . . . . . . . . . . . .
4.4. Changes in ion channels in injured neurons . . . . . . . . . . . . .
4.5. Changes in neuronal excitability. . . . . . . . . . . . . . . . . . . . .
Structural and synaptic plasticity of axotomized neurons . . . . . . . .
5.1. Functional changes in central synapses . . . . . . . . . . . . . . . .
Facilitation of spinal reflexes after nerve injury . . . . . . . . . . . . . . .
Remodeling of spinal cord circuitry . . . . . . . . . . . . . . . . . . . . . . .
7.1. Central sprouting of afferent projections . . . . . . . . . . . . . . .
7.2. Changes in spinal cord neurons . . . . . . . . . . . . . . . . . . . . .
7.3. Changes in intraspinal inhibitory pathways . . . . . . . . . . . . .
Plastic changes and reorganization at cortical and subcortical levels
8.1. Reorganization of somatosensory cortex . . . . . . . . . . . . . . .
8.2. Reorganization of motor cortex . . . . . . . . . . . . . . . . . . . . .
8.3. Reorganization at subcortical levels . . . . . . . . . . . . . . . . . .
8.4. Mechanisms of cortical and subcortical plasticity . . . . . . . . .
Reshaping CNS plasticity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. Introduction

OBS no
relation
ship
betwee
n nerve
regener
ation
and
pain/
SX!
Taylor,
2010

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
Even pain free patients can have an unhealed nerve (Taylor, 2010)

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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 longlasting 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
patients 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

X. Navarro et al. / Progress in Neurobiology 82 (2007) 163201

refinement of surgical repair techniques (Lundborg, 2000a,


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.
2. 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 functional significance of
regeneration is to replace the distal nerve segment lost during
degeneration, allowing reinnervation of target organs and
restitution of their corresponding functions. The main events

165

that occur at the peripheral nerve level are summarized next


(Fig. 1). For more information, recent reviews can be consulted
(see Fawcett and Keynes, 1990; Sunderland, 1991; Fu and
Gordon, 1997; Verdu and Navarro, 1998; Hall, 2001; Makwana
and Raivich, 2005).
After injuries that cause rupture of peripheral nerve fibers,
axons and myelin sheaths distal to the lesion site are degraded
by a process of Wallerian degeneration. Degeneration also
affects retrogradely a short segment of the proximal nerve
stump. The degenerative end products are eliminated by the
cooperative action of Schwann cells and infiltrating macrophages (Perry and Brown, 1992; Stoll and Muller, 1999). The
first signs of degeneration are observed within 24 h after nerve
injury, and they are prolonged for about 12 weeks following a
proximo-distal progression. Elimination of myelin sheaths
allows for clearance of regeneration-inhibitory factors associated to myelin, mainly myelin-associated glycoprotein in the
peripheral nerve. Schwann cells rapidly initiate detachment of
myelin sheaths after axotomy, probably by activation of
receptor tyrosine kinase erbB2 (Guertin et al., 2005).
Denervated Schwann cells are able to phagocyte myelin debris
to some extent; however, recruitment of hematogenous
macrophages is the main pathway for phagociting myelin
and axonal debris (Tanaka et al., 1992). From 2 to 3 days after
injury there is an important infiltration of macrophages into the

Fig. 1. Schematic of the main events of degeneration and regeneration after peripheral nerve injury. (A) Normal nerve fiber, maintaining synaptic contact with target
cells. (B) Transection of the fiber results in distal fragmentation of axon and myelin sheaths. Macrophages and Schwann cells phagocyte degraded materials.
Chromatolysis at the neuron soma and dendritic arbor retraction occur. (C) Fine sprouts emerge from the proximal axonal end, and elongate in association with the
proliferated Schwann cells in the distal segment, that line up in bands of Bungner. (D) Axonal reconnection with target cells and maturation of the nerve fiber. The
regenerated axon remains of smaller caliber and with shorter internodes than normal. The neuron returns to a normal transmitting phenotype. Taget cells may suffer
atrophy and phenotypic changes during denervation.

166

X. Navarro et al. / Progress in Neurobiology 82 (2007) 163201

degenerating nerve, attracted by cytokines, such as monocyte


chemoattractant protein 1, leukemia inhibitory factor (LIF) and
interleukin (IL)-1 secreted by reactive Schwann cells (Tofaris
et al., 2002). Schwann cells in the distal nerve are stimulated by
the loss of axonal contact, probably through proteins released
by disintegrating axons (Karanth et al., 2006), and later by
cytokines secreted by macrophages, to proliferate after injury.
De-differentiated Schwann cells line up within the endoneurial
tubes to form the bands of Bungner, that later provide support
for regenerating axons. The highest rate of Schwann cell
multiplication is reached by 3 days after lesion, and then
continues with decreasing frequency for 23 weeks to reach a
threefold increase in number (Salonen et al., 1988).
Proximal to the lesion, growth cones emerge from the
severed axons, induced by local factors (Kato and Ide, 1994),
and elongate if they find a favorable terrain. In the absence of a
guiding structure, such as the distal nerve stump, regenerating
axons make a tortuous course and form a neuroma, composed
of immature axonal sprouts and connective tissue (Fried et al.,
1991). If regenerating axons gain the distal nerve, they elongate
within the endoneurial tubes, in association with the Schwann
cell and the basal lamina, constituting regenerative units. The
materials for axonal growth are mainly provided by the cell
body via axonal transport (Hoffman and Lasek, 1980;
McQuarrie and Lasek, 1989), but more recently the contribution of local axonal synthesis and degradation of proteins has
been identified (Verma et al., 2005; Willis et al., 2005). The rate
of axonal regeneration is initially very slow, and reaches a
constant value by 34 days after injury, that is about 23 mm/
day. The factors that stimulate and control axonal regeneration
originate from multiple sources, but the most important
influences derive from the local environment of the lesion.
Axonal elongation requires an adequate substrate of trophic and
tropic factors, provided by reactive Schwann cells and the
extracellular matrix within the degenerated nerve stump (Verdu
and Navarro, 1998).
Several sprouts emerge initially from each parent axon
(Witzel et al., 2005) and may advance in the distal nerve;
thereby the total number of axons in the distal segment may
exceed the number of parent axons in the proximal nerve for
long time (Jenq and Coggeshall, 1985). When axons reach
synaptic loci at peripheral tissue, supernumerary axonal sprouts
are withdrawn gradually. Nerve fibers that regenerate through
erroneous distal pathways to targets that cannot reinnervate,
such as motor axons to the skin, are preferentially eliminated
(Brushart, 1993; Brushart et al., 1998). The functional
significance of regeneration is to replace the distal nerve
segment lost during degeneration and to reinnervate target
tissues. However, the regenerative process usually does not
reconstitute a normal nerve structure neither allows for a
normal function, especially when the lesion is severe. After
nerve injury and repair, the diameter of regenerated axons, their
conduction velocity and excitability remain below normal
levels for a long time (Fields and Ellisman, 1986a,b), and
consequently recovery of reinnervated organs is incomplete and
often inadequate. The limitation of nerve regeneration is more
marked when the lesion creates loss of continuity in the nerve,

and the amount of regeneration is lower with increasing


interstump gap length in a given nerve either when left
unrepaired or after surgical repair (But et al., 1996; Krarup
et al., 2002).
In spite of the fact that peripheral axons can regenerate
through the injury site towards distal territories, reinnervation of
targets does not always lead to adequate recovery of motor and
sensory functions. The selectivity of axon-target reconnection
plays an important role in the impairment of function after nerve
injury and regeneration. Target organ specificity, or adequate
reinnervation of each type of end organ (muscle, sensory
receptor, etc.) by their original axons is far from perfect after
nerve transection even if refined repair is applied (Molander and
Aldskogius, 1992; Bodine-Fowler et al., 1997; Valero-Cabre
et al., 2004), although preferential motor reinnervation has been
observed (Brushart, 1993). Cell adhesion molecules differentially expressed by motor or sensory Schwann cells may play a
limited role for preferential guidance of regenerating axons in
adult animals (Martini et al., 1992; Eberhardt et al., 2006), but
later improvement in target specificity is the result of
progressive withdrawal or pruning of misdirected axons, which
suffer retrograde atrophy and degeneration when no appropriate
distal reconnection is established.
Factors contributing to poor long-term functional recovery
after peripheral nerve injuries include: (1) Damage to the
neuronal cell body due to axotomy and retrograde degeneration, excluding the possibility of regeneration. (2) Inability for
axonal growth due to the nerve lesion or to underlying diseases.
Laceration of the nerve with an associated tissue gap or distal
degeneration due to generalized neuropathy may both impede
regeneration. (3) Poor specificity of reinnervation by regenerating axons, when target organs become reinnervated by
nerve fibers with different function. Aberrant reinnervation is
pronounced during regeneration over long distances. Plasticity
of central connections may compensate functionally for this
lack of specificity; in man plasticity has, however, limited effect
on disturbed sensory localization or fine motor control after
injuries.
3. 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 neurons (Arvidsson et al., 1986; Ygge, 1989;
Vestergaard et al., 1997; Groves et al., 1999; Tandrup et al.,
2000). Regarding death of motoneurons, a non-significant loss
of 010% has been found after sciatic nerve injury (VandenNoven et al., 1993; Lowrie et al., 1994; Valero-Cabre et al.,
2001). In contrast, avulsion or transection of ventral roots in the
adult leads to retrograde cell death of 5080% of motoneurons
in a few weeks (Koliatsos et al., 1994; Martin et al., 1999;

X. Navarro et al. / Progress in Neurobiology 82 (2007) 163201

Natsume et al., 2002; Hoang et al., 2003). Sympathetic neurons


in the superior cervical ganglion undergo dramatic changes
after cutting the postganglionic nerves, with a neuronal loss of
about 50% in 3 days (Hou et al., 1998). A 4060% decrease in
the population of preganglionic sympathetic neurons in the
intermediolateral nucleus of spinal cord was found after
surgical transection of the cervical sympathetic trunk (Tang and
Brimijoin, 2002). Neuronal death postaxotomy depends on
several factors, mainly including age, severity of injury and
proximity of injury to the cell body. Neurons in the adult are
less susceptible to die than immature neurons (Snider et al.,
1992; Lowrie et al., 1994), whereas lesions near the cell bodies
cause a higher proportion of neuronal death than distal lesions
(Ygge, 1989). The process of neuronal death is prolonged and
more severe if axonal regeneration is prevented (Tornqvist and
Aldskogius, 1994). The loss of motoneurons reaches significant
levels, about 50%, in chronic human amputees (Kawamura and
Dyck, 1981). Neuronal vacuolation and apoptotic death
following nerve injury has a progressive increase during the
first month and then a gradual decline over a period of 6 months
in the rat (Groves et al., 1997, 1999).
In past years much attention focused on the role of
neurotrophic factors in the maintenance and survival of neurons
and in promoting axonal regeneration after nerve injury (for
reviews, see Persson and Ibanez, 1993; Terenghi, 1999; Markus
et al., 2002; Boyd and Gordon, 2003). After peripheral nerve
injury, the adult peripheral nervous system responds by
increasing the availability of neurotrophic factors, either by
autocrine or paracrine sources. Additional exogenous supply of
neurotrophic factors may enhance the regenerative response of
peripheral neurons. The spectrum of neurotrophic factors
reported to stimulate axonal regeneration includes nerve growth
factor (NGF), brain-derived neurotrophic factor (BDNF),
neurotrophin-3 (NT-3) and neurotrophin-4/5 (NT-4/5), insulin-like growth factors (IGF-I and IGF-II), ciliary neurotrophic
factor (CNTF), basic fibroblast growth factor (FGF-2) and glial
cell line-derived neurotrophic factor (GDNF). Thus, it may be
postulated that the potentiation of neuronal reaction and
regeneration can be better explained by a complex mixture of
different neurotrophic factors and neurotropic molecules rather
than an individual component, especially considering the
variable dependency of different neuronal populations on
neurotrophic factors.
3.1. Neuronal reaction and chromatolysis
If Wallerian degeneration serves to create a microenvironment distal to the injury that favors axonal regrowth of
surviving neurons, the neuronal retrograde reaction represents
the metabolic changes necessary for regeneration.
The most consistent morphological changes in the neuronal
body after axotomy are dissolution of the Nissl bodies
(chromatolysis), nuclear eccentricity, nuclear and nucleolar
enlargement, cell swelling, and retraction of dendrites (Lieberman, 1971; Kreutzberg, 1995). The disappearance of the
prominent basophilic-stained Nissl granules is particularly
evident. These granules are ribosome clusters and ordered

167

arrays of rough endoplasmic reticulum, which are no longer


observed after axotomy, when they become disorganized,
freeing polyribosomes and ribonucleotides into the cytoplasm.
The intensity and the time course of the neuronal response are
mainly influenced by severity of the injury, distance of lesion to
cell body, type of neuron, and age. Quantitative image analysis
revealed that chromatolysis started significantly as early as 8 h
following cranial nerves section and was not fully reversed by 3
months after axotomy. The reaction was more intense and
longer lasting following axotomy without reinnervation than
with reinnervation (Guntinas-Lichius et al., 1996). Marked
chromatolysis was found in motoneurons after nerve avulsion
and eventually some of them underwent apoptotic death,
suggesting that a neuronal response continuum may exist after
axotomy beginning as chromatolysis and evolving into either
survival and regeneration or apoptosis of neurons (Martin et al.,
1999). The transition between chromatolysis and apoptosis
coincided with accumulation of metabolically active mitochondria within the perikaryon and oxidative damage to nucleic
acids and proteins in axotomized neurons. On another hand,
when their axons are able to effectively regenerate and
reinnervate targets, neurons slowly return to a normal function
and morphology. Thus, spinal motoneurons that regenerated
their axons showed a normal distribution and morphological
properties at 5 months after sciatic nerve crush in the rat.
Nevertheless, by 1012 months these motoneurons exhibited
several morphological alterations, such as cell body enlargement, dendritic thickening and clustering in the ventral horn
compared with the contralateral side (Bowe et al., 1992). Those
alterations likely represent delayed and progressive changes in
the neurons that successfully reinnervated peripheral targets.
Disorganization of ribosome clusters is related to increased
protein synthesis, suggesting that chromatolysis represents the
morphological changes in the injured neuron soma associated
with an anabolic response (Lieberman, 1971; Fu and Gordon,
1997). This interpretation is supported by biochemical changes
in axotomized neurons, showing reduced DNA repression,
increased RNA synthesis with nuclear RNA transferred to the
cytoplasm, and increased cellular protein content (Watson,
1974). Biochemical changes develop within hours after axotomy,
coincident with the early chromatolytic morphological changes.
The concentration of enzymes of the oxidative pentose phosphate
shunt, required for RNA synthesis, is also raised (Harkonen and
Kauffman, 1974), whereas production of neurotransmitters and
cytoskeleton proteins is decreased (Frizell and Sjostrand, 1974;
Heiwell et al., 1979; Hoffman and Lasek, 1980). The axotomized
neurons shift from a transmitting state to a regenerative
state, underlied by prominent changes in gene expression, which
lead to a decrease in the synthesis of neurotransmission-related
products and an increased synthesis of growth-associated
proteins and structural components of the membrane.
4. 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

168

X. Navarro et al. / Progress in Neurobiology 82 (2007) 163201

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.
4.1. Axonal injury signaling
Signals responsible for the initiation and maintenance of
the regenerative neuronal response include a variety of
mechanisms acting at sequential time phases (Cragg, 1970;
Ambron and Walters, 1996; Perlson et al., 2004; Hanz and
Fainzilber, 2006). During seconds after a nerve lesion, the
axoplasm of lesioned axons is in continuity with the
extracellular medium before plasmatic membrane is sealed.
The rapid influx of calcium and sodium ions causes electrical
responses that propagate retrogradely. The first signal to reach
the neuronal body after axonal injury is thus a high frequency
burst of action potentials generated at the lesion site; this
discharge promotes an influx of calcium through voltagedependent ion channels, that can contribute to activate several
protein kinase pathways, including calcium/calmodulindependent kinase 2 (CMAK2), protein kinase (PK) A, PKC,
and mitogen-activated protein kinase (MAPK) (Ghosh and
Greenberg, 1995). In addition, the intense excitation causes
the release of transmitters, such as glutamate, neuropeptides
and BDNF at the spinal cord. These in turn may activate also
PKA, PKC and MAPK.
Later on, a second set of signals are conveyed by retrograde
axonal transport, these include the early deprivation of targetderived trophic factors (Raivich et al., 1991; Lee et al., 1998)
and the arrival of activating signals from the own injured axons
and from non-neuronal cells. Pioneering work on Aplysia
(reviewed in Ambron and Walters, 1996; Perlson et al., 2004)
and more recent findings in mammals (Hanz and Fainzilber,
2006) has led to renewed interest on activated proteins
emanating from the injury site during the second phase of
signaling. These activated proteins, termed positive injury
signals, are endogenous axoplasmic proteins that undergo
post-translational modifications at the lesion site upon
axotomy, and then incorporate to the retrograde transport
system for trafficking to the cell body. In addition, axonal
protein synthesis is needed for growth cone formation and
maintenance of the regrown axon (Willis and Twiss, 2005).
Several transcription factors have also been identified in
peripheral axons and may participate in positive retrograde
signaling (Lee et al., 2004; Lindwall and Kanje, 2005; Agthong
et al., 2006). Recent works suggest that this retrograde transport
requires the local synthesis of carrier proteins, including
importins and vimentin, that interact with the retrograde
transport motor dynein (Hanz et al., 2003). During the
following days infiltrating macrophages and reactive Schwann
cells in the degenerating nerve release cytokines and
neurotrophic factors that reach the injured neuronal body by
a general increase of retrograde transport (Curtis et al., 1993,
1994, 1998), and would contribute to sustain the regenerative
program of the neuron.

4.2. Activation of transcription factors and gene regulation


The axonal signals induced in response to nerve injury
activate several signaling pathways genes in neuronal cell
bodies that may lead to two opposing consequences: cell death
or regenerative response. Amongst these are some kinases such
as the MAPKs Erk1 and Erk2, c-jun N-terminal kinase (JNK)
and p38 kinase. Following axotomy, Erk activation has been
observed in transected sciatic nerve and DRG (Sheu et al.,
2000; Obata et al., 2004a). The increased activity of Erk is
influenced by endogenous neurotrophic factors such as NGF
and GDNF (Wiklund et al., 2002). JNK is rapidly activated after
nerve injury and persists elevated for weeks until either
neuronal death or axonal regeneration occurs (Kenney and
Kocsis, 1998; Herdegen and Waetzig, 2001). Inhibition of JNK
rescued in vitro motoneurons from death by withdrawal of
trophic factors (Maroney et al., 1998). Recently, an effective
cross-talk between the Erk1/2 and JNK pathways coordinated
by MEKK1 has been shown to participate in neurite regrowth in
PC12 cells (Waetzig and Herdegen, 2005). Similarly, p38 is
transiently activated in axotomized neurons (Murashov et al.,
2001) and in small-to-medium DRG neurons after chronic
constriction injury (Obata et al., 2004b). The expression of p38
may interfere with mitotic arrest but its role on neurite growth is
smaller (Herdegen and Waetzig, 2001). Moreover, inhibition of
p38 leads to enhanced axonal regeneration (Myers et al., 2003).
Downstream events influenced by axotomy-activated
kinases include up-regulation or activation of several transcription factors. Activated JNK induces up-regulation and
phosphorylation of the transcription factors c-Jun, JunD and
Fos into the nucleus, leading to formation of AP-1 complexes
that activate many downstream genes (Kenney and Kocsis,
1998; Raivich and Behrens, 2006). The expression of
immediate early genes (IEGs) after axotomy has been shown
to be induced according to the nerve and the type of injury
(Herdegen et al., 1992; Haas et al., 1993; Kajander et al., 1996;
Kenney and Kocsis, 1997). After sciatic nerve lesions in rats,
there is a substantial increase in c-jun protein in DRG cells at
early (3 h) (Kenney and Kocsis, 1997) and later (24 h) stages
(Jenkins and Hunt, 1991), compatible with biphasic activation
by axonal signals and by loss of target tissue-derived NGF.
Neuronal deletion of c-jun hinders the expression of regeneration-associated genes, reduces the speed of target reinnervation
and also completely blocks central axonal sprouting (Raivich
et al., 2004). The activation of transcription factor cAMP
responsive element binding protein (CREB) in the early stages
after injury is mediated by multiple protein kinase pathways
and some of them (PKA, PKC and CMAK2) regulate CREB
phosphorylation partially through the Erk pathway. Phosphorylation of CREB in the rat spinal dorsal horn is induced by
neurotrophins, such as BDNF, and reduced by blocking tyrosine
kinase receptors (trk) (Miletic et al., 2004; Miyabe and Miletic,
2005). Another transcription factor affected by nerve injury is
activating transcription factor (ATF)-3. ATF-3 is induced in all
DRG neurons after peripheral, but not central axotomy, what
makes it a reliable nerve injury marker (Tsujino et al., 2000),
and its pattern of induction correlates with the increased

X. Navarro et al. / Progress in Neurobiology 82 (2007) 163201

sensory axon regeneration promoted by a conditioning lesion


(Seijffers et al., 2006). ATF-3 expression in subpopulations of
DRG cells can be modulated by exogenous trophic factors,
suggesting that its expression is induced by the loss of targetderived NGF and GDNF (Averill et al., 2004). The members of
the signal transducer and activator of transcription (STAT) gene
family are the main mediators in the signal transduction
pathway of cytokines. After phosphorylation, STAT proteins
are transported into the nucleus and produce transcriptional
activity. STAT3 probably acts as a retrograde signaling
transcription factor promoting the survival and regeneration
of both sensory and motor neurons after nerve injury (Lee et al.,
2004). Following axotomy in rat facial and hypoglossal nerves,
a significant increase of STAT3 protein was found. In addition,
activation of STAT3 by phosphorylation was observed within
3 h in neurons and persisted for more than 3 months (Schwaiger
et al., 2000). The increased axonal regeneration rate of DRG
neurons and the improved axonal growth in the spinal cord after
a conditioning injury requires also the activation of STAT3 (Qiu
et al., 2005). The PI3K-Akt pathway, which is a growth factor
receptor signaling pathway, is probably vital for neuronal
survival after injury. Akt activation was enhanced in response to
hypoglossal nerve injury in the adult (surviving neurons),
whereas its activity was down-regulated in injured neonate
motoneurons (dying neurons). In addition, it enhanced axonal
regeneration in vivo (Namikawa et al., 2000). The transcription
factor nuclear factor kappa B (NFkB) has been defined as a
neuronal survival signal due to its up-regulation in mouse
dorsal horn neurons in response to peripheral nerve transection
(Pollock et al., 2005). NFkB has been suggested to be a
mediator in the regulation of the glutamate transporter EAAC1
expression by glucocorticoid receptors (Wang et al., 2006). In
contrast, NFkB expression was decreased after nerve crush in
Aplysia (Povelones et al., 1997).
The modifications in the activity of transcription factors
result in characteristic changes of gene expression in the injured
and regenerating neurons. The introduction of gene chip array
technologies has led to a dramatic increase in the identified
number of regulated genes in neurons and in associated glial
cells following several types of peripheral nerve injuries
(Costigan et al., 2002; Hu et al., 2002; Kubo et al., 2002; Xiao
et al., 2002; Cameron et al., 2003; Schmitt et al., 2003;
Boeshore et al., 2004; Vogelaar et al., 2004; Bosse et al., 2006;
Del Signore et al., 2006; Yang et al., 2006). Hundreds of genes
have been found either up- or down-regulated by axotomy, but
the function of the majority of them remains unknown. Gene
expression changes affect the encoding of transcription factors,
cytoskeletal proteins, cell adhesion and guidance molecules,
trophic factors and receptors, cytokines, neuropeptides and
neurotransmitter synthesizing enzymes, ion channels, and
membrane transporters. Table 1 summarizes relevant modifications in gene and protein expressions at the neuronal level
described following sciatic nerve lesion in adult murine models.
More detailed analysis of this issue is out of the scope of this
review.
One of the prominent changes after peripheral axotomy
consists in the increase of regenerative-associated proteins,

169

amongst them, the most characterized is growth-associated


protein (GAP)-43 (Skene, 1989) that is up-regulated from the
first day after axonal lesion, and is usually labeled to identify
growing axonal profiles. GAP-43 is rapidly transported along
the axon to the growth cones, where the protein accumulates.
Axonal regeneration is characterized by a distinct regulation of
cytoskeletal proteins. Tubulins are significantly increased in
axotomized motor and sensory neurons whereas neurofilament
proteins NF-L, NF-M and NF-H are decreased, probably
reflecting an increase in axoplasm fluidity in order to facilitate
axonal transport (Hoffman et al., 1987; Wong and Oblinger,
1990; Tetzlaff et al., 1996). The reduced axonal caliber and
impulse conduction velocity have been correlated with the
transport of neurofilaments in the regenerated nerve fibers.
Molecules associated with both anterograde and retrograde
axonal transport, such as kinesin light chains and dynein, are
up-regulated in their expression during nerve regeneration (Su
et al., 1997).
The main studies on neuronal injury and regeneration
programs have followed analyses of proteins associated with
axonal growth and cytoskeleton components, growth factors,
the expression of specific regulated proteins such as
neuropeptides and neurotransmitter systems, or the changes
in expression of ion channels and receptors potentially involved
also in the development of neuropathic pain (see reviews by
Bosse et al., 2001; Goldberg, 2003; Makwana and Raivich,
2005; Hokfelt et al., 2006; Zhou and Snider, 2006).
4.3. Changes in neuropeptide expression
One of the most relevant changes in the neuronal phenotype
after axotomy is the down-regulation of neurotransmitters and
genes encoding transmitter-related proteins. However, there are
also marked changes in the expression of neuropeptides in the
axotomized neurons and in their axonal projections, as well as
in the spinal cord (Table 2). This is in agreement with the
general view of the reaction of neurons in response to axotomy,
when the synthetic machinery of the neuron is reprogrammed
from transmitter synthesis to production of molecules of
importance for survival and regeneration. A characteristic of In CRPS
the NS
neuropeptides is the plasticity in their expression, reflecting the must
be
fact that release has to be compensated by de novo synthesis at stressed
(or
the neuronal body. Neuropeptides may exert different actions injured)
and contribute to neural signaling when the nervous system is that
could
stressed or injured (Palkovits, 1995; Hokfelt et al., 2000).
also lead
In axotomized motoneurons, the most characteristic changes to
involve the opposite changes in choline acetyltransferase increase
in Sx I
(ChAT) and calcitonin gene-related peptide (CGRP) immunor- suppose
eactivity (Caldero et al., 1992; Borke et al., 1993; Piehl et al., ?
1993). Maximal reduction in ChAT immunostaining occurred
at 7 days after nerve damage and the amount of the decrease
was related to the severity of the injury. The recovery of ChAT
to normal levels was related to the timing of reinnervation after
nerve crush, but not after transection or resection injuries. In
contrast, a rapid increase in CGRP immunoreactivity, maximal
at 310 days after lesion, preceded the decrease in ChAT levels.
Later changes were dependent on the type of injury. Increased

170

X. Navarro et al. / Progress in Neurobiology 82 (2007) 163201

Table 1
Summary of the changes in the molecular expression in axotomized neurons after peripheral nerve injury
Lesion

Location

References

"
"
"
"
"
"
"

Transection
CCI
Crush
Ligation
Transection
Crush
Spinal ligation

DRG
DRG
DRG
DRG
MN
DRG
DRG

Kashiba and Senba (1999)


Obata et al. (2003)
Ernfors et al. (1993)
Fukuoka et al. (2001)
Gu et al. (1997)
Tonra et al. (1998)
Shen et al. (1999)

Trk

Crush

DRG

Ernfors et al. (1993)

Ret (GDNF receptor)

"
=

Transection
Transection

MN
DRG

Hammarberg et al. (2000)


Bennett et al. (2000)

GFRalpha2
GFRalpha1, GFRalpha3
Ret and GDNFalpha1

#
"
"

Transection
Transection
Crush

DRG
DRG
DRG/MN

Bennett et al. (2000), Hoke et al. (2000)


Bennett et al. (2000)
Naveilhan et al. (1997)

NT-3

=
=

Spinal ligation
Transection

DRG
SC

Shen et al. (1999)


Funakoshi et al. (1993)

trkB

"
"

Transection
Crush

MN
SC/DRG

Hammarberg et al. (2000)


Ernfors et al. (1993)

NGF

=
"

Transection
Spinal ligation

MN
DRG

Gu et al. (1997)
Shen et al. (1999)

NGF-R
16 kDa pancreatitis-associated protein (Reg-2)

"
"

Crush
Transection

MN
DRG

Ernfors et al. (1989)


Averill et al. (2002)

"
"
"

Transection
Transection
CCI

MN
DH
DH

Gu et al. (1997)
Kajander et al. (1996)
Kajander et al. (1996) and Ro et al. (2004)

"

Transection

DRG

"

Crush

MN

Jenkins and Hunt (1991), Broude et al. (1997)


and Kenney and Kocsis (1997)
Jenkins and Hunt (1991)

Signal transd. and activ. of transc. 3 (STAT3)


Activating transcription factor 3 (ATF-3)
NFkB

"(A)
"
"
"(A)

Transection
Transection
Transection
PNSL/CCI

DRG
MN/DRG/DH
DH
DRG

Qiu et al. (2005)


Tsujino et al. (2000)
Pollock et al. (2005)
Ma and Bisby (1998)

Isl 1
DRG11, LmX1b, Pax3

"
=

Crush
Crush

DRG
DRG

Vogelaar et al. (2004)


Vogelaar et al. (2004)

"
"
"(A)
"
"
#
"(P)

Crush
Transection
CCI
CCI
Ligation
CCI
CCI

DRG
MN
DRG
DRG/MN/DH
DRG
DH
DH

Ohtori et al. (2004)


Zelano et al. (2006)
Obata et al. (2004a)
Zhang and De Koninck (2006)
Madiai et al. (2003)
Wang et al. (2006)
Miletic et al. (2004)

Neurotrophic factors/receptors
BDNF

Transcriptional factors
c-fos

c-jun

Others
TNF-alpha receptor 1 (p55)
Nectin-3
P38 mitogen-activated protein kinase (MAPK)
Monocyte chemoattractant protein-1 (MCP-1)
Fibroblast growth factor 2 (FGF-2)
Glutamate transporter EAAC1
cAMP response element binding protein (CREB)

All the injuries were performed on the sciatic nerve in murine adult animals. The changes indicated are mainly based on studies on mRNA expression or
immunoreactiviy; some are based on phosphorylation (P) or activity (A). Measurements were performed in sensory neurons of dorsal root ganglia (DRG) or
motoneurones (MN) of the ventral horn; in some cases, determinations were described as expression in dorsal horn (DH) or spinal cord (SC). Note that for each
molecule, references are grouped according to type of injury, as in some cases the expression varies depending on the injury model or the cell type. The arrows (":
increase; #: decrease) represent up- or down-regulation.

CGRP staining persisted longer after nerve transection than


after crush and was still evident when nearly complete
reinnervation was achieved. These observations suggest that
different mechanisms regulate ChAT and CGRP in response to
nerve injury. Transient up-regulation of galanin, vasoactive
intestinal polypeptide (VIP) and substance P mRNAs has been

observed within subpopulations of motoneurons ipsilateral to


nerve lesion for periods lasting 23 weeks after injury (Zhang
et al., 1993a).
Sympathetic neurons also exhibit a notable plasticity in their
neuropeptide phenotype after injuries in adult animals
(Zigmond, 1997). Sympathetic neurons that normally express

X. Navarro et al. / Progress in Neurobiology 82 (2007) 163201


Table 2
Characteristic changes in the expression of neuropeptides in neurons after
axotomy
Neuropeptide

Motoneurons

Sympathetic
neurons

Sensory
neurons

ChAT
CGRP
CCK
Galanin
NPY
Somatostatin
Substance P
VIP

#
"
"/#
"
"
"
"
"

"
"
#
#
#
"a

#
"/#
"
"
"
"
"

a
Decrease of ChAT and VIP in the subpopulation of sudomotor sympathetic
neurons.

neuropeptide Y (NPY) show a reduced expression of NPY and


tyrosine hydroxylase after axotomy, while they overexpress
VIP, galanin and substance P. The NPY, VIP and galanin
expressions are regulated by both the removal of target-derived
NGF and the exposure to LIF, whereas the expression of
substance P after axotomy occurs primarily because of the
effects of LIF (Zigmond and Sun, 1997; Shadiack et al., 2001).
Primary sensory neurons change their phenotype both with
regard to messengers, receptors and function after peripheral
nerve injury, so that DRG neurons adapt to the new situation by
suppressing excitatory transmitters, enhancing inhibition and
promoting survival and regenerative mechanisms. Particularly,
substance P and CGRP are present in many small DRG neurons
under normal circumstances. They contribute to synaptic
transmission in the dorsal horn, in addition to efferent effects in
the periphery (vasodilation, permeability). Substance P and
CGRP are markedly down-regulated after axotomy (McGregor
et al., 1984; Nielsch et al., 1987; Noguchi et al., 1990; Villar
et al., 1991), a phenomenon that is dependent upon interruption
of target-derived NGF to the neuronal body (Eriksson et al.,
1997). However, substance P expression increases in A large
neurons (Noguchi et al., 1995) and there are controversial
results regarding the total content and redistribution of
substance P in DRG and dorsal horn after partial injuries
(Cameron et al., 1997; Ma and Bisby, 1998; Swamydas et al.,
2004).
Other peptides such as VIP, peptide histidine-isoleucine,
galanin and NPY are normally expressed at low levels in
sensory neurons, but are dramatically increased after axotomy
(McGregor et al., 1984; Shehab and Atkinson, 1986; Villar
et al., 1989, 1991; Wakisaka et al., 1991). These changes seem
to be involved in dorsal horn regenerative and/or compensatory
processes following peripheral nerve damage. Under normal
conditions, galanin occurs in a small population of small size
sensory neurons in the DRG as well as in spinal dorsal horn
interneurons. However, following peripheral nerve injury,
expression of galanin in primary afferents and terminals in the
superficial dorsal horn has been found to be up-regulated
(Wiesenfeld-Hallin and Xu, 1998). Galanin synthesis is
promoted by increased production of LIF after injury, an
effect that may be mediated by interleukin-6 (Murphy et al.,
1999). In parallel, galanin-R1 receptor mRNA was down-

171

regulated in DRG neurons after axotomy, and a small decrease


in galanin-R2 receptor mRNA levels was also seen (Zhang
et al., 1998). It has been suggested that under normal conditions
galanin exerts tonic inhibition of nociceptive input to the central
nervous system. After peripheral nerve injury the inhibitory
control exerted by galanin, released from DRG neurons, is
increased, acting on galanin-R1 receptors at the dorsal horn
interneurons (Hokfelt et al., 2006). In normal DRG neurons
NPY is only barely detected, whereas NPY Y1-receptor is
strongly expressed at the cell soma membrane and Y2-receptor
mRNA levels are low. After axotomy there is a marked increase
of NPY in large and medium DRG neurons, in their central
projections to dorsal column nuclei, as well as in some dorsal
horn neurons (Wakisaka et al., 1991; Ohara et al., 1994). NPY
receptors show a complex regulation; there is a decrease in Y1receptor and an increase in Y2-receptors that are transported
centrifugally. Interestingly, after sciatic nerve axotomy, the
deletion of Y1-receptor protected knockout mice from the
axotomy-induced loss of DRG neurons and increased their
release and synthesis of CGRP and substance P (Shi et al.,
2006). Immunoreactivity to NPY is also present in the
terminations of Ab afferent fibers in the nuclei gracile and
cuneate, where it may mediate changes in mechanosensory
second-order neurons (Ossipov et al., 2002). These findings
suggest that NPYergic mechanisms participate in the adaptive
changes of sensory neurons in response to injury (Hokfelt et al.,
1998). Cholecystokinin (CCK) reduces the antinociceptive
effect of opioids. The levels of CCK and CCK receptors, as well
as CKK release, exhibit considerable plasticity early after nerve
lesion and inflammation (Zhang et al., 1993b; Afrah et al.,
2001; Wiesenfeld-Hallin et al., 2002). In particular, neuropathic
pain after injury to the peripheral and central nervous system
does not respond well to opioids, which has been attributed to
increased activity in the endogenous CCK system.
4.4. Changes in ion channels in injured neurons
Axotomy leads to the focal accumulation of anterogradely
transported vesicles containing proteins, including ion channels. Some of these may insert in the membrane of the injured
axons, increasing the density of channels and altering the local
excitability properties. Voltage sensitive channels, particularly
for sodium and potassium, have been shown to accumulate in
neuroma formed after nerve ligation in animal models and in
humans (Devor et al., 1993; England et al., 1994, 1998;
Kretschmer et al., 2002). Axotomy also triggers plastic changes
in the expression of several ion channels, transducers and
receptors in the injured neurons. The altered gene expression is
related with the modifications of neuronal phenotype, including
electrical hyperexcitability. Neurotrophic signaling and
impulse traffic appear to be key factors in ion channel
regulation. In fact, delivery of exogenous neurotrophins is able
to prevent or modify the lesion-induced neuronal phenotypic
changes.
Following injury to their axons within peripheral nerve,
DRG neurons down-regulate some sodium channel genes and
up-regulate others. As a result, a different repertoire of sodium

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channels is inserted into the neuron membrane following injury,


a molecular change that contributes to hyperexcitability in
these cells. Following nerve injury, it has been found that the
expression of tetrodotoxin (TTX) sensitive sodium channels
Nav1.3, normally expressed only during development, is upregulated in primary sensory neurons, whereas channels
Nav1.1, Nav1.2, Nav1.6, Nav1.7, Nav1.8 and Nav1.9 are
down-regulated (Waxman et al., 1994; Dib-Hajj et al., 1996;
Sleeper et al., 2000; Xiao et al., 2002; Lai et al., 2003). These
findings have deserved considerable interest as potential
contributors to the genesis and maintenance of neuropathic
pain post-injury (for reviews, see Waxman et al., 2000; Wood
et al., 2004). Similar, but less extensive changes in sodium
channels have been observed after partial injury models of
neuropathic pain (Dib-Hajj et al., 1999). Interestingly, those
changes in ion channels expression do not occur after
transection of the central axon of sensory neurons. Sodium
currents in injured neurons are concomitant with changes in
gene expression after axonal transection. The slowly inactivating and the persistent TTX-resistant sodium currents produced
by the Nav1.8 and Nav1.9 channels are attenuated, whereas a
rapidly repriming sodium current produced by the newly
synthesized Nav1.3 channels, which recovers rapidly from
inactivation, emerges within axotomized small DRG neurons
(Cummins and Waxman, 1997; Sleeper et al., 2000). The
changes in large sensory neurons with Ab fibers are slightly
different; they express tetrodotoxin-sensitive sodium currents,
but with a faster repriming kinetics than in small neurons both
before and after axotomy, and also down-regulate the
tetrodotoxin-resistant current following nerve section (Everill
et al., 2001). The accelerated recovery from inactivation of the
inappropriately expressed Nav1.3 channels produces a decrease
in refractory period that contributes to hyperexcitability of
DRG cells following axonal transection. These changes in
sodium currents persist for at least 60 days after axotomy,
consistent with the long-lasting changes in sodium channel
gene expression (Dib-Hajj et al., 1996). However, the abnormal
expression of sodium channels and their corresponding currents
can be reversed by the intrathecal administration of NGF and
GDNF (Leffler et al., 2002), and by neuronal activity promoted
by electrical stimulation via a mechanism independent of
trophic factors (Klein et al., 2003).
Nevertheless, it has been also determined that axotomyinduced changes in sodium currents were not correlated with an
axotomy-induced change of excitability in small DRG neurons
(Flake et al., 2004), suggesting that concomitant changes in
other ionic channels occurred and it is the sum of changes in
ionic currents what determines neuronal excitability following
axotomy.
Immunocytochemical investigation on the expression of
potassium channels in DRG cells cultured from control and
axotomized adult rats showed that voltage-gated potassium
channels Kv1.2 and 2.1 largely decreased following axotomy,
whereas Kv1.1 and 1.3 had smaller decreases, and Kv1.4 and 1.6
were not altered by axotomy (Ishikawa et al., 1999). Large
afferent neurons show also a reduction in overall potassium
currents after nerve ligation (Everill and Kocsis, 1999), and all

types of sensory neurons show a reduction in delayed rectifier


potassium current and Ca2+-sensitive potassium conductance
(Abdulla and Smith, 2001a). These results indicate that, in
relation to changes in sodium channel expression, there are
decreases in specific potassium channels following axotomy
that may lead to changes in electrical excitability of the DRG
neurons. At the peripheral neuroma level, Kv1.1 channels
accumulated in an abnormal distribution, with patches along
the internodal segments of myelinated axons (England et al.,
1998). It has been hypothesized that such up-regulation of
Kv1.1 is an adaptive mechanism to stabilize the injured axon
membrane, which has been made hyperexcitable by the
changes in sodium channels.
Voltage-gated calcium channels modulate nociceptive
transmission at the level of the neuronal synapse in the central
nervous system. The role of the L, N, and P/Q types of calcium
channels varies with the nature of neural injury (Vanegas and
Schaible, 2000). One indication of the important role played by
these channels is the dense expression of the N-type channels in
the superficial laminae I and II of the dorsal horn, the site of
synapse for nociceptive primary afferent neurons. With
depolarization, there is an influx of Ca2+ ions into neurons
and release of neurotransmitters such as GABA, glutamate and
norepinephrine. Nerve injury leads to a reorganization of the
high-voltage activated calcium current properties in a subset of
cutaneous afferent neurons, which show faster inactivation
kinetics than control neurons (Baccei and Kocsis, 2000).
Studies on peripheral nerve injury models pointed to a distinct
pattern of Ca2+ channel subunit expression, with up-regulation
of the a2d subunit that is correlated with allodynic pain
behavior (Newton et al., 2001).
Although less investigated, ion channel expression is also
modified in motoneurons after axonal lesion. In the axotomized
facial motoneurons Nav1.1 mRNA decreased whereas Nav1.3
mRNA reappeared (Iwahashi et al., 1994; Patko et al., 2003).
Furthermore, Ca2+-sensitive potassium channel subunits,
small-conductance SK1 and SK3 mRNAs were more abundant
in the axotomized facial nuclei motoneurons than in controls.
These alterations can partly explain the increase in excitability
observed in the axotomized motoneurons following facial nerve
lesion.
4.5. Changes in neuronal excitability
Passive membrane properties, in particular neuronal input
resistance, remain relatively stable in the majority of neurons
after axotomy. The major exceptions are vertebrate motoneurons. Several reports have demonstrated that axotomized
motoneurons exhibit changes in membrane electrical properties, consisting of increased input resistance and time constant,
decreased rheobase and axonal conduction velocity, and
variable changes in afterhyperpolarization duration that shortens in S motoneurons but is prolonged in F motoneurons (Kuno
et al., 1974; Foehring et al., 1986; Pinter and Vanden Noven,
1989; Titmus and Faber, 1990). These changes are consistent
with dedifferentiation of motoneuronal properties following
axotomy. In experiments where muscle reinnervation was not

X. Navarro et al. / Progress in Neurobiology 82 (2007) 163201

allowed, these changes were maintained chronically (Pinter and


Vanden Noven, 1989), whereas following reinnervation normal
electrical properties were recovered (Foehring et al., 1986),
suggesting that functional contact with muscle is required for
the full expression of the normal range of neuron electrical
properties. Changes in input resistance appear to be correlated
with structural simplification of dendritic trees, changes in
specific membrane resistance and with reduction in cell body
size (Titmus and Faber, 1990). In addition, the firing properties
are also modified in axotomized motoneurons, which show a
steeper frequencyintensity curve and a low threshold for the
generation of spikes in the soma-dendritic membrane (Takata
et al., 1980).
Increases in excitability in all types of DRG sensory neurons
within weeks of axotomy have been found, although
electrophysiological changes appear to vary among types of
neurons and with the type of injury. In large and medium Acells axotomy induced by sciatic nerve section or spinal nerve
ligation causes a reduction of excitation threshold, an increase
in duration and in rise time of the action potential, but no
significant changes in conduction velocity and adaptation
properties. On the other hand, in small C-cells axotomy reduced
action potential threshold but did not significantly change
resting membrane potential, action potential duration, or
maximal depolarization rate (Gurtu and Smith, 1988; Koerber
et al., 1995; Zhang et al., 1997; Kim et al., 1998; Abdulla and
Smith, 2001b; Abdulla et al., 2003; Ma et al., 2003). In
addition, nerve injury led to a significant reduction of the
rheobase, an index of neuronal excitability, in all types of cells.
It has been suggested that axotomy would increase the
excitability of DRG neurons not by altering input resistance or
threshold potential, but by increasing apparent input resistance
near the resting membrane potential in A-cells and by
decreasing the resting membrane potential in C-cells (Kim
et al., 1998). The incidence of spontaneous activity, recorded
extracellularly from dorsal root fibers, was significantly higher
after nerve lesions than in sham animals, and occurred in all
types of DRG neurons (Zhang et al., 1997; Kim et al., 1998;
Abdulla and Smith, 2001b; Ma et al., 2003). There is some
controversy on whether the nerve injury-induced electrical
instability is restricted to axotomized neurons (Sapunar et al.,
2005) or extends also to adjacent intact neurons that may
contribute to hyperalgesia (Ma et al., 2003). The electrophysiological changes promoted by axotomy were more intense
in animals that exhibited signs of neuropathic pain, and
interestingly the onset of autotomy coincided with alterations in
the excitability of large, putative non-nociceptive neurons
(Abdulla and Smith, 2001b; Ma et al., 2003). Nevertheless,
changes in the electrical properties of cell bodies alone may not
entirely explain the increased spontaneous activity and the
signs of neuropathic pain after injuries to sensory nerves.
Axotomy produces significant changes in several measurable electrophysiological parameters in sympathetic ganglion
cells, although mature neurons are able to maintain relatively
normal electrical activity despite injury. Thus, resting
membrane potential or input resistance remained unchanged
after axotomy. Under activation, action potential duration and

173

amplitude were significantly increased, whereas duration and


amplitude of the afterhyperpolarization that followed the action
potential showed considerable reduction in axotomized
neurons, with a maximal change by 14 days after injury
(Gordon et al., 1987; Kelly et al., 1988). The reduction in
afterhyperpolarization rapidly recovered in regenerating
neurons, but, in contrast, changes in its amplitude appeared
to be independent of the occurrence of axonal regeneration.
5. 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 motoneurons were shown to decrease by a third at
13 months after axotomy. This reduction in dendritic size is
due to a loss of preterminal and terminal dendritic segments.
Following reinnervation of the target muscle, the axotomized
motoneurons did not recover their original number of dendritic
branches, but the dendritic membrane area and volume was
normalized due to an increase in dendritic diameters and an
increased number of dendrites per neuron (Brannstrom et al.,
1992a,b; Borke et al., 1995). Nevertheless, other studies based
on reconstruction of the entire dendritic trees of neck
motoneurons have reported an expansion of the dendritic tree
following axotomy (Rose and Odlozinski, 1998). The distal
dendritic arborizations of these motoneurons exhibited axonlike characteristics, supporting the claim that axotomy leads to
a remodeling of the neuronal polarity (Rose et al., 2001). A key
factor in the production of such dendraxons appears to be the
proximity of the axotomy to the neuronal soma (Linda et al.,
1992; Rose and Odlozinski, 1998). These processes might be
generated as replacement for the injured axon, but have also the
potential to make inappropriate connections within the central
nervous system that would be detrimental for functional
recovery.
Qualitative and quantitative cytological evidences show a
reduction in number and area of coverage of synaptic terminals
on chromatolyzed motoneurons from a few days after axotomy.
The degree of synaptic detachment on motor neurons is
influenced by the severity of nerve injury (Svensson et al.,
1991). The reduction in number and percentage of boutons on
the surface membrane is due to detachment of synapses, which
involves disappearance of both pre- and postsynaptic membrane thickenings and widening of the synaptic cleft (Sumner
and Sunderland, 1973; Chen, 1978). Recent results suggest that
during synaptic remodeling after nerve injury, nitric oxide (NO)
acts as a signal for synaptic detachment and inhibits synapse
formation (Sunico et al., 2005). The separation of synaptic
terminals from the neuron membrane is associated with the
presence of reactive astrocytes and microglia. Most areas of

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surface membrane bared of synaptic contact are occupied by


astrocytic processes. Loss and recovery of presynaptic boutons
occur in parallel with changes in astroglial ensheathment of the
motoneurons, that appears to be influenced by functional
changes in the lesioned neurons (Chen, 1978; Aldskogius and
Svensson, 1993; Aldskogius et al., 1999; Lan et al., 2003).
Microglial cells, although extending to neuronal surface
membrane, cover only a small portion of it. Most microglia
are seen located at some distance from surface membrane and
are frequently separated by sheets of astrocytic processes,
although they may play a role in the activation of astrocytes and
in elimination of dead neurons (Aldskogius et al., 1999). If
regeneration is allowed, synaptic restoration takes place in
parallel to peripheral target reinnervation. By contrast, after
permanent axotomy synaptic frequency and cover remain
reduced to 3050% of control values during months (Purves,
1975; Johnson et al., 1998). The amount of synaptic loss and
recovery is variable and affects various types of synapses to
different degrees (Purves, 1975; Chen, 1978; Brannstrom and
Kellerth, 1999; Lan et al., 2003). For example, after
motoneuron axotomy, excitatory S type boutons are eliminated
to a larger degree than inhibitory F type terminals (Borke et al.,
1995; Linda et al., 2000). The preferential elimination of
glutamatergic terminals onto lesioned motoneurons may reflect
an active reorganization of the synaptic input to diminish the
excitotoxic influence on these neurons. The expression of the
major histocompatibility class I complex in lesioned neurons
and astroglia has been reported to play a role in the regulation of
synaptic elimination, mainly influencing the elimination of
inhibitory terminals (Zanon and Oliveira, 2006).
5.1. Functional changes in central synapses
The synapse made between Ia muscle spindle afferents and
alpha motoneurons (Ia-MN synapse) in the spinal cord has been
by far the most widely studied model of central synapse in
physiological and pathological conditions. After nerve lesions
and regeneration three distinct phases in the Ia-MN synaptic
function have been described: an early increase in the
postsynaptic responses, followed by a longer lasting decline
and a phase of recovery when the nerve is allowed to
reinnervate target muscles. The excitatory postsynaptic
potentials (EPSPs) induced in motoneurons by stimulation of
Ia afferents are significantly enlarged already during the first
day following peripheral nerve section in adult animals
(Mendell, 1984; Miyata and Yasuda, 1988; Manabe et al.,
1989; Seburn and Cope, 1998). This early increase in synaptic
transmission strength, which lasts for about 3 days, is
attributable to lack of activation of the synapse that results
when Ia afferents are transected, to reduced activity of
homonymous motoneurons, and likely due to an increase in
the probability of transmitter release. Section of the afferent
fibers is necessary for the increase in synaptic transmission
strength, but concomitant section of the motor fibers amplifies
the effect (Cope et al., 2001).
The second phase of progressive decline in the EPSP
amplitude at the Ia-MN synapse develops by 1 week after

axotomy, which is time related with stripping of spinal cord


synapses (Horch and Lisney, 1981; Mendell, 1984). The
posttetanic potentiation of EPSPs is decreased after axotomy, a
regressive change that has been related to a change in synaptic
release properties more than to changes in the electrical
properties of motoneurons (Gustafsson et al., 1986). However,
the EPSPs are restored to normal size when the nerve is allowed
to reinnervate the muscle, even if a long delay precludes
adequate recovery of muscle activity, sensory activity or
motoneuron properties (Goldring et al., 1980; Mendell et al.,
1995). The degree to which central synaptic efficacy declines
and recovers following section and regeneration of a peripheral
nerve depends partly upon the type of motoneurons; those
supplying slow muscles show faster and better recovery than
fast ones. Partial recovery of synaptic strength has also been
observed when the cut Ia afferents are forced to reinnervate
skin (Mendell et al., 1995), and with treatment of the muscle
nerves with exogenous supply of neurotrophins (Munson et al.,
1997; Mendell et al., 1999). The higher amplitude of evoked
EPSPs is due to a higher probability of transmitter release
(Hellgren and Kellert, 1989; Seburn and Cope, 1998), although
hyperexcitability of sensory and motor neurons (Eccles et al.,
1958) may also play a role. Neuronal deprivation or exposition
to neurotrophic factors, such as BDNF, NT-3, NT-4/5 and
GDNF, might be the signals for regenerating neurons to modify
their phenotype, thus enhancing or depressing synaptic
contacts (McAllister et al., 1999; Mendell and Munson,
1999). Neurotrophins induce changes in the expression of Na+
and K+ channels (McAllister et al., 1999) and glutamate
receptors (Chew and Gallo, 1999). Induced changes in the
subunit configuration of NMDA and non-NMDA receptors in
spinal motoneurons after injury may account for changes in the
Ia-MN transmission (Popratiloff et al., 1996; Alvarez et al.,
2000).
A similar process has been described for sympathetic
neurons of the superior cervical ganglion (Purves, 1975;
Sanchez-Vives and Gallego, 1993). Within 72 h of axon
interruption, the amplitude of EPSPs recorded in principal
neurons in response to preganglionic stimulation declined,
being maximally reduced by 7 days following axotomy. Little
or no difference was found in the electrical properties of
axotomized neurons in comparison with normal neurons.
Recovery in EPSPs occurred to normal amplitude if functional
peripheral connections were re-established. On the contrary, if
axons were prevented from regenerating to their target organ,
neurons did not generally recover normal synaptic function, and
most affected cells died within a month.
6. 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-Cabre and
Navarro, 2001, 2002b).

X. Navarro et al. / Progress in Neurobiology 82 (2007) 163201

Regarding motor spinal reflex restitution after nerve injury,


Scott (1985) and Scott and Panesar (1995) showed complete
recovery of the stretch reflex at 4 months after sciatic nerve
crush in cats and similar to normal function of reinnervated
muscle spindles. In contrast, a permanent absence of stretch
reflex responses was found even 3 years after tibial nerve
section in cats, which was attributed either to stripping of
central synapses or to poor muscle spindle reinnervation (Cope
and Clarck, 1993; Cope et al., 1994; Abelew et al., 2000). In
fact, the density of reinnervating profiles is decreased and the
distribution is altered with respect to control spindles after
nerve lesions (Verdu and Navarro, 1997), probably underlying
deficits in stimulus transduction.
To avoid the confounding effect of receptor dysfunction,
electrical stimulation of either regenerated nerves or ipsilateral
or contralateral intact nerves has been used in the assessment of
spinal motor reflexes. After nerve or ventral root section,
stimulation of Ia afferent fibers revealed a progressive decline
in the monosynaptic response of axotomized motoneurons
(recorded from the ventral roots) and increase in the central
delay time during the first 2 weeks, whereas longer latency
polysynaptic responses were increased. Monosynaptic
responses reappeared by about 5 weeks post-lesion and tended
to increase in amplitude thereafter (Downman et al., 1953).
Synaptic transmission is depressed following interruption of
either limb of the segmental reflex arch. The reduction in EPSP
amplitude is reversed following reinnervation of the peripheral
tissue by the lesioned fibers, whether or not the regenerating
fiber finds the correct muscle (Mendell and Munson, 1999).
Recovery of the H wave reflex (recorded from target
muscles), the electrical counterpart of the monosynaptic stretch
reflex, by stimulation of afferent fibers proximal to the injury
indicates that the spinal reflex circuits are functional as soon as
the muscle is reinnervated. The H reflex is highly facilitated at
early stages of reinnervation, resulting in a three- to fourfold
increase of the H/M amplitude ratio (Fig. 2), thus indicating a
relative increase of the Ia-motoneuron synaptic response to
electrical stimulation of intact afferents. Advancing muscle
reinnervation reverted this facilitatory effect, and as the M wave
amplitude increased with time the H/M ratio declined to near
normal. However, levels of the H/M ratio at 3 months postlesion remained significantly higher than in control animals,
particularly in experimental situations with a low degree of
muscle reinnervation, such as following nerve resection and
autograft or tube repair (Valero-Cabre and Navarro, 2001,
2002a). When muscle reinnervation was hampered, the H wave
amplitude remained increased during many months (Hellgren
and Kellert, 1989). Interestingly, a prominent strengthening of
monosynaptic reflexes in the immediately adjacent spinal cord
segments to a ventral root injury has also been found. The
reflexes were almost doubled in size at 6 and 12 weeks
postoperatively (Havton and Kellerth, 2004). The remaining
motoneurons in those adjacent segments seem to undergo
compensatory synaptic rearrangements, receiving more excitatory boutons, leading to increased excitability and enhanced
reflexes (Holmberg and Kellerth, 2000). Moreover, sciatic
nerve injury during the first week in the rat, a critical

175

Fig. 2. Recordings of compound muscle action potentials in the rat gastrocnemius muscle of (A) the intact contralateral limb, (B) the limb subjected to
sciatic nerve section and suture repair at 1 month and (C) at 2 months
postsurgery. Note the progressive recovery in amplitude of the M wave, and
the marked increase in amplitude of the H wave, resulting in an enhanced H/M
ratio after nerve injury and regeneration. Horizontal scale: 2 ms/division;
vertical scale: 10 mV/division.

development period when axotomy causes marked neuronal


death, leads to permanent enhancement of reflex responses
from reinnervated muscles that is maintained during adulthood
(Navarrete et al., 1990).
Withdrawal reflexes elicited by electrical stimulation
characteristically consist of three bursts of muscle activity
(C1, C2 and C3) of gradually longer latency, lower amplitude
and higher threshold, which are likely mediated by different
populations of sensory afferent fibers (Ab, Ad and C fibers,
respectively) (Meyerson et al., 1995; Navarro et al., 1999).
After sciatic nerve injury, crossed extensor reflex responses
dependent on myelinated afferent fibers (C1 and C2), similar to
the behavior shown by the stretch reflex (H wave), showed a

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X. Navarro et al. / Progress in Neurobiology 82 (2007) 163201

marked increase in amplitude during the first stages of


regeneration, and tended to decline as reinnervation progressed
(Valero-Cabre and Navarro, 2002b). However, at the end of 3
months follow-up, the reflex amplitude remained at significantly higher levels than in controls, more in animals presenting
a low degree of sensory-motor reinnervation. In contrast,
component C3 of the crossed extensor reflex, mediated by
unmyelinated C afferents, reappeared in a lower proportion of
animals, and had an amplitude similar to baseline values
(Valero-Cabre and Navarro, 2002b). Thus, after nerve injuries
reflexes mediated by myelinated sensory afferents appear to
exhibit a higher degree of facilitation than those mediated by
unmyelinated fibers.
Spinal reflex facilitation correlates with the severity of the
injury and the degree and time course of muscular reinnervation. These observations are compatible with the fact that
neurotrophic factors released by Schwann cells and target cells
are able to modulate the physiological behavior of intact or
axotomized neurons (McAllister et al., 1999; Mendell and
Munson, 1999). In adult animals, all these changes persist long
time after reinnervation and may impair motor unit activation
and control of movement, and account in part for the poor
clinical outcome achieved after severe nerve injuries (Cope and
Clarck, 1993; De Medinaceli, 1988; Gramsbergen et al., 2000;
Valero-Cabre and Navarro, 2002a).
Different mechanisms may account for the observed patterns
of facilitation of reflex responses following nerve injuries.
Mechanisms that may contribute to the abnormalities reported
in reflex responses following nerve injuries include increase of
neuronal and synaptic excitability (Eccles et al., 1958; King and
Thomson, 1995), decrease of the effectiveness of propiospinal
and descending inhibitory systems (Castro-Lopes et al., 1993;
Sanna et al., 1993), and remodeling of sensory afferent
projections within the spinal cord (Woolf et al., 1992; Shortland
and Fitzgerald, 1994).
7. 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 after complete nerve
section followed by surgical repair mainly arises from
topographic intrafascicular changes generated after the injury,
the random growth of regenerative sprouts and misrouting of
regenerated axons (Abernethy et al., 1992; Madison et al., 1996;
Puigdellvol-Sanchez et al., 2006). Regenerating sensory axons
can reinnervate foreign target territories and inappropriate
receptors, including reinnervation of muscle receptors by
cutaneous afferents and vice versa, or reinnervation of tactile
receptors by nociceptive afferents (Koerber et al., 1989).
Studies using neuroanatomical and electrophysiological
techniques proved that central reorganization induced by nerve

lesion produces changes in the spinal cord receptive fields, the


functional efficacy of central connections and the laminar
projections of afferent fibers, so that the properties of the
central projections of regenerated sensory neurons are not well
matched with their peripheral receptor properties (Koerber
et al., 1995). Koerber and Mirnics (1996) and Koerber et al.
(2006) found that, at 6 months after tibial nerve section
and repair in the cat, the somatotopic organization in the
affected areas of the dorsal horn was lost; the receptive fields of
dorsal horn cells were larger than normal and consisted of
multiple small discontinuous skin areas, in agreement
with the random and disperse nature of axon regeneration
following nerve section. At longer intervals (912 months) the
receptive fields shrank, approaching normal sizes, but the
somatotopic organization remained partially scrambled.
Moreover, shortly after regeneration, focal electrical stimulation of the skin within the receptive field of a dorsal horn
neuron revealed that numerous fibers that were not connected
to the dorsal horn cell could be electrically activated. At longer
recovery times the incidence of afferent coupling increased
significantly. This plasticity process implies significant
changes in synaptic efficacy. Over time some original synaptic
inputs would be unchanged or even strengthened while others
might weaken or disappear, in order for receptive fields to
return towards normal sizes; on the other hand, pre-existing
silent inputs must be activated or new synaptic inputs
established in order to make the receptive fields more
continuous (Koerber et al., 2006).
7.1. Central sprouting of afferent projections
After a peripheral nerve lesion, DRG neurons show variable
responses regarding sprouting or regenerative growth of their
central axonal branch. Myelinated afferent terminals labeled
with cholera-toxin beta-subunit show an advantage in collateral
sprouting into the adjacent denervated neuropil in lamina III
after nerve lesion. Intact and unlesioned sensory neurons
positive for CGRP are able to sprout vigorously into segments
denervated by rhizotomy in a nonsomatotopic manner. In
contrast, isolectin B4 (IB4) labeled sensory neurons maintain a
somatotopic distribution centrally, which is not altered by prior
nerve lesion (Belyantseva and Lewin, 1999). Following nerve
injury there is a dramatic decrease in IB4 expression in the
superficial dorsal horn, that is partially recovered if peripheral
regeneration is allowed (Molander et al., 1996). An ultrastructural quantitative assay following constrictive injury to the
rat sciatic nerve has also demonstrated a significant decrease in
the density and number of central boutons of IB4-labeled
afferents during the first 2 weeks due to degeneration, followed
by recovery by regrowth of terminals, in contrast with no
changes in CGRP-labeled afferents (Bailey and Ribeiro-daSilva, 2006). These data indicate a considerably heterogeneous
response to injury and regeneration amongst different types of
afferent sensory neurons, particularly between peptidergic
(NGF-dependent) and non-peptidergic (GDNF-dependent)
sensory neurons, which is likely related to different expression
of neurotrophic factors (see Fig. 3).

X. Navarro et al. / Progress in Neurobiology 82 (2007) 163201

Fig. 3. Immunohistochemical stainings for Bandeiraea simplicifolia isolectin


IB4, parvalbumin and substance P in the dorsal horn of the spinal cord of adult
rats that were subjected to section followed by epineural suture repair of the
right sciatic nerve 2 months before. Pictures show the dorsal horn innervated by
the injured nerve (ipsilateral) and the corresponding contralateral dorsal horn.
Peptidergic C fibers are labeled by substance P whereas IB4 mainly labels nonpeptidergic C fibers in the superficial laminae. After 2 months of injury, the
injured sciatic nerve projection area still displays a clear reduction in IB4
staining. Substance P shows also a slight decrease. Parvalbumin is expressed in
the inner part of lamina II and in some scattered cell bodies between laminae II
and III and is not strongly modified by the lesion. Bar: 200 mm.

There has been extensive controversy regarding the


rearrangement of the central terminals of injured and intact
sensory afferents in the spinal cord following nerve lesions, and
its potential contribution to neuropathic pain and mechanical
hypersensitivity. After peripheral nerve lesions, the central
axons of injured myelinated Ab fibers have been found in
several studies using retrotracing and intrafiber injection
techniques to sprout from their normal termination territory
within deep laminas IIIV of the dorsal horn to partially invade
laminas II and I, which are normally restricted to receive inputs
from C and Ad sensory fibers (Woolf et al., 1992, 1995;
Shortland and Woolf, 1993; Koerber et al., 1994). Intact
myelinated afferents also showed an enlarged projection into
areas normally provided by a neighbor-injured nerve, although
reorganization was limited to the dorsoventral plane in adult
animals (Doubell et al., 1997). In contrast, nerve lesions in
neonatal animals induced a more extensive growth of uninjured
terminals outside their normal termination region, permanently
altering the somatotopic representation maps and the laminar
distribution (Shortland and Fitzgerald, 1994). The death or
atrophy of a number of small sensory DRG cells and the
transganglionic degeneration of their terminations within the

177

spinal cord dorsal horn after nerve injuries (White and Kocsis,
2002) would induce sprouting of Ab and Ad afferents from the
same spinal level as well as of Ab and C fibers from other spinal
levels into the empty dorsal horn laminas I and II. Even if
regeneration was allowed after sciatic nerve crush, collateralization of Ab fibers lasted for months on the spinal cord gray
matter (Woolf et al., 1995). The myelinated endings that sprout
into laminas I and II, and also into laminas IIIV (Koerber et al.,
1994), would raise the number of synaptic contacts with correct
and mismatched spinal interneurons, thus increasing the
strength and duration of polysynaptic reflex responses
(Valero-Cabre and Navarro, 2002a) and underlying the
development of abnormal sensory input and hyperalgesia
(Shortland et al., 1997).
Nevertheless, more recent studies have raised concerns
about the specificity of the used tracer (cholera toxin B subunit)
and the changes of axotomized thin fibers for its transport, and
do not support the hypothesis that Ab afferents sprout into the
superficial lamina after nerve section. Only a very limited
number of large A fibers was found to sprout into inner lamina
II, a region normally innervated by C fibers, but not into outer
lamina II or lamina I, and no obvious changes were found in the
rostrocaudal distribution or in the laminar locations of axonal
collaterals (Bao et al., 2002; Hughes et al., 2003; Shehab et al.,
2003; Koerber et al., 2006). When detected, A fiber sprouting
into lamina II after nerve injury seems to derive mainly from
small Ad fibers that terminate in lamina I (Ma and Tian, 2001).
Moreover, the suggestion that central terminals of intact
myelinated afferents sprout into regions of lamina II occupied
by adjacent nerves that have been axotomized peripherally has
been also contradicted (Shehab et al., 2004). In contrast,
sprouting of the central projections of undamaged small fibers
(C and Ad) into the region occupied by the central projection of
fibers whose peripheral projections had been interrupted by
spinal nerve ligation has been demonstrated (Hu et al., 2004).
Studies using intraaxonal injection of neurobiotin have
shown that afferent fibers make connections many millimeters
rostral and caudal to the region where their receptive field is
represented in the somatotopic map of the dorsal horn (Wilson
and Kitchener, 1996). Intracellular recording from dorsal horn
neurons has shown that these long-ranging projections make
functional, but weak, synaptic connections. The somatotopic
reorganization following nerve lesions in adult animals might
be explained by an increased synaptic efficacy and formation of
new synaptic boutons of those existing projections, that can
activate second-order neurons that were originally outside the
corresponding receptive field. Electrophysiological observations suggest that, following sciatic nerve transection or partial
injury, large myelinated A afferent fibers establish synaptic
contact also with interneurons and transmit innocuous
information to substantia gelatinosa (Okamoto et al., 2001;
Kohno et al., 2003). This functional reorganization of the
sensory circuitry may constitute an underlying mechanism, at
least in part, for sensory abnormalities following peripheral
nerve injuries. This plasticity process apparently does not
require notable structural changes or collateral sprouting of
central fibers (Koerber et al., 2006).

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7.2. Changes in spinal cord neurons


Clinical and experimental evidences show that noxious
stimuli, initiated by burst activation due to the nerve injury, may
sensitize central neural structures. Experimental evidence of
these changes is illustrated by the development of wind-up,
classic central sensitization, long-term potentiation, and
expansion of receptive fields of CNS neurons, as well as by
the enhancement of flexion reflexes and the persistence of pain
or hyperalgesia (Melzack et al., 2001; Woolf and Salter, 2006).
Peripheral deafferentation has long been known to develop
increased spontaneous activity in neurons of the spinal cord
dorsal horn, as well as an expansion of their receptive fields
(Wall et al., 1981; Takaishi et al., 1996; Chapman et al., 1998;
Dalal et al., 1999). Loss of peripheral inputs is not by itself a
requisite for such ongoing activity, since there seems to be no
difference in the amount of spontaneous discharges between
neurons with and those without connection to a peripheral
receptive field. It is the altered physiology of primary afferent
neurons that transynaptically impacts the physiology of secondorder sensory neurons. Peripheral nerve injury induces
modification of a significant number of genes in the dorsal
spinal cord neurons. Regulated genes include calcium and
sodium channel subunits, AMPA and GABA receptor subunits,
and several signal transduction pathways (Yang et al., 2004). In
rats subjected to a chronic constriction injury, that developed
hyperalgesia, Hains et al. (2004) found an up-regulation of
sodium channels of Nav1.3 type in dorsal horn second-order
nociceptive neurons but not in astrocytes or microglia, and unit
recordings demonstrated hyperresponsiveness of dorsal horn
sensory neurons. Enhanced excitability of spinal neurons may
be also associated with a decrease of the postsynaptic
potassium-chloride transporter KCC2 (Coull et al., 2003).
Therefore, dorsal horn neurons per se can be the source of
ongoing neural activity, in addition to ectopic impulses
generated in the DRG neurons and in injured axons, and
contribute to the development of neuropathic pain and
hyperesthesia.
The underlying changes at the level of spinal synapses may
occur by an activity-dependent modulation of synaptic
transmission dependent on NMDA and AMPA glutamate
receptors, and the release of tachykinins. Modulation of
inhibitory GABAergic control into the distant collateral
branches of primary afferent fibers might play a further role
in those synaptic changes. Wind-up is characterized by a
progressive increase in excitability during the course of lowfrequency repetitive C fiber stimulation and is of relatively
short duration (seconds to minutes), whereas central sensitization and long-term potentiation, which have longer duration (h),
can be elicited by high-frequency stimulation (Woolf and
Salter, 2006). Spontaneous afferent discharges caused by
peripheral nerve injury would also produce a similar sensitized
state. Wind-up reflects attenuation of GABAergic tone from
superficial laminas, enhancement of transmission by neuropeptides release and activation of neurokinin receptors, as well as
recruitment of NMDA receptors. All these phenomena can lead
to the unmasking of previously silent synapses. Sustained or

repetitive activation of primary afferent pain fibers changes the


function and activity of central pathways, in a process called
central sensitization. Central sensitization is generated and
maintained by transmitter/receptor systems in the spinal cord
and above, resulting in expansion of receptive fields, increased
excitability of spinal neurons and enhanced synaptic efficacy in
both stimulated nociceptor terminals and not activated lowthreshold neurons (Simone et al., 1989). Central sensitization is
the consequence of activation of several transduction pathways,
including PKC, PKA, NO/PKG, and CMAK2 cascades, that
lead to phosphorylation of NMDA and AMPA receptors, and
their increased expression in synaptic membranes (for reviews,
see Woolf and Salter, 2000, 2006; Willis, 2002). It has been
described that NMDA binding density increased bilaterally in
both the dorsal and the ventral horns of the spinal cord up to
300% of control values following a peripheral nerve lesion
(Croul et al., 1998).
Peripheral nerve lesions also induce changes in several
transmitter and receptor systems in the spinal cord neurons.
Neuropeptides such as substance P, CGRP and NPY,
inappropriately elaborated and released by primary afferent
fibers after nerve injury, may in turn exert effects on ion channel
expression and on axonal sprouting, and therefore contribute to
the long-term changes in excitability of dorsal horn cells that
accompany the central sensitization in neuropathic lesions
(Abdulla et al., 2003). Neurokinin-1 receptor density is largely
increased in the superficial dorsal horn, and extends its normal
presence rostrocaudally and also to deeper laminae after nerve
crush, section or constriction injuries (Croul et al., 1998; Goff
et al., 1998), suggesting a contribution in the hyperalgesic
behavior. In fact, behavioral manifestations of pain produced by
peripheral nerve injury could be attenuated by prior administration of neurokinin-1 antagonists (Cahill and Coderre,
2002). Significant increases in dynorphin expression occur in
ipsilateral laminae III and VVII of the dorsal horn within 5
days after peripheral nerve injury and remain elevated at least
20 days (Malan et al., 2000). Dynorphin may promote
nociceptive transmission by enhancing the release of excitatory
transmitters and neuropeptides from afferent fibers. The spinal
opioid system is also specifically modified in peripheral nerve
lesions models. The threshold dose of intrathecal morphine to
inhibit spinal nociceptive reflexes was increased in rats after
sciatic nerve section, indicating a decreased efficacy of the
spinal opioid system (Xu and Wiesenfeld-Hallin, 1991). Opioid
receptors display an important reduction in laminae III during
the first 2 weeks after nerve transection, that was more marked
after extensive dorsal rhizotomy (Besse et al., 1992; Goff et al.,
1998), but smaller with partial nerve injury (Porreca et al.,
1998). Following sciatic nerve crush, a significant reduction in
density of serotonin 5-HT3 receptor alpha subunit in
motoneurons was observed in the ventral horn that returned
to normal after completion of regeneration but was maintained
for a longer period if regeneration was impeded (Rende et al.,
1999), whereas no changes were detected for 5-TH1 and 5-HT2
receptors (Croul et al., 1998). Axotomy also induces an
increase of galanin-R2 receptors in motoneurons ipsilateral to
the lesion, but no changes in the expression of galanin-R1 and -

X. Navarro et al. / Progress in Neurobiology 82 (2007) 163201

R2 in the dorsal horn, suggesting that galanin may play a


modulatory role on spinal excitability and influence the
development of central sensitization, evidenced by wind-up
and facilitation of spinal reflexes (Kerr et al., 2001; Brumovsky
et al., 2006).
In addition, spinal glial cells release proinflammatory
cytokines and excitatory neuromodulators after axonal injuries,
which once central sensitization is initiated, enhance the
hyperexcitability of dorsal horn neurons (Watkins et al., 2001;
Milligan et al., 2003; Ohtori et al., 2004). Activated microglia
has also recently been implicated in the development of
neuropathic pain, particularly by means of their expression of
purinergic receptor P2X4, and of p38 MAPK (Jin et al., 2003;
Tsuda et al., 2005).
7.3. Changes in intraspinal inhibitory pathways
Peripheral nerve injuries also alter spinal pathways
involving inhibitory interneurons. After peripheral nerve insults
there is an apoptotic death of a number of neuronal cells in the
dorsal horn of the spinal cord (Azkue et al., 1998). This loss
appears to affect mainly small inhibitory interneurons, and is
attributable to NMDA receptors since it can be blocked by
NMDA antagonists. An early and progressive decrease of
dorsal horn GABAergic interneurons (Castro-Lopes et al.,
1993; Ibuki et al., 1997; Moore et al., 2002) and of inhibitory
Renshaw interneurons (Sanna et al., 1993) has been reported
after sciatic nerve lesions in the rat. There is also an attenuation
of inhibitory GABAergic tone in the substantia gelatinosa
interneuron pool (Laird and Bennett, 1992), and changes in the
postsynaptic response to GABA and glycine that become less
inhibitory on some neurons of lamina I (Moore et al., 2002),
although the expression of GABA B receptor subunits is not
altered in the dorsal horn after nerve injury (Engle et al., 2006).
The reduction of activity of inhibitory interneurons in the spinal
cord may therefore lead to increased excitation of ascending
sensory pathways, motoneurons and antagonist muscle inhibition.
Chronic axotomy of a peripheral motor nerve causes a
gradual elimination in the number of intramedullary axon
collaterals originating from the axotomized motoneurons
(Havton and Kellerth, 1990a). There is also an initial concurrent
decrease in the amount of recurrent inhibition exerted by
remaining motoraxon collaterals through Renshaw interneurons in the spinal cord for up to 6 weeks after the injury, whereas
the same action tends to return to normal by 12 weeks (Havton
and Kellerth, 1990b). The recovery of the recurrent inhibitory
reflex action exerted by the axotomized spinal motoneurons has
been correlated with changes in their synaptic vesicle structure
(Havton and Kellerth, 2001).
8. 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

179

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 activity-dependent
multiple-step phenomenon affecting wide neural networks
including spinal cord, brainstem, thalamus and also cortical
regions directly or indirectly involved in the processing of the
impacted functions (for reviews, see Kaas, 1991; Jain et al.,
1998; Lundborg, 2000b; Chen et al., 2002; Wall et al., 2002;
Kaas and Collins, 2003). For years it was believed that plastic
reorganization across structures followed the same direction as
the physiological flow of activityi.e. bottom-up for sensory
pathways and top-down for motor pathways. Recent experiments, however, have disclosed a more complicated picture, in
which both local circuitry (Majewska and Sur, 2003) and
complex loops of feed-forward and feedback connections
between cortical and subcortical locations may determine the
degree of remodeling (Kaas et al., 1999; Krupa et al., 1999).
Plasticity following peripheral injury and deprivation has
been mainly monitored in primary somatosensory and motor
cortices, given their large surface, accessibility and the existing
knowledge of their normal function, somatotopic organization
and connectivity. These regions and their subcortical nodes will
be the focus of this review. Nevertheless, similar observations
of plastic reorganization have been made for the primary visual
cortex (Gilbert and Wiesel, 1990; Kaas et al., 1990), the
primary auditory cortex (Robertson and Irvine, 1989) and later
on, brain cognitive regions involved in language or attention.
More recently it has been proven that after extensive and long
lasting sensory deafferentation, cortical reorganization can
cross regional modality boundaries, resulting into the recruitment of visual regions for processing tactile information and
language in blinds (Sadato et al., 1996; Amedi et al., 2003) or
the implication of auditory regions in the processing of visual
information in congenital deafness (Finney et al., 2001).
8.1. Reorganization of somatosensory cortex
Somatosensory cortex plasticity has been studied after
interventions resulting into interruption or modification of
incoming peripheral sensory activity. Those comprise fast
reversible interventions such as local anesthetic or ischemic
peripheral nerve blockade, totally irreversible procedures such
as limb amputation or unrepaired nerve injury, and slowly
reversible procedures such as mild or surgically repaired nerve
injury. Peripheral nerve transection implies an acute deafferentation with immediate and evolving long-standing plastic
changes on the corresponding cortical representation areas as
well as in adjacent brain regions. Early evidences for
reorganization in the somatosensory cortex were obtained
from primate experiments (Merzenich et al., 1983a, 1983b;
Wall et al., 1986; Garraghty and Kaas, 1991a; Garraghty et al.,
1991; Silva et al., 1996). Hand peripheral nerve injuries, for
example result in an obvious loss of evoked activity in the
corresponding cortical map in response to stimulation of the
skin covered by the injured nerve. Short after, the same region

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Fig. 4. Changes in cortical representations in the monkey somatosensory area 3b due to amputation or nerve injury followed by axonal regeneration. (A) Normal
cortical representation of fingers (D1D5) and palm (P) of the hand. (B) Effects of acute median nerve transection. The cortical area corresponding to the median

Obs: Moseley have found a negative correlation between


the sensation (feeling that the affected areas de- or
increases in size) and the reorganization of the Cortex; in
CRPS the hand feels bigger, but the cortex schrinks - in
LBP the back "disappears", but the cortex gets bigger

X. Navarro et al. / Progress in Neurobiology 82 (2007) 163201

becomes responsive to inputs originated in other body parts


with adjacent cortical representations. The result is shrinkage in
size of the cortical field deprived from its original inputs, and its
takeover by immediately adjacent representations for the
processing of information conveyed by intact sources. Initially,
receptive fields in the reorganized cortex are large, with hardly
discernible somatotopy. Over time, the receptive fields become
smaller and a new somatotopy representing the adjacent nondenervated parts of the body emerges and stabilizes. The extent
and time progression of cortical reorganization following nerve
transections seems to depend on the innervation pattern of the
nerves rather than on the extent of deprived skin or central
cortical territory. In fact, peripheral deafferentation affecting a
large surface of sensory cortex may result in long periods of
inactivity before plastic mechanisms start to occur. After
combined transection of median, ulnar and radial nerves, large
areas of the hand sensory cortical map remain silent for a period
of at least 1 year and perhaps permanently (Dykes et al., 1995;
Jain et al., 1998). Cortical reorganizations of a larger scale can
take place after an extensive deafferentation induced by
multiple dorsal rhizotomy. For example, in monkeys studied
more than 10 years after complete deafferentation of inputs
from the arm, the deprived hand and arm cortical representation
showed evoked activity in response to inputs from the face, an
expansion of more than 10 mm in length (Pons et al., 1991).
This observation suggested that axonal or dendritic outgrowth
after injuries could take place far over the limits of thalamocortical projection zones, comprising 13 mm (Wall et al.,
1983).
Cortical reorganization has been shown to occur throughout
species. After sciatic nerve transection in the rat the saphenous
nerve representation in primary somatosensory cortex S1
expands into the hindpaw region normally representing sciatic
inputs occupying an area about three times larger than its
normal representation. This expansion, initially observed 12
days after transection, was maintained after chronic deafferentation lasting up to 56 months, but covering only about
half of the total hindpaw representation area (Wall and Cusick,
1984). However, this apparent steady state of the rat hindpaw
cortical map presented additional, nearly complete reorganization at times longer than 78 months. The late reorganization
supports the concept that reorganized cortical maps can
continue to be altered throughout life (Cusick, 1996). For
humans with peripheral nerve injuries, such results imply that
the short-term post-injury status might not stabilize and can
become further altered at longer times, even decades later.
If peripheral nerves are repaired and axonal regeneration
occurs, the cortical remodeling may be totally or partially
restored depending on the severity of the injury and the
capability to accurately reinnervate their former targets.
Following a crush injury, axons regenerate inside their original

181

endoneurial sheaths achieving a highly specific reinnervation of


appropriate targets (Molander and Aldskogius, 1992; BodineFowler et al., 1997; Valero-Cabre et al., 2004). In these
circumstances, the corresponding cortical hand or paw map is
re-established to a normal pattern (Wall et al., 1983). However,
after complete or partial nerve transection even when followed
by surgical repair, there is a large degree of misdirection in
axonal growth in the repair site, and consequently regenerating
motor and sensory axons can aberrantly reinnervate on a
permanent basis targets that do not match their original organ,
function or territory. The result is an abnormal pattern of input
or output activity to the cortical maps. Therefore, it results in
reorganization of the somatosensory cortex with a new and
distorted mapping of the skin areas originally innervated by the
damaged nerve (Wall et al., 1986; Florence et al., 1994; see
Kaas et al., 1983; Jain et al., 1998 for reviews). In such a case,
the former well-defined cortical representations of individual
fingers disappear and change into a discontinuous and patchy
map within the regenerated nerve cortical area (Fig. 4). Neurons
in the reorganized cortex that recover tactile responsiveness
from reinnervated skin regions have multiple receptive fields
such that neurons at the same cortical site respond to
stimulation of non-adjacent skin areas (Wall et al., 1986). In
monkeys, the abnormal topographical features of the new
innervation pattern remain apparent in the somatosensory
cortical areas as long as 3 years after repair (Wall and Kaas,
1986). In humans who suffer nerve section and repair, sensory
mislocalizations seem to persist permanently after nerve
regeneration, indicating that the errors in target reinnervation
cannot be corrected by brain plasticity.
The changes in cortical maps appear to follow a fast time
course. In fact, sensory deafferentation by anesthetic blockade
of a finger in primates and humans induces acute functional
changes, resulting in minutes in an expansion of the cortical
representations of intact fingers slightly into the maps of
denervated fingers (Calford and Tweedale, 1991; Rossini et al.,
1994). When the nerve block wears-off, the original map
distribution re-emerges in a matter of minutes to hours. The
rapid time-course of these changes suggests that there is an
extended network of reciprocal connectivity across cortical
representations of different sensory areas, so that sensory inputs
from one finger normally inhibit existing inputs from adjacent
fingers. Finger deafferentation by anesthetic block would
remove this inhibition, thus resulting into a takeover of adjacent
territories (Wall et al., 2002).
On the other hand, amputation of individual fingers induces
a slower cortical reorganization with progressive shrinkage of
the affected territory accompanied by the expansion of
adjacent cortical regions (Fig. 4). Parts of primary somatosensory cortex that normally responded to stimulation on the
amputated finger become responsive to the stimulation of

nerve becomes silent due to acute deafferentation. (C) Chronic median nerve transection when regeneration is not allowed. The cortical area, originally receiving
input from the median nerve, is now occupied by expanding adjacent cortical areas of radial and ulnar innervated skin. (D) Effects of median nerve crush followed by
regeneration. The cortical representation of fingers and palm returns to practically normal. (E) Median nerve transection followed by suture repair and axonal
regeneration. There is a remodelling of the cortical median nerve representation characterized by small discontinuous patches, some of them overlapping, resulting in
a disorganized somatotopic pattern. (F) Amputation of the third finger (D3). Representations of the second and fourth digits expand to occupy the area previously
receiving input from the third finger. Reprinted from Lundborg (2000a,b) with permission from Elsevier.

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X. Navarro et al. / Progress in Neurobiology 82 (2007) 163201

neighboring fingers or hand areas (Kelahan et al., 1981;


Merzenich et al., 1984; Manger et al., 1996; Weiss et al., 2000).
This new organization emerges within weeks after injury, and
becomes permanent on chronic amputations. In a time-course
study after forelimb amputation in rats, the deafferented
forelimb S1 cortex remained unresponsive to any sensory input
during the first week, whereas islets of new shoulder
representation were observed in the forelimb area by 4 weeks
after the event. These islets of foreign representations enlarged
thereafter but by 4 months portions of the forelimb cortical area
still remained unresponsive (Pearson et al., 2001, 2003). These
findings suggest that limb amputation results in a slower
reorganization of the somatosensory cortex than more limited
nerve injuries.
Studies on cortical maps in humans after chronic upper limb
amputation indicate that areas of primary somatosensory cortex
may become functionally reactivated by inputs originated in the
limb stump or even the face. Furthermore, a sensory map
corresponding to the different portions of the missing limb can
be traced in the stump or in the face of such subjects
(Ramachandran, 1993). Nevertheless, parts of the deprived
cortex may still remain unresponsive many weeks after the
lesion (Wall et al., 2002). Following traumatic amputation of
the upper limb, rapid cortical changes showing a medial
displacement of the face area towards the hand representation
(Elbert et al., 1994; Borsook et al., 1998) emerge, and
consequently abnormal identification of touch stimuli given to
the face is referred in the missing hand (Flor et al., 1995, 1998).
The basis of phantom sensations secondary to amputation
seems to include reorganization phenomena at cortical and
subcortical levels. Sometimes painful sensations arise from
areas with complete sensory loss, probably because of a severe
cortical reorganization combined with the deafferentation
injury (Birbaumer et al., 1997; Knecht et al., 1998). The extent
of shifts in cortical representation has been found to correlate
with the amount of pain in the phantom limb (Ramachandran
and Hirstein, 1998), thus becoming an example that cortical
reorganization does not always result into adaptive solutions. A
somatosensory evoked potential study in a multiple digit-tohand replantation in a young male showed that as soon as the
digital nerves were reinnervated by ulnar and median nerve
axons different parts of the somatosensory cortex became
responsive to inputs from the reimplanted fingers, that over time
progressively reactivated the original representations of the
permanently lost fingers (Wiech et al., 2000).
8.2. Reorganization of motor cortex
Peripheral nerve injuries block the flow of output information from motor cortices to the denervated muscles, thus
resulting in paralysis. In a rodent model, Donoghue and Sanes
provided seminal observations of motor cortex plasticity as a
result of a motor nerve injury (Sanes et al., 1988, 1990;
Donoghue et al., 1990). They examined the short- and longterm changes following an unrepaired facial nerve transection,
denervating the vibrissa muscles. As a result, cortical motor
representations corresponding to denervated muscles became

initially silent, so that their electrical stimulation was unable to


yield muscle activation. In a few of hours however, stimulation
of the same region elicited forearm and eyelid with motor
representations adjacent to that of the vibrissae muscle
activity. Such observations indicated a rapid 12 mm shift in
the border between cortical representations that persisted for at
least 4 months. Similar results were observed after forearm
amputation, which resulted in a dramatic increase in the
shoulder representation, invading that of the adjacent forearm
muscle within a week (Sanes and Donoghue, 2000).
Accompanying such border shifts, stimulation thresholds
required to elicit movements in expanded representations were
at or below normal levels, thus suggesting the withdrawal of
inhibitory local circuitry.
In humans, the use of transcranial magnetic stimulation
(TMS) has helped to identify plastic changes of motor system
reorganization after injuries (Chen et al., 2002). The pattern
resulting from peripheral nerve reversible or permanent
inactivations consists in enlarged representation cortical areas
and large motor evoked potentials for muscles immediately
proximal to the nerve lesion, in parallel to the reduction and
eventual disappearance of the motor maps of completely
denervated muscles. Some of these changes can be apparent
minutes after ischemic nerve block, weeks after spinal cord
injury, and a few months after amputation (Mano et al., 2003).
The combination of TMS with reversible nerve blockade has
been extremely useful to study the dynamics of motor cortical
representations in human subjects (Brasil-Neto et al., 1992,
1993). Nerve block induced by regional anesthesia or ischemia
causes within minutes a transient increase in motor evoked
potential amplitude elicited from the representation of muscles
located immediately proximal to the inactivation site. This
effect reverses about 20 min after cessation of anesthesia,
suggesting that motor cortex excitability can be rapidly
increased during deafferentation. The number of scalp positions
from which TMS elicits responses on muscles proximal to the
block was also increased compared to pre-blockade levels,
which indicates an expansion of muscle representation into
deefferented territories. Simultaneous motor nerve conduction
(M wave) and stretch reflex (H wave) tests indicated that the
neuromuscular junction and the spinal cord neurons play no
role. Furthermore, the amplitudes of motor evoked potentials to
TMS, but not to transcranial and spinal electrical stimulation,
were larger during ischemia, implying that the site of change
was in the motor cortex (Brasil-Neto et al., 1993). Supporting
these observations, resting regional cerebral blood flow shows
bilateral increases in the sensorimotor cortex and decreases in
supplementary motor regions, suggesting that increased motor
excitability might be associated with enhancement in postsynaptic activity, and in such circumstances, a strong excitatory
drive from supplementary motor region is not needed (Sadato
et al., 1995). Taken as a whole, such a body of observations
implies that rapid motor reorganization after peripheral block is
an extensive network effect. It could be caused as a result of
sensory deafferentation, which might initially deactivate the
somatosensory cortex and through cortico-cortical horizontal
projections (Classen et al., 2000) disinhibit specific motor

X. Navarro et al. / Progress in Neurobiology 82 (2007) 163201

regions. Alternatively, intrathalamic connectivity between


somatosensory nuclei such as ventral-posterior medial
(VPM) and lateral (VPL) and thalamic motor nuclei such as
ventral-anterior or ventral-lateral projecting into pre-motor
cortex or supplementary motor area (Sadato et al., 1995) could
indirectly mediate motor cortical effects. More complex
bilateral contributions through transcallosal inhibitory projections between primary motor cortices cannot be discarded.
Cortical reorganization also occurs in human patients after
peripheral nerve lesions. In patients with facial palsy, for
example, both TMS and PET studies revealed an enlargement of
the hand representation with medial extension into the original
cortical face area (Rijntjes et al., 1997). In patients with
anastomosis of musculocutaneous and intercostal nerves to
repair traumatic cervical root avulsion, TMS studies showed that
the biceps muscle cortical control was transferred to clusters of
neurons corresponding to the intercostal muscle cortical area.
Under such circumstances coupling of activation between these
two muscle groups occurred, so that subthreshold rhythmic
depolarization of biceps motor units could be recorded during
respiration. However, with time the original biceps area regained
access to the biceps muscle via the intercostal nerve, a change
that was associated with improved independence of biceps
contraction from respiration (Mano et al., 1995).
An striking dynamic process of interhemispheric functional
reorganization in the motor cortex was recently described in
adult rats subjected to brachial plexus avulsion repaired by
transferring the seventh cervical nerve root from the
contralateral healthy side to the injured limb (Lou et al.,
2006). The ipsilateral motor cortex was able to activate the
injured forepaw by 5 months after the injury, the time at which
the grasping force started to recover. Later, 810 months after
the operation, motion of the injured forepaw was evoked by
stimulating the motor cortex on either side, reflecting the
emergence of a bilateral representation of the injured forepaw
in the primary motor cortex. Finally, from 8 to 16 months the
contralateral cortex gained exclusive control of the injured
forepaw. This sequence of events suggests that an extensive
functional plastic transfer occurs between the two hemispheres,
and such a shift, seems not dependent on the corpus callosum,
but on mechanisms involving long range central axonal
sprouting and withdrawal. It is however unknown if a similar
phenomenon may underlie the capacity of some human
patients, suffering a brachial plexus lesion repaired by C7
transfer, to move their injured hand without holding voluntary
movement of the healthy hand (Gu et al., 1998). Ipsi- and
contralateral interhemispheric plasticity has been demonstrated
after large stroke in humans and animals (Wieloch and
Nikolich, 2006).
Profound long-standing reorganization changes occur
within the primary motor cortex after chronic amputation in
primates and humans. Studies in primates subjected to forelimb
amputation, examined years after amputation, showed that in
all cases stimulation of the motor cortex originally devoted to
the missing hand, evoked movements of the stump, shoulder
and trunk, indicating a substantial reorganization of motor
cortex (Wu and Kaas, 1999; Qi et al., 2000). Similar changes

"smudging"

183

have been reported for humans with both upper- and lower-limb
amputations (Hall et al., 1990; Cohen et al., 1991; PascualLeone et al., 1996; Chen et al., 1998). Those observations were
coincident with the pioneer rodent studies after limb
amputations (Sanes et al., 1990) that are referred at the
beginning of this section. The threshold of TMS evoked muscle
activity is reduced and the percentage of motoneurons activated
by a given intensity pulse is higher on the amputated side for
muscles proximal to the amputation compared to the normal
side. In contrast, electrical brain and spinal cord stimulation did
not reveal differences between the two limbs (Chen et al.,
1998). These findings suggest again that motor plastic changes
following amputation occurs predominately at the cortical level
without the intervention of the spinal cord or the brainstem.
The cortical reorganization following a limb amputation can
be reversed if the severed body part is reimplanted and allows a
functional use. After early reimplantation of a traumatically
amputated hand, the cortical representation of arm muscles was
enlarged overlapping within the partially deprived cortical hand
area that, on the contrary, was not changed in size and activation
threshold (Roricht et al., 2001). An interesting recent case
addressing this issue is a patient submitted to a double hand
transplantation occurring 4 years after bilateral amputation by
using cadaver allografts. By using functional magnetic
resonance imaging (fMRI), it was shown that hand transplantation was followed by an expansion of corresponding representations of the former hands in both motor cortices; the center of
gravity of motor representation experienced shifts between 7 and
10 mm in only 6 months. Such a change occurred in parallel with
an increase in use of the transplanted hand (Giraux et al., 2001).
Therefore, new peripheral sensory inputs combined with viable
motor activity provided by late allograft hand implantation
allowed to reverse the functional reorganization that emerged
after amputation, so that the hand and arm motor and
somatosensory representations returned to their original cortical
locations and tended to recover their normal extent, although
regions of overlapping with those corresponding to the elbows
remained. Such case strongly suggests that plastic reorganization induced after severe deafferentation can be reversed even at
chronic stages, thus indicating that an already remodeled cortex
retains the ability to reorganize its pattern of representations
regardless of the time post-injury. Alternatively, the use of
artificial prosthesis in amputees is also able to limit the extent
and reverse the effects of plastic reorganization. Lotze et al.
(1999) trained a group of acute and chronic hand amputees in the
use of a myoelectric hand prosthesis. They demonstrated that its
daily use could prevent the shrinking of the motor and
somatosensory hand cortical areas, and further expansions of
non-deafferented surrounding regions, such as the lips or the
face. Furthermore, such maintenance of the original cortical
representation patterns correlated negatively with the presence
and severity of phantom limb pain.
8.3. Reorganization at subcortical levels
Peripheral injuries cause rapid molecular, functional, and
structural changes at both cortical and subcortical levels.

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Recent comparisons of extents of subcortical and cortical map


shifts indicate that initial subcortical changes can be more
extensive than cortical, and that over time cortical and
subcortical amount of change may reach new balances (Wall
et al., 2002). The result is that injuries in a particular nerve or
root induce a concurrent cascade of functional changes initiated
by the nerve injury and progressing to reorganization process of
the entire pathway, from peripheral neurons to cortex.
Structural alterations begin with the degeneration of central
axons and terminations of peripheral sensory neurons, and may
continue trans-synaptically inducing structural atrophy and
degeneration at spinal, brainstem, thalamic and, likely, cortical
levels. It has been suggested that the higher the level in the
neuraxis, the larger the degree of functional plasticity that such
a region might have potential to undergo after nerve injury (Kis
et al., 1999).
Evidence for subcortical plasticity and its relation with
peripheral and cortical events comes mainly from animal
models, in which invasive mapping methods allow the precise
study of functional reorganization at most levels within the
neuraxis. Fast plastic changes have been demonstrated in the
rodent thalamus, in which anesthesia-induced peripheral block
of ascending cutaneous afferents induced an immediate and
reversible reorganization of the VPM nucleus (Nicolelis et al.,
1993). Furthermore, concomitant changes in the somatosensory
cortex and the thalamus were seen to occur, being the spatial
extent of the reorganization very similar at both sites (Faggin
et al., 1997). Similarly, new receptive fields appeared in dorsal
columns nuclei of the cat within minutes after anesthesia of the
cutaneous fields, suggesting that the new responses arose from
unmasking of pre-existing inputs (Pettit and Schwark, 1993). In
humans affected by chronic deafferentation, enlarged and
functionally abnormal receptive fields in the thalamus, as well
as increased spontaneous bursting of thalamic neurons have
been also reported (Rinaldi et al., 1991; Davis et al., 1996). The
evidence of increased glial activation in the thalamus many
years after peripheral nerve injury is indicative of persistent
thalamic reorganization that may reflect chronic altered afferent
activity (Banati et al., 2001).
Mapping of the hand representation in the brainstem cuneate
nucleus and in somatosensory cortical area 3b after combined
acute section of both median and ulnar nerves in primates
showed substantial changes at both locations, starting within
minutes post-injury and continuing over several days (Xu and
Wall, 1997, 1999a,b). Interestingly, post-injury maps of dorsal
hand inputs conveyed through the intact radial nerve expanded
to occupy about 66% of the cuneate hand map, but only about
37% of area 3b hand map; thus, although maps processing such
inputs enlarged at both levels, brainstem map expansion
accounted for almost double and receptive fields were larger
when compared to corresponding areas of cortical changes. In a
later stage after chronic, non-regenerating median and ulnar
nerve section and ligation, the cuneate and the VPL nucleus of
the thalamus showed similar patterns of reorganization as those
observed in the cortex (Garraghty and Kaas, 1991b; Xu and
Wall, 1999b; Churchill et al., 2001). The hand subnuclei
became largely responsive to stimulation applied at the back of

the hand, mediated by the spared radial nerve. It appears that


acute changes, characterized by relatively larger reorganization
in cuneate than cortical map changes, progressed to a later stage
whereby cortical and thalamic map changes caught-up to the
levels of brainstem reorganization. The more extensive
thalamic and cortical reorganizations emerging progressively
weeks to months after sensory loss may also depend on the
growth of new connections (Kaas, 1999).
Thalamic maps also show marked reorganization after
chronic limb amputation. For example, studies on primates
carried out several years after hand amputation demonstrated
that neurons in the VPL nucleus hand map were activated by
intact inputs from the remaining upper limb stump and also
from the face (Florence et al., 2000). This expansion of
thalamic receptive fields involving the upper arm and the
face tended to be larger than in somatosensory area 3b. In
primates studied 26 weeks after digit amputation, peripherally denervated thalamic neurons displayed enlarged
receptive fields, which did not augment in surface by an
additional cortical lesion. However, at longer periods of
reorganization (>4 months), when the new receptive fields of
deafferented neurons had already decreased in size, a
subsequent cortical lesion induced the expansion of the
thalamic field size (Chowdhury et al., 2004). The normal
corticothalamic modulation of thalamic receptive fields in
intact animals seems thus ineffective during the early stages of
injury-induced reorganization when new receptive fields are
being formed, but is reinstated after the new receptive fields
have become stabilized (Kaas et al., 1999). The fact that
neurons in the denervated thalamic region retained their unique
receptive fields after cortical lesion indicates that their new
inputs are not being relayed from a reorganized cortex,
supporting the traditional view that plasticity occurs in or
below the thalamus, independently form cortical reorganization occurring first.
Different observations seem to suggest a directionality in the
reorganization process, which might occur first at a given level
to be afterwards translated through feed-forward projections
onto hierarchically superior structures once consolidated
(reviewed by Kaas et al., 1999). Thus, extensive cortical
reorganizations would depend on similar processes in
subcortical structures, as a pre-condition for cortical changes
to co-occur. Nevertheless, work by Nicolelis group (Faggin
et al., 1997; Krupa et al., 1999) has challenged this view and
emphasized the importance of thalamo-cortical loops, i.e. feedforward and feedback projections in the induction and
maintenance of subcortical plasticity. By making simultaneous
recordings of neuronal activity at both thalamus and
somatosensory cortex before and after a sensory nerve block,
it was reported that, when the cortex was blocked by a local
anesthetic, thalamic plastic reorganization was reduced by half
(Krupa et al., 1999). This discovery indicates that subcortical
plasticity might be at least in part determined by corticosubcortical projections. Under physiological conditions, such
cortico-thalamic feedback activity serves to specifically
reinforce the core of thalamic neurons involved in receiving
sensory information by inhibiting the surrounding units (Kaas

X. Navarro et al. / Progress in Neurobiology 82 (2007) 163201

et al., 1999). Their role in deafferentation-induced or useinduced plasticity remains however to be further clarified.
8.4. Mechanisms of cortical and subcortical plasticity
Different mechanisms are involved in the initiation and the
sustaining of long-standing reorganization changes at cortical
and subcortical levels after nerve injury. The fast changes,
occurring within minutes after deafferentation, are probably
based on the unmasking of previously present, but functionally
inactive, synaptic connections. Such unmasking of latent
excitatory synapses might explain the rapid expansion of
adjacent motor and sensory cortical territories that follows
nerve block in humans and nerve lesions in animals.
Unmasking of connections can occur as a result of increased
excitatory neurotransmitter release, increased density of
postsynaptic receptors alone or combined with changes in
their affinity, changes in membrane conductance enhancing the
postsynaptic effects of weak inputs, decreases of inhibitory
interactions as a result of removal of inhibitory projections or
withdrawal of inhibitory projections in control of excitatory
inputs. Within hours of nerve injury the stimulus threshold for
activation of newly emerged evoked responses in the deprived
somatosensory cortex is similar to pre-injury levels, supporting
the notion that functional borders between nerve representations in the cortex are actively maintained by selective
inhibition of overlapping inputs (Barbay et al., 1999).
Immediate unmasking of inhibitory responses has also been
found in the thalamus after peripheral denervation (Rasmusson
et al., 1993). Removal of inhibition of excitatory synapses due
to reduction of GABAergic inhibition has been suggested as the
most important to cause short-term plastic changes (Chen et al.,
2002). This is based on the predominant presence of GABA
interneurons in intracortical locations, and the fact that their
intracortical projections can extend horizontally for up to 6 mm
or more (Jones, 1993). In agreement with the role of inhibitory
interneurons in shaping cortical areas, the administration of
GABA receptor antagonists produces enhanced evoked
responses to stimulation and expansion of the receptive fields
of somatosensory cortex neurons (Chowdhury and Rasmusson,
2002; Li et al., 2002). Additionally, the topic use of the GABA
antagonist bicuculline onto the cortical representation of the
forelimbs in rodents allows for a rapid activation of vibrissa
muscles, which have an adjacent motor representation (Jacobs
and Donoghue, 1991). In humans, systemic GABA antagonist
drugs lead to decreases in motor excitability as tested by TMS
evoked motor activity (Ziemann et al., 1996). Using magnetic
resonance spectroscopy, GABA levels in the human sensorimotor cortex have been found quickly reduced within minutes
of deafferentation (Levy et al., 2002). Peripheral deafferentation led to a reduction in the number of neurons containing
GABA or its synthesizing enzyme, glutamic acid decarboxylase, in the thalamus and in the somatosensory cortex (Land
and Akhtar, 1987; Welker et al., 1989). Several months after
nerve injury, changes mainly reductions in the cortical
distribution of GABA were still visible (Garraghty et al., 1991),
suggesting that decreased intracortical inhibition may enhance

185

inputs from additional cutaneous afferents. A long-lasting but


reversible lowering of ChAT immunoreactivity was also found
in the primary somatosensory cortex of cats sustaining
complete unilateral forelimb denervation (Avendano et al.,
1995). It has been proposed that such reduction in cholinergic
transmission might contribute to the loss of GABA inhibition in
the deafferented cortex by decreasing the activation of
inhibitory cortical interneurons, thus maintaining the projection
neurons to the deafferented cortex in a tonic state of increased
excitation.
TMS studies aimed at investigating the cortical reorganization induced by temporal nerve block or amputations suggested
that the underlying mechanisms could also involve changes in
the expression of voltage-gated sodium, potassium and/or
calcium channels (Chen et al., 1998; Ziemann et al., 1998).
Recently it has been demonstrated that after peripheral nerve
injury, third-order nociceptive neurons located in the VPL
nucleus of the thalamus undergo changes in expression of
sodium channels (Zhao et al., 2006). Ten days after sciatic nerve
constriction in rats, when allodynia and hyperalgesia were
evident, in situ hybridization and immunocytochemical analysis
revealed up-regulation of Nav1.3 mRNA, but no changes in the
expression of other types such as Nav1.1, Nav1.2, or Nav1.6 in the
thalamic neurons. Single unit recordings carried out along
demonstrated increased background activity and evoked
neuronal responsiveness to peripheral stimuli. A similar increase
in the expression of the Nav1.3 sodium channels in second-order
dorsal horn neurons and third-order thalamic neurons along the
pain pathways occurs early after spinal cord injury. Such a
change in channel phenotype is accompanied by neuronal
hyperexcitability, and expanded peripheral receptive fields at
both levels (Hains et al., 2003, 2005). These results demonstrate
that injuries to the peripheral and central nervous system trigger a
series of plastic events that result into final increases in the
excitability of neurons in the sensory pathways, contributing to
the physiopathology of neuropathic pain. In contrast, no changes
were detected in Nav1.3 density or distribution in injured or
uninjured upper motor neurons within the rat primary motor
cortex following spinal cord injury (Hains et al., 2002). The
potential role of changes in electrophysiological properties
of relay neurons in influencing territorial reorganization at
cortical level needs further study. Meanwhile, it can be
hypothesized that spinal and thalamic neurons with enhanced
levels of excitability would relay into higher somatosensory
nodes increased patterns of activity in response to peripheral
inputs. Such increases should in turn generate activity-dependent
surface expansions of cortical representations at the expense of
those that do not receive facilitated inputs.
CNS plastic reorganization occurring over longer periods of
time likely involves more stable functional or structural
mechanisms, including intracortical and cortico-subcortical
phenomena of long-term potentiation (LTP) and long-term
depression (LTD), or the formation of de novo connections by
means of axonal sprouting and synaptogenesis (Kaas, 1991).
When following nerve injury the normally dominant excitatory
and associated inhibitory inputs are removed, by deafferentation or nerve lesions, weaker and previously latent existing

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synapses can become strengthened over time, stabilizing and


reinforcing their postsynaptic effects on the basis of the new
activation patterns. LTP and LTD of postsynaptic effects, which
require AMPA and NMDA receptor activation and increased
intracellular calcium concentration, have been demonstrated to
occur in the motor (Hess and Donoghue, 1994), the
somatosensory (Castro-Alamancos et al., 1995) and the visual
(Berry et al., 1989) cortices. Such phenomena can be induced
by means of intracortical electrical stimulation, but also
generated by peripheral injuries or sensory deprivation. For
example, whisker deprivation in the rat, a manipulation that
reduces cortical responses to deprived whiskers in barrel field
somatosensory cortex, induces LTD-like depression at intracortical excitatory synapses, preventing further LTD-like
activity and releasing competitive LTP phenomena in
surrounding regions (Allen et al., 2003). The role of specific
neurotransmitters in the generation of post-lesional LTP/LTD
mechanisms seems to be time dependent. Following median
nerve section in primates, expansion of the area 3b map of the
hand was reduced when an NMDA receptor antagonist was
systemically administered during the first month after injury, an
effect that did not occur when this antagonist was given after
this critical time (Garraghty and Muja, 1996; Myers et al.,
2000). Thus, it was proposed that LTP/LTD NMDA receptor
mechanisms partly contribute to cortical map reorganization
during the first month after injury, but such mechanisms might
not be needed to maintain such changes at later times.
The consolidation of longer lasting plastic reorganization
might require structural processes consisting in the generation
of new projections through sprouting of axon collaterals,
dendritic elongation and branching and formation of new
synaptic connections. The extent and relevance of these
mechanisms, however, remain still poorly understood, particularly given the highly inhibitory CNS environment, which
normally prevents sprouting and regeneration of axons after
injuries. Nevertheless, afferents in the spinal cord and in the
cuneate nucleus have been shown to display abnormally large
termination fields after limb amputation in adult monkeys
(Florence and Kaas, 1995), which is indicative of new growth.
The extended terminal labeling appeared patchy and sparse
over a distance of 12 mm, but was seen at all post-injury times
tested for up to 13 years. Tracing studies also proved that
chronic amputation can cause broader surface increases of up to
1014 mm (Pons et al., 1991), mediated by cortico-cortical
projections linking cortical areas 1 and 3b, consistent with long
range intracortical axonal sprouting (Florence et al., 1998).
The issues of how long and at which levels can such new
central connections grow are controversial. Physiological
mapping of primary somatosensory cortex representation
carried out more than 1 month after forelimb amputation in
adult rats revealed an extensive expansion of the motor shoulder
representation in the forepaw field. Nevertheless, no anatomical
evidence of direct cortico-cortical connections between the
original shoulder representation in the trunk subfield and the
forepaw subfield was found (Pearson et al., 2001). These
observations suggested that subcortical sites might play a major
role in providing the substrate of large-scale cortical

reorganization. Within subcortical nuclei a few millimeters


shortcut may be sufficient to induce the rapid and stable shift of
cortical representation areas, which if developed at cortical
level would require the elongation of considerably long
intracortical projections. Supporting this view, tracing studies
demonstrated aberrant sprouting of gracile nucleus neurons,
normally relaying hindlimb sensory information, into the
cuneate nucleus, which relays information from the forelimbs,
following forelimb deafferentation by extensive dorsal rhizotomies in the rat (Sengelaub et al., 1997). Similarly, the face
afferents from the trigeminal nucleus of the brainstem were
able to sprout and grow millimeters into the cuneate nucleus in
adult monkeys after lesions of the spinal cord dorsal columns or
therapeutic amputation of an arm (Jain et al., 2000). Also, in
monkeys many years after dorsal rhizotomies resulting in
extensive thalamic and cortical reorganization, there was
evidence of neuronal atrophy and loss of axons of the cuneate
and the VPL nuclei (Jones and Pons, 1998; Woods et al., 2000).
Therefore, secondary transneuronal atrophy associated with
retraction of axons and compensatory axonal sprouting seems
to play a significant influence on the reorganization of
somatotopic maps in the brain cortex.
Structural changes in the patterns of dendritic arborization
within the cortex have been recently related to plastic
reorganization after nerve injuries. In adult rat primary
somatosensory cortex, neurons have less extended dendritic
arborizations close to the border between the forepaw and the
lower jaw representations. After partial denervation of the
forepaw following median and radial nerve transection, the
border between these two body part representations shows
during the first month a progressive medial shift. In parallel the
dendritic arbors of cortical supragranular neurons become
reorganized reflecting the new border location (Hickmott and
Steen, 2005). Relatively fast structural changes in dendritic or
axonal structure occurring during cortical reorganization after
peripheral denervation might be aimed at adapting the patterns
of connectivity so that neurons can better develop their
modified activity. It has been found that the deprived cortical
barrel field of rodents presents, in fact, a net increase rather than
a decrease of excitatory synapses in superficial layers (Machin
et al., 2006), and an increased turnover of dendritic spines
(Trachtenberg et al., 2002). After median and ulnar nerve
ligation in monkeys, the deprived cortical area 3b, investigated
350 months later, showed a progressive expansion in distal
regions of the dendritic arbor of both layer II/III pyramidal and
layer IV spiny stellate neurons compared to unaffected cortical
areas (Churchill et al., 2004). This expansion correlated with
the degree of functional reorganization, supporting the notion
that latent inputs gain expression after nerve injury via their
influence onto distally located dendritic sites, thus implicating
intracortical connections in sustaining cortical reorganization.
The use of high resolution microscopic imaging techniques has
shed further light into the structural dynamics of axon,
dendrites and dendritic spines in the brain cortex of alive
animals. Longitudinal recordings have revealed changes in the
turnover of synapses and dendrites as a result of sensory
stimulation or sensory deprivation (Trachtenberg et al., 2002;

X. Navarro et al. / Progress in Neurobiology 82 (2007) 163201

Majewska et al., 2006; Majewska and Sur, 2006). In adult


animals the presynaptic (axon terminals) and postsynaptic
(dendritic spines) structures were relatively stable, although
1020% showed remodeling over a 3-week period in different
sensory cortices. Axon terminals were more stable than
dendritic spines. Although activity dependent processes play
a major role, particularly during postnatal development and
after peripheral deprivation, adult reorganization seems to
occur primarily through changes in the strength and efficacy of
existing synapses, rather than implicate active remodeling of
connectivity.
Finally, recent works are addressing the molecular underpinnings of activity-dependent neural plastic properties. Tropea
et al. (2006) studied the genes activated during dark-rearing and
monocular deprivation plasticity in the primary visual cortex of
rodents. Monocular deprivation, which results in dramatic
reorganization of primary visual cortex, up-regulates genes
encoding molecules associated with synaptic activity (glutamatergic and GABAergic), as well as molecular pathways
related to neuronal growth and neuronal degeneration,
including transcriptional factors and neurotrophic proteins
implicated in mechanisms that may adaptively match cortical
connections to differential levels of inputs.
Several observations strongly suggest that neurotrophins
control cortical plasticity during the critical development
period, but also may play a role in deprivation-induced
plasticity in adult mammals. For example, intracortical infusion
of neurotrophins (NGF, NT-4 and BDNF) in rats monocularly
deprived during the critical period, counteracted the deprivation
effects, and BDNF also affected spontaneous and evoked
activity in visual cortical neurons (Lodovichi et al., 2000).
Different neurotrophins may act on different neuronal targets,
at which they can modulate electrical activity, synaptic
transmission at both presynaptic and postsynaptic levels, or
intracortical inhibitory connections (for reviews, see Berardi
et al., 1999, 2003; McAllister et al., 1999). BDNF has been
shown to mediate developmental and activity-dependent
regulation of GABAergic inhibition in the visual cortex
(Huang et al., 1999). BDNF may also mediate the rapid and
long-term effects of activity on dendritic morphology since its
expression and release are activity-dependent. Overexpression
of BDNF alters the form and stability of dendritic arbors via
autocrine and paracrine mechanisms (Horch, 2004). It has been
recently proven that polymorphism in the BDNF gene of
normal human subjects has an impact on their ability to trigger
use-dependent motor cortex reorganization (Kleim et al., 2006).
It may be postulated that nerve injuries disrupt the expression
and distribution of trophic molecules and receptors, triggering
the retraction of processes of neurons deprived from activity
and concurrently inducing the expansion of non-deprived
neuronal clusters into their territories.
9. 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

187

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 peripheral nerve injuries utilizes
normal physiological properties of neural systems to modify the
efficiency and extent of connectivity, and affects a wide neural
network of interconnected structures by feed-forward and
feedback projections. These changes are reversible provided
that meaningful patterns of activity conveyed by regenerated
peripheral afferents or efferents are reinstated. However, when
nerve regeneration is hampered or when profound misrouting
of regenerated axons to mismatched targets occurs, both usual
phenomena after severe nerve lesions, plasticity of central
connections in adult mammals has limited effects and may be
even detrimental for the recovery of fine sensory processing and
motor control.
It has been argued that expanded cortical and subcortical
representations might help in optimizing the use of existing
central resources for motor execution or sensory processing of
intact muscles and sensory receptor fields. It is well known that
perinatal deprivation from visual or auditory input triggers a
series of cross-modal plastic processes that improve processing
of the intact sensory modalities in adulthood (Cohen et al.,
1997; Sadato et al., 1996; Amedi et al., 2003). Nevertheless,
plastic changes following peripheral injury do not always result
into better adaptation. On the contrary, the reorganization of
somatosensory systems is related to development of neuropathic pain and phantom pain in amputees. Furthermore, in
patients suffering from dystonia expanded and incorrect
somatomotor associations are at the root of the incapacitating
consequences (Quartarone et al., 2006). It is believed that a
deficient control of intrinsic plastic properties (also referred to
as homeostatic plasticity) due to excessive training might
trigger such maladaptive reorganization, resulting into abnormal sensory-motor associations and abnormally enlarged
cortical representations at the expense of neighboring areas.
In order to therapeutically address the effects of maladaptive
plasticity, recent research has studied the possibilities to
modulate the abnormal enlargement or shrinkage of cortical
representations by manipulating the flow of sensory inputs or
motor outputs. In intact individuals, evidence in favor of such a
possibility has been provided through the study of training/
learning-induced plasticity. Such paradigms have shown that in
intact non-human primates and human subjects training in
sensory discrimination tasks, whether somatosensory (Recanzone et al., 1992; Pascual-Leone and Torres, 1993), auditory
(Recanzone et al., 1993), visual (Schoups et al., 2001; Schwartz
et al., 2002) or involving skilled motor tasks (Nudo et al., 1996;
Xerri et al., 1999), progressively results into better performance
levels, which in turn correlate with a sharpening of receptive
fields and the expansion of corresponding cortical maps.
As discussed in prior sections, the inactivation of afferent or
efferent activity by means of a nerve block generates immediate
and reversible repercussions on cortical and subcortical maps.
Using an opposite approach, electrical stimulation of selective

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X. Navarro et al. / Progress in Neurobiology 82 (2007) 163201

Fig. 5. Schematic summary of the main plastic changes that develop after nerve injury at the different levels of the somatic sensorimotor nervous system.

nerve fascicles in patients with chronic nerve injuries or


amputations has demonstrated that somatosensory localization
remains accurate despite the presumed central reorganization
that takes place after nerve injury (Schady et al., 1994; Dhillon
et al., 2005). These observations open the basis for treatments
attempting to restore normal neural processing and cortical
maps by acting on the injured nerve. Different strategies have
been implemented, including peripheral nerve electrical
stimulation, TMS on localized cortical regions, specific sensory
training, delivery of alternate modality stimulation, or
deprivation of inputs from intact nerve territories. Some of
those approaches are briefly reviewed in this section.
A short period of electrical stimulation of the proximal
stump after sciatic nerve transection and repair, a procedure
known to induce an acceleration of the initial axonal
regeneration rate, has been proved able to ameliorate the
degree of accurate muscle reinnervation (Al-Majed et al.,
2000), but also to prevent the increased spinal reflex responses
that occur during the early phases of reinnervation (Puigdemasa
et al., 2006). The positive effects of short-term electrical
stimulation are mediated via the neuronal cell body, implicating
an enhanced growth program and modulation of excitability.
During the regeneration/reinnervation period, enhanced sensory inputs and/or motor activity by means of chronic
electrostimulation or exercise may also positively influence
the neuromuscular functional outcome after nerve injury
(Marqueste et al., 2004). Furthermore, activation of sensory
afferents via electrical stimulation can result in modulation of

spinal reflex circuits, both in normal subjects and in patients


with upper motoneuron pathology (Field-Fote, 2004). Nevertheless, the effects of patterns of electrical stimulation to
injured nerves on CNS plasticity remain to be investigated.
Periods of electrical transcutaneous nerve stimulation have
been combined with TMS mapping of motor cortex representations in intact humans and rodents. Results show increased
motor excitability and nerve specific increases in muscle
representations, accompanied by significant shifts in the center
of gravity of the activated muscles, which outlast the duration
of the stimulation by around 2 h (Ridding et al., 2001; Luft
et al., 2002; Charlton et al., 2003). Such effects are though to be
mainly mediated through proprioceptive sensory afferents
triggering excitability changes at somatosensory and motor
cortices. Other paradigms combine synchronized patterns of
transcutaneous peripheral nerve electrical stimulation with
TMS on the primary motor cortex, in what has been called
paired associative stimulation (PAS). PAS paradigms can
generate large and lasting increases in motor excitability of
muscles corresponding to the targeted cortical territories,
whereas repeated motor practice also affects sensorimotor
organization (Classen et al., 2004; Rosenkranz and Rothwell,
2006). The sign and intensity of its effects might vary as a
function of the interval between electric and magnetic pulses,
and it tends to be mainly facilitatory (Classen et al., 2004).
These techniques could be used to efficiently reshape the
excitability and size of specific cortical regions altered after
peripheral or central injuries in conditions such as dystonia

X. Navarro et al. / Progress in Neurobiology 82 (2007) 163201

(Quartarone et al., 2006) or maladaptive reorganization


following cortical stroke.
As a clinical routine, specific rehabilitation programs are
used in patients for improving the outcome after nerve injuries.
Early intervention sets the stage for optimal functional
recovery. Focus is usually first placed on protection of the
affected area from complications stemming from disuse and
immobility, and then on enhancement of strength, sensory
discrimination and dexterity (Frykman and Waylett, 1981;
Robinson and Shannon, 2002). Intensive programs of sensory
re-education of reinnervated hands after nerve injury or digital
reimplantation can improve tactile discrimination and threshold
perception, although this effect may wane after cessation of
training (Shieh et al., 1998). Sensory training rehabilitation
typically involves repetitive practice of tasks that require
sensory feedback from the affected sensory targets. Sensory reeducation or increased stimulation can improve sensory
function, presumably by modulating plasticity mechanisms
that restore more normal function within the somatosensory
network in the CNS. Florence et al. (2001) evaluated the
consequences of enriched sensory experience in monkeys
subjected to transection and repair of the median nerve. Using
multiunit recording techniques, they showed that an enriched
sensory environment had substantial positive effects on
receptive field sizes in cortical area 3b with smaller and
better-localized fields, as well as slight changes in the hand
representation map organization that remained nevertheless
abnormal. In contrast, there was no evidence for significant
sensory-dependent changes in the functional properties and
receptive fields of thalamic neurons. Based on the finding that
phantom limb pain is associated with plastic changes in the
somatosensory cortex, an intensive sensory discrimination
training programme reduced limb pain and improved sensory
discrimination ability in amputee patients with intractable
phantom limb pain compared with control medically treated
patients (Flor et al., 2001). The refinements in receptive field
size in somatosensory cortex likely provide better resolution in
the sensory map and may explain the improvements in
detection, localization and discrimination functional outcomes
after rehabilitation in humans.
Based on the concept of cross-modal mediated brain
plasticity, a Sensor Glove system has been applied to provide
auditory inputs related with touching objects as substitution for
tactile inputs in patients with hand nerve injuries. In an attempt
to reduce and modulate the central functional reorganization
following nerve injury and repair, the somatosensory cortex is
fed with alternative sensory inputs at early times after injury
before regenerating axons reinnervate the skin (Rosen and
Lundborg, 2004). In a clinical study on patients subjected to
median nerve repair, superior recovery of tactile gnosis was
found by the use of the Sensor Glove at 6 months follow-up
(Lundborg, 2003; Rosen and Lundborg, 2003). After hand
transplantation, early use of the Sensor Glove also resulted in an
earlier re-establishment of the cortical representation of the
transplanted hand as compared with controls not using the
glove (Lanzetta et al., 2004). These results suggest that the
auditory stimuli could help in maintaining the cortical sensory

189

map from the affected hand until some degree of real tactile
sensibility was restituted. Studies using fMRI in healthy
subjects have demonstrated activation of the somatosensory
cortex induced by auditory stimuli, but only in subjects trained
to substitute touch sensibility by hearing (Lundborg et al.,
2005).
A different strategy, that can be applied once target
reinnervation has occurred, involves inhibition of somatosensory inputs from areas proximal to the previously denervated
peripheral territory, which have developed an overextended
cortical representation. Local anesthesia of the forearm skin
during 2 weeks, combined with sensory re-education, resulted
in significant improvement compared to placebo in touch
perception and tactile gnosis after 6 weeks in patients with
median or ulnar nerve repair (Rosen et al., 2006). Furthermore,
transient deafferentation of the contralateral forearm and hand
resulted in significantly improved tactile discrimination,
threshold for perception and grip strength in the injured nerve
territory (Bjorkman et al., 2005). Similar modulatory effects
have been found in stroke patients, in whom anesthesia of the
upper arm or of the unaffected hand seemed to reverse
inhibition to the injured brain area, leading to transient
improvements in hand motor function and tactile discriminative
skills in the affected hand (Muellbacher et al., 2002; Voller
et al., 2006).
The concept of a self-optimizing nervous system able to
exert compensations is certainly appealing, but unequivocal
proofs that plastic changes following peripheral nerve injury do
result into better adaptation remain to be provided. Activitydependent stimulation, sensory or motor intensive training
programs, and stimulation to modulate excitability of corticosubcortical connections, are among the strategies able to alter
CNS reorganization previously induced by a nerve injury. Such
interventions might eventually be effective for increasing
sensory discrimination, improving motor control, reducing
dystonia and synkinesia, or ameliorating neuropathic pain,
although more definite studies are needed to asses the
magnitude and durability of any positive change and the
physiopathological mechanisms involved.

Acknowledgments
The authors research was supported by grants from the
Ministerio de Ciencia y Tecnologa (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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