REVIEW ARTICLE
published: 10 October 2012
doi: 10.3389/fphys.2012.00399

Maladaptive spinal plasticity opposes spinal learning andrecovery in spinal cord injury
Adam R. Ferguson 1*, J. Russell Huie 1*, Eric D. Crown 2 , Kyle M. Baumbauer 3 , Michelle A. Hook 4 ,Sandra M. Garraway 4 , Kuan H. Lee 4 , Kevin C. Hoy 4 and James W. Grau 4
1

Department of Neurological Surgery, Brain and Spinal Injury Center, University of California San Francisco, San Francisco, CA, USA
Abbott Laboratories, Chicago, IL, USA
3
Department of Neurobiology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
4
Cellular and Behavioral Neuroscience, Department of Psychology, Texas A&M University, College Station, TX, USA
2

Edited by:Jeffrey C. Petruska, University ofLouisville, USA
Reviewed by:
Vaughan G. Macefield, University ofWestern Sydney, Australia
David Magnuson, University ofLouisville, USA*Correspondence:
Adam R. Ferguson and J. Russell
Huie, Department of Neurological
Surgery, Brain and Spinal Injury
Center, University of California,
San Francisco, 1001 Potrero Ave.,
Building 1, Room 101,
San Francisco, CA 94110, USA.
e-mail: adam.ferguson@ucsf.edu;
huier@neurosurg.ucsf.edu

Synaptic plasticity within the spinal cord has great potential to facilitate recovery
of function after spinal cord injury (SCI). Spinal plasticity can be induced in an
activity-dependent manner even without input from the brain after complete SCI. A
mechanistic basis for these effects is provided by research demonstrating that spinal
synapses have many of the same plasticity mechanisms that are known to underlie
learning and memory in the brain. In addition, the lumbar spinal cord can sustain
several forms of learning and memory, including limb-position training. However, notall spinal plasticity promotes recovery of function. Central sensitization of nociceptive(pain) pathways in the spinal cord may emerge in response to various noxious inputs,
demonstrating that plasticity within the spinal cord may contribute to maladaptive
pain states. In this review we discuss interactions between adaptive and maladaptive
forms of activity-dependent plasticity in the spinal cord below the level of SCI. The
literature demonstrates that activity-dependent plasticity within the spinal cord must
be carefully tuned to promote adaptive spinal training. Prior work from our grouphas shown that stimulation that is delivered in a limb position-dependent manner oron a fixed interval can induce adaptive plasticity that promotes future spinal cordlearning and reduces nociceptive hyper-reactivity. On the other hand, stimulation thatis delivered in an unsynchronized fashion, such as randomized electrical stimulation or
peripheral skin injuries, can generate maladaptive spinal plasticity that undermines future
spinal cord learning, reduces recovery of locomotor function, and promotes nociceptive
hyper-reactivity after SCI. We review these basic phenomena, how these findings relate to
the broader spinal plasticity literature, discuss the cellular and molecular mechanisms, andfinally discuss implications of these and other findings for improved rehabilitative therapies
after SCI.
Keywords: pain, nociception, plasticity, spinal cord injury, spinal cord learning, recovery of function

INTRODUCTION
Research into spinal plasticity over the past 50 years has shownthat neurons within the spinal cord gray matter have a remarkable degree of plasticity, and in recent years we have seen asurge of interest in this field (Raineteau and Schwab, 2001;
Edgerton et al., 2004; Cai et al., 2006; Grau et al., 2006). Spinal
synapses can be strengthened or weakened in response to external stimulation, demonstrating the basic properties required foruse-dependent learning and memory. This capacity is of great
importance after spinal cord injury (SCI). Prior work has shownthat peripheral injury or inflammation can induce chronic neuropathic pain states and that this outcome is due, in part, tosensitization of nociceptive pathways within the spinal cord (forreview see Woolf and Salter, 2000; Ji et al., 2003). Aspects ofthis process have been shown to be mechanistically analogous
to brain-dependent learning and memory, and thus represents

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a lasting form of maladaptive spinal plasticity. Work from ourteam over the past 15 years has built upon this foundation,
focusing on the ways in which central sensitization impacts andinforms both adaptive and maladaptive forms of spinal learning and memory (Ferguson et al., 2006; Grau et al., 2006; Hooket al., 2008; Huie et al., 2012a,b). Our work suggests that exposure
to uncontrollable/unpredictable peripheral stimulation induces a
central sensitization-like state that inhibits adaptive spinal learning and undermines recovery of locomotor function after spinal
contusion injury.
The present review discusses the features of spinal cord plasticity with a specific emphasis on protecting against maladaptive
plasticity in nociceptive systems and promoting adaptive formsof spinal plasticity for rehabilitation after SCI. We will first review
the cellular and physiological evidence for use-dependent spinal
cord plasticity and draw parallels to brain-dependent plasticity.

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We then review behavioral evidence for learning and memory
within the spinal cord and discuss how specific changes instimulation parameters can tip the balance between adaptive andmaladaptive outcomes. Finally, we discuss how noxious input
below the level of SCI may induce a similar nociceptive plasticity
that undermines recovery, and the potential application of appropriate spinal cord training to overcome these maladaptive effects
to restore function after SCI.

CELLULAR AND ELECTROPHYSIOLOGICAL EVIDENCE FORSYNAPTIC PLASTICITY IN THE SPINAL CORD
Research of spinal plasticity over the past 50 years has eroded
the perception of the spinal cord as a simple conduit of neural
information. We now know that that the spinal cord is capableof supporting a number of forms of plasticity, yet spinal plasticity remains understudied in comparison to the field of brain
plasticity. We will begin this review by highlighting some of the
major findings that reshaped our view of the spinal cord, in orderto provide the reader with a contextual background for our later
discussions of the ways in which spinal plasticity is modulated.
Synaptic changes in the spinal cord have been often studied in the context of spinal nociceptive plasticity. In the early
1980s Clifford Woolf demonstrated that tissue injury to the lateral hind-paw produces cutaneous hypersensitivity to light tactile(von Frey) stimulation both on the ipsilateral and contralateralhind-paw (Woolf, 1983). This suggested that post-injury pain
hypersensitivity was due, in part, to an increase in excitabilityof spinal cord neurons. This increase in spinal activity, known
as “central sensitization,” reflects a form of neuroplasticity in the
spinal cord (Woolf and Salter, 2000).
In many ways central sensitization involves changes in the
spinal cord gray matter that mimic hippocampal-mediatedactivity-dependent plasticity. In the hippocampus, tetanic stimulation of afferent pathways can increase responsiveness ofsubsequent post-synaptic potentials, a phenomenon known as
long-term potentiation (LTP) (Bliss and Lomo, 1973). LTP is
widely believed to be a synaptic mechanism for learning andmemory in the CNS. Early pharmacological evidence suggested
that both hippocampal LTP and hippocampal-dependent learning tasks are blocked by antagonists to the glutamate NMDA
receptor (Collingridge and Bliss, 1987). Other lines of evidence
suggested that electrophysiologically overdriving (saturating) LTP
prevented both later LTP and spatial learning (McNaughton et al.,
1986; Moser et al., 1998). Recent data have shown that spatial
learning experience produces LTP in the hippocampus that is
detectable both electrophysiologically (as increases post-synaptic
currents) and biochemically as an increase in phosphorylation of
the glutamate AMPA receptor and trafficking of AMPA receptors
to synapses (Whitlock et al., 2006). These AMPA receptor changes
are thought to be fundamental to LTP and other forms of plasticity at excitatory synapses in the CNS (Malinow and Malenka,
2002).
Many of the characteristics of hippocampal LTP have been
identified in the spinal cord, providing a potential cellular mechanism for central sensitization. For example, tetanic stimulationof primary nociceptive afferents (C-fibers) has the capacity toincrease post-synaptic responses in the superficial spinal lamina,

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Nociception vs. spinal learninga phenomenon known as “wind-up” (Mendell and Wall, 1965;
Mendell, 1966). In addition, like hippocampal LTP, central sensitization can be blocked with NMDA receptor antagonists (Woolf,
1983; Woolf and Thompson, 1991; Dougherty et al., 1992), providing a strong pharmacological link between nociceptive sensitization and LTP. This apparent common mechanism betweenchanges in nociception and LTP (which has been suggested as a
substrate for learning and memory) has led led to the idea thatnociceptive sensitization may act as a form of ‘pain memory’(Woolf and Costigan, 1999; Ji et al., 2003). Work by Sandkuhlerand colleagues have provided direct evidence that nociceptive
stimuli can produce spinal LTP (Liu and Sandkuhler, 1995;
Sandkuhler and Liu, 1998). In addition, this team has recently
found that high doses of short-acting opioids can reverse spinal
pain memory, as measured by losses of hyper-reactivity, reduced
spinal LTP, and reduced phosphorylation of glutamate AMPA
receptors (Drdla-Schutting et al., 2012). Together, these data provide strong evidence that activity-dependent plasticity in pain
pathways reflects a form of learning and memory within the
spinal cord.
Spinal glia have also been implicated in spinal LTP. Once
believed to simply provide structural support, the capacity for
glial cells to affect glutamatergic signaling through the release of ahost of neuromodulators has led researchers to assess the importance of glia in CNS plasticity (Muller, 1992; Allen and Barres,2005). Using high-frequency stimulation of the sciatic nerve to
induce LTP of C-fiber-evoked field potentials in the dorsal horn,
Ma and Zhao demonstrated that glial activity is required for thiseffect, as spinal treatment with the glial metabolic inhibitor fluorocitrate blocked the induction of spinal LTP (Ma and Zhao,
2002). As spinal pain memory is believed to be encoded by a LTPlike effect in the dorsal horn, this finding illustrates the essential
role of glia in modulating spinal plasticity. A similar effect has
been demonstrated behaviorally as well. Watkins et al. induced
pain hyper-reactivity in rats using a peripheral injection of thecommon irritant formalin. They found that if glial activity was
inhibited using fluorocitrate prior to formalin administration, theinduction of this hyper-reactivity was blocked (Watkins et al.,1997). Others have investigated the key glial products that mediate neuromodulation of nociceptive plasticity in the spinal cord,and have shown a number of these products to be involved,
including nitric oxide, prostaglandins, and the cytokines IL-1b,
IL-6, and tumor necrosis factor alpha (TNFα). TNFα in particular has been shown to enhance spinal LTP in rats with neuropathic
pain (Liu et al., 2007). In both hippocampal culture and in vivo
spinal cord, TNFα has been shown to increase trafficking of
AMPA receptors to synaptic sites, providing a potential mechanism for TNFα-induced increases in spinal LTP (Beattie et al.,
2002; Ferguson et al., 2008b; Choi et al., 2010). Recent work
aimed at elucidating the role of spinal glia and TNFα in maladaptive forms of spinal nociceptive plasticity is discussed later in thisreview.
Similarly, metabotropic glutamate receptors (mGluRs) modulate spinal plasticity within pain pathways by altering the plasticityof the ionotropic NMDA and AMPA receptors (Mills et al., 2002).
In particular, the group I mGluRs (mGluR1 and mGluR5) havebeen shown to enhance ionotropic receptor-dependent central

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nociceptive plasticity in the spinal cord (Fisher and Coderre,
1996a,b). These systems have also been implicated in braindependent plasticity as well as multiple forms of spinal plasticity.
We will return to a discussion of mGluRs in the “cellular andmolecular mechanisms” section of this review.
In summary, the spinal cord is capable of supporting memory
for prior noxious experience that manifests behaviorally, pharmacologically, and electrophysiologically. This spinal memory
depends on mechanisms similar to learning and memory in thehigher CNS, including induction and expression of LTP at spinal
synapses. Spinal LTP is mediated by at least some of the same
receptor pathways as in the brain, providing further evidence of acommon mechanism of plasticity. Notably, the expression of LTP
in spinal pain pathways has been shown to contribute to central
sensitization in nociceptive systems, providing a mechanism forsome maladaptive neuropathic pain states.

SPINAL CORD LEARNING AND MEMORY
Plasticity within the spinal cord is not limited to maladaptive plasticity within nociceptive pathways. The spinal cord also
demonstrates several forms of adaptive motor plasticity. In thefollowing section, we will move beyond spinal nociceptive pathways to investigate how spinal plasticity in motor pathways can
induce robust behavioral changes, and how these changes can beused as outcome measures in a simple model of learning in the
spinal cord.
Inducing adaptive plasticity in spinal motor systems can haveprofound effects on locomotor behavior. For example, following
complete thoracic transection, the lumbar spinal cord can regain
the capacity to sustain weight-supported stepping with extensive
step training (Lovely et al., 1986; Barbeau and Rossignol, 1987;
de Leon et al., 1998; Harkema et al., 2011). The capacity for locomotor re-training after SCI is thought to be possible because thelumbar spinal cord contains central neural networks that control
reciprocal activity of extensor and flexor efferents during locomotion (Grillner, 1975; Grillner and Zangger, 1979). These “central
pattern generators” in the lumbar cord can be tuned by generatinga specific pattern of afferent input during physical rehabilitation training, thereby promoting recovery of function (Dietz andHarkema, 2004; Prochazka and Yakovenko, 2007; Edgerton et al.,2008).
However the specific learning capacities of the spinal cordthat underlie this recovery of function remain a topic of intensive study. Work from the field of neurobiology of learning andmemory has revealed that the isolated spinal cord can support simple forms of motor learning. There is well-documented
evidence that spinal neurons can sustain single stimulus learning (habituation/sensitization), stimulus association (Pavlovian
conditioning), and response-outcome (instrumental) learning(Sherrington, 1906; Thompson and Spencer, 1966; Fitzgerald andThompson, 1967; Grau et al., 1998).
Early demonstrations of habituation and sensitization in the
spinal cord provided fundamental evidence that the spinal cord
could learn from repeated activity, and demonstrated a form of
spinal memory that manifested behaviorally. Repeated exposure
to a stimulus was found to decrease (habituate) a spinally mediated flexion response. This habituation was not due to adaptationwww.frontiersin.org

Nociception vs. spinal learningat sensory receptors in the periphery or to a change at theneuromuscular junction, suggesting that the memory for stimulus training history resided in spinal interneuronal synapses(Sherrington, 1906; Prosser and Hunter, 1936; Thompson andSpencer, 1966). In contrast to habituation, which occurred withmoderate stimuli, exposure to a single strong stimulus had
the capacity to increase subsequent responsiveness in a process
known as “sensitization”. Groves and Thompson (1970) went on
to characterize different interneuronal pools that were responsible
for habituation and sensitization, providing one of the early neurobiological theories of activity-dependent plasticity in the spinal
cord.
Another line of work revealed that spinal neurons were capable of encoding relationships between different stimuli, a hallmark of Pavlovian (classical) conditioning. For example, theisolated spinal cord was shown to be capable of associating weakthigh stimulation (conditioned stimulus; CS) with strong plantar stimulation of the foot (unconditioned stimulus, US). With
repeated CS–US pairings the thigh stimulation came to modulate
the flexion withdrawal reflex, a type of Pavlovian conditioning
known as “pairing-specific enhanced sensitization” (Fitzgerald
and Thompson, 1967; Groves et al., 1969). A similar form of
Pavlovian conditioning had been demonstrated in the aquaticmollusk, Aplysia, in classic work in the Kandel laboratory (Carew
et al., 1981). Together these data suggest that not all forms oflearning and memory require the brain.
Much of our recent work has focused on response-outcome(instrumental) training of the spinal cord, with the goal of uncovering the basic principles that dictate spinal cord learning. The
translational goal of this work is to provide basic knowledge that
can help improve training-based rehabilitative therapies after SCI.
Our spinal training model is based on the Horridge paradigm
originally developed in headless insects and then later adapted tospinalized mammals to study learning and memory within the
spinal cord (Horridge, 1962; Buerger and Fennessy, 1970; Grau
et al., 1998). Horridge found that after experimentally instituting a relationship between leg position and electrical stimulationof an ankle flexor, insects could learn to hold the hind limb in aflexed position. This acquired leg flexion emerged after repeatedtrials, demonstrating an acquisition curve that resembles braindependent escape learning. To rule out the possibility that thechange in flexion response reflected a peripheral mechanism suchas muscle tetanus, Horridge used a clever design that involved
testing insects in “master/yoked” pairs. One insect, the master,
received leg stimulation only when the leg was extended. The
other rat served as a yoked control that received passive leg stimulation whenever the master received stimulation. Although bothrats received equal stimulation, only the master insect learned
to hold the leg in a flexed position, suggesting that the acquired
flexion response was not due to a simple unconditioned effectof stimulation, but rather depended on the response-outcome
contingency between leg position (response) and stimulation(outcome).
Master/yoked training of the hind limb after spinal transection in rats revealed that the mammalian spinal cord is also
sensitive to response-outcome relationships (Figure 1A; Buerger
and Fennessy, 1970). Building upon this foundation, our group

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Nociception vs. spinal learning

FIGURE 1 | Effects of instrumental vs. uncontrollable nociceptive
stimulation on spinal function. (A) Modes of stimulation. (i) Instrumental
spinal training. For Master rats, electrical stimulation is delivered to the tibialis
anterior muscle when the hindlimb is unflexed, and terminated when thehindlimb is flexed. Over a 30 min training session, master rats learn to keep
the hindlimb flexed to reduce stimulus exposure (spinal learning). This spinal
training promotes future adaptive plasticity. (ii) Uncontrollable stimulation.

The yoked rats receive stimulation whenever the master does, regardless of
their hindlimb position. (B) Exposure to this uncontrollable (yoked) stimulation
causes a learning deficit that is evident when these rats are later tested withthe spinal learning assay. Spinal learning is assessed by monitoring the abilityof spinally transected rats to maintain the hindlimb in a flexed position as
manifested by increasing average response duration in each 1 min time binfor 30 min test during instrumental training. Modified from Grau et al. (1998).

has shown that this example of spinal cord plasticity meets the
behavioral criteria (Grau et al., 2006) for instrumental learningand has a lasting effect on spinal function that impacts clinically
relevant phenomena (e.g., Grau et al., 1998, 2004; Ferguson et al.,2006; Hook et al., 2008). Over the past 14 years we, and others(Jindrich et al., 2009), have shown that by imposing a relationship between leg position and stimulation of the tibialis anterior
muscle (master condition/controllable stimulation) we can produce beneficial effects that improve future spinal cord training(Figure 1B, master; Grau et al., 1998). In this sense the spinal
cord shows memory for training history and can re-learn the flexion response more rapidly after instrumental training (Figure 1B,
master vs. naïve).
However, not all spinal memory for stimulus training is adaptive. Rats that are given stimulation that is independent of leg
position (yoked condition/uncontrollable stimulation) show persistent deficits in future learning when tested with responsecontingent stimulation. This spinal learning deficit appears toreflect a long-term form of maladaptive spinal plasticity that
endures for at least 48 h in completely transected rats (Figure 1B,

yoked; Grau et al., 1998; Crown et al., 2002b). Thus, using thismaster/yoked learning paradigm has allowed us to observe andmanipulate the expression of both adaptive and maladaptive
forms of plasticity in the spinal cord.
The training-dependent effects of stimulus controllability on
future spinal learning can be interpreted as “plasticity of plasticity” or “metaplasticity,” that regulates the capacity for futurelearning in a bidirectional manner (Abraham and Bear, 1996;
Crown et al., 2002a,b; Grau et al., 2006; Ferguson et al., 2008b).
On the one hand, controllable stimulation produces a positive
and adaptive form of plasticity that promotes future spinal learning and limits the development of nociceptive plasticity. The
benefits of controllable stimulation are discussed in detail in Grau
et al. (2012) within this same issue. On the other hand, uncontrollable stimulation produces a lasting, maladaptive effect that
undermines the capacity for future spinal learning. A large bodyof work from our group and others has focused on the stimulus parameters that are critical to this effect, the neurobiologicalmechanisms that mediate this form of maladaptive plasticity, andhow it may relate to the development of central sensitization.

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Perhaps most importantly, we have worked to uncover how suchan effect impacts recovery of function following SCI.
The remaining sections of this review will delve into these
critical issues. The general theme is that uncontrollable/yokedstimulation produces a maladaptive form of spinal metaplasticity
that is associated with impaired spinal learning, reduced recovery
of function after SCI, and nociceptive hyper-reactivity (Ferguson
et al., 2006; Hook et al., 2008). The findings above suggest thatthe specific patterning of peripheral stimulation exerts exquisite
control over the nature of activity-dependent plasticity that develops in the spinal cord. In sections that follow we will review theenvironmental conditions that determine whether stimulation
impacts spinal function in an adaptive or maladaptive mannerand the underlying neurobiological mechanisms.

STIMULATION PARAMETERS FOR MODULATING SPINALLEARNING
The capacity for adaptive spinal cord learning is thought to contribute to functional recovery after SCI (Edgerton et al., 2001;
Grau et al., 2006). However, the specific stimulus conditions that
promote effective spinal cord learning are not fully understood.
Similarly, those conditions that lead to a spinal learning deficit
require elucidation. Given that SCI is likely to be accompaniedby peripheral noxious input from other concomitant injuries (aswell as noxious input as a result of secondary injury processes),a more complete understanding of the stimulus parameters that
may undermine adaptive spinal plasticity is essential. This section will highlight findings that have shed light on the conditions
under which maladaptive plasticity may be induced.
After careful study of yoked animals, Crown and Grau (2001)
developed a computer program that emulated the shock schedule produced by master rats during the early phase of training.
This enabled the experimental evaluation of the effects of uncontrollable stimulation in a single “virtually yoked” rat to explore
the parameters that disable future learning ability. The program
delivers 80 ms, 1.5 mA AC current (60 Hz) stimulation on a randomized variable interstimulus interval that ranges from 0.2 to
3.8 s (mean interval = 2 s). Through a series of parameteric studies Crown et al. (2002a) found that delivering as little as 6 min of
uncontrollable stimulation to either the leg or the tail after complete spinal transection produces lasting (>48 h) impairments inspinal learning (Crown et al., 2002a; Joynes et al., 2003). Laterwork went on to show that the same stimulation procedure produced long-term (>6 weeks) impairments in recovery of function
after contusive SCI (Grau et al., 2004). As these effects are seen
in both transection and contusion injuries the findings suggestthat intermittent, uncontrollable stimulation has a generalized
negative effect on adaptive spinal plasticity.
The finding that intermittent uncontrollable stimulation to
the tail produced the same disruption of adaptive motor learning as stimulation to the leg provided important support for theidea that these maladaptive changes are centrally mediated in the
spinal cord. But the question remained, what is it about theseparticular stimulation parameters that drives such robust inhibition of spinal learning and recovery? Is it the uncontrollability,
the number of shocks presented, the unpredictability, or somecombination thereof that is essential to this phenomenon?

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Nociception vs. spinal learning

The lasting differences in learning capacity between master/yoked pairs suggested that controllability is an essential characteristic. The differential effects of controllable and uncontrollable stimulation on spinal plasticity can be invoked even when
the total amount of stimulation is equalized using master/yokedtraining protocol. In master/yoked training, rats are run in pairs
where one rat (master) is given response-contingent stimulationand the other rat (yoked) receives stimulation whenever the master does. Even though the two rats receive stimulation at the sametime, only master rats show instrumental learning. But is it necessary that stimulation pulses be separated at all to induce theyoked learning failures? Is it the total amount of shock delivered that predicts the induction of a spinal learning deficit, or the
discontinuous nature of shock administration? Delivering 80 ms
stimulation at an average of 2 s intervals over 6 min produces a
total of approximately 180 shocks, and a total stimulation timeof approximately 15 s. Thus, to test whether these temporal gaps
are necessary, we applied a continuous 1.5 mA AC (60 Hz) shockfor 15 s to one group, while another group received a continuous AC shock for the entire 6-min session. A third group received
the typical intermittent stimulation schedule, and a control group
received no stimulation. All rats were then subsequently tested for
instrumental learning. As expected, the rats that received no stimulation were able to learn, and those that received intermittent
stimulation failed. Interestingly, both groups that received continuous stimulation were able to learn, suggesting that the long-term
effect of shock stimulation depends upon whether the pulses are
separated by a temporal gap. Moreover, presenting a continuous
tailshock while rats received intermittent legshock negated theadverse effect of intermittent stimulation, suggesting that continuous stimulation induces an opponent process that counters theinduction of the learning deficit (Crown et al., 2002a).
Further work revealed that continuous and intermittent stimulation have divergent effects on nociceptive reacitivity. Exposure
to continuous shock reduces reactivity (antinociception) to a noxious thermal stimulus applied to the tail (tail-flick test; Crown
et al., 2002a). In contrast, exposure to intermittent shock has noeffect on thermal reactivity (Crown et al., 2002a), but enhances
reactivity to tactile stimulation. Rats were given uncontrollable
intermittent stimulation to the hindleg and then tested for tactile
reactivity on the ipsilateral and contralateral leg using calibrated
von Frey hairs. The results indicated that uncontrollable stimulation to the leg produces a bilateral tactile hyper-reactivity,
whereas controllable (instrumental) stimulation has the opposite
effect, mitigating central sensitization (Figure 2; Ferguson et al.,2006; Hook et al., 2008; Huie et al., 2012b). Thus, it appears thatone key feature that may differentiate the effects of intermittent
stimulation from other stimulation schedules is the induction of
nociceptive sensitization.
The enhanced reactivity to tactile stimulation observed after
intermittent shock resembled the mechanical allodynia observed
after peripheral inflammation and injury (Ji et al., 2003; Hooket al., 2008). Given this, we hypothesized that the maladaptive effect of uncontrollable stimulation may be linked to the
induction of a state akin to central sensitization. If so, it would
be expected that the spinal learning deficit should be induced
not only within the confines of specific electrical stimulation

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Nociception vs. spinal learning

FIGURE 2 | Training history alters nociceptive hyper-reactivity. (A)Uncontrollable stimulation (6 min, 80 ms stimuli, variable inter-stimulusinterval: 0.8–3.2 s, 1.5 mA AC) to the leg produces tactile hyper-reactivity on
both the ipsilateral and contralateral leg. The same stimulation patternundermines spinal cord learning on both leg for over 24 h and impairs
recovery of locomotor function for over 6 weeks (adapted from Ferguson

et al., 2006). (B) Master and yoked training have differential effects on central
sensitization to intradermal capsaicin. Rats that have been trained with
controllable stimulation (Master) have decreased tactile responsiveness
immediately post-capsaicin injection [adapted from Hook et al. (2008)].
Similar effects are reported with central sensitization by intradermal formalinin Ferguson et al., 2012 within this same issue.

parameters, but by using more generalized nociceptive activators.
We discovered that intradermal injection of the inflammatory
agent carrageenan, an agent often reported in the pain literature
to induce central sensitization, also produced a marked inhibition of spinal learning (Figure 3; Ferguson et al., 2006). This effect
was time-dependent with the most dramatic loss of spinal learning at 3–6 h, and recovery of learning by 24 h after injection. This
time-course precisely mirrors the established time-course for central sensitization by carrageenan (Hargreaves et al., 1988; Zhang
et al., 2003). Similar effects have subsequently been observed withother peripheral nociceptive stimuli including intradermal capsaicin and formalin (Hook et al., 2008). These findings suggestthat intermittent stimulation undermines adaptive spinal modifications by inducing nociceptive plasticity that is akin to central
sensitization.
In all of the experiments reviewed above, intermittent shock
was presented in a variable manner using a program that emulated the temporal distribution of shocks produced by a masterrat. Does this temporal variable matter, or would intermittent shock undermine spinal plasticity independent of whether
it is presented in variable or regular (fixed spaced) manner?
Baumbauer et al. (2008) explored this issue and found that spacing does not matter when rats are given just 6 min of stimulation(approximately 180 shocks); both fixed and variably spaced shock
impaired subsequent learning (Figure 4; Baumbauer et al., 2008).
In contrast, when rats were exposed to an extended series ofshocks (1800 given over 30 min), only variable shock induced alearning deficit. Introducing temporal regularity (predictability)
not only eliminated the learning deficit, it induced a protective
effect analogous to instrumental control that both prevented,
and reversed, the learning deficit (Baumbauer et al., 2009). The
protective effect of fixed spaced shock lasted 24 h was mediatedby a protein synthesis-dependent process, and involved a formof NMDAR-mediated plasticity (Baumbauer et al., 2009). Theseobservations suggest that both instrumental control and temporal
predictability can negate the adverse consequences of intermittent

stimulation. Variable shock may lead to a central sensitization-likestate independent of shock number because this pattern of stimulation emulates the erratic pattern of neural activity observedin C-fibers (Sandkuhler, 2007). Further, intermittency may be an
essential feature because repeated shock onsets are required todrive an electrophysiological response over extended periods; acontinuous stream of shock pulses may lead to a form of physiological habituation that reduces C-fiber induced activity (Groves
and Thompson, 1970).
In summary, several studies have demonstrated that the patterning of peripheral stimulation after SCI can have an enormous
effect on whether adaptive or maladaptive plasticity emerges
in the lumbar spinal cord. Response-contingent (master), predictable nociceptive stimulation promotes future spinal cordlearning whereas unpredictable, intermittent nociceptive stimulation undermines future spinal learning and generates central sensitization. Therefore, discovering the biological mechanisms forthese stimulus-induced forms of spinal plasticity has implications
for both pain modulation and recovery of function after SCI.

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CELLULAR AND MOLECULAR MECHANISMS DICTATINGSPINAL LEARNING
The preceding sections have outlined the fundamental featuresof spinal cord learning, and highlighted the importance of stimulus patterning in tipping the balance between adaptive andmaladaptive forms of spinal plasticity. In the present section
we will discuss the cellular and molecular mechanisms dictating spinal learning potential. The purpose of this line of researchhas been to discover biological mechanisms that modulate spinal
learning, with the goal of developing therapeutic approaches topromote rehabilitation and recovery of function after SCI (Grauet al., 2006). Because of its rapid-throughput nature (30 min),the instrumental training assay has provided a powerful tool toidentify a number of neuropharmacological targets for improving
adaptive spinal cord function. In general, this work has focusedon either promoting adaptive plasticity to improve future spinal

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Nociception vs. spinal learning

FIGURE 3 | Peripheral inflammation with intradermal carrageenan produces transient impairment in spinal cord learning on the contralateral leg. The
timecourse of these learning deficits mimic the known timecourse for carrageenan-induced central sensitization. Adapted from Ferguson et al. (2006).

FIGURE 4 | Stimulation parameters affecting spinal learning. (A) If
nociceptive electrical stimulation is delivered to the tail in a randomized,
intermittent fashion, rats will fail to learn when later tested with
controllable stimulation to one hindlimb. This deficit is exhibited after either
short (360 s) or long (1,800 s) trains of intermittent, randomized stimulation.

(B) If stimulation is administered to the tail with a fixed interval between
stimulations over the course of 360 s, rats will also later fail to learn, but if
the train of fixed stimulation is extended to 1800 s rats then exhibit
enhanced learning when later tested. Adapted from Baumbauer et al.
(2008).

learning, or preventing maladaptive plasticity to reverse learning deficits and limit nociceptive plasticity. This section will
first briefly consider the mechanisms that mediate spinal learning, and will then focus on the neurobiological pathways thathave been implicated in the maladaptive effect of uncontrollable,intermittent nociceptive stimulation.
Adaptive spinal cord learning in the Horridge paradigm isblocked by intrathecal lidocaine, indicating that spinal neuronal

activity is required for the learned flexion response (Crown
et al., 2002b). In addition, intrathecal antagonists to glutamate
NMDA and AMPA receptors have each been independently
shown to block acquisition of the flexion learning (Joynes
et al., 2004; Hoy et al., 2012). These findings mimic what isobserved in visuo-spatial learning paradigms, indicating thatspinal cord learning in the Horridge paradigm depends on biological mechanisms similar to hippocampal-dependent learning in

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Ferguson et al.

the brain (Whitlock et al., 2006). This suggests that mechanismsthat enhance hippocampal-dependent learning have potential toenhance spinal cord training as well. Gomez-Pinilla et al. (2007)
tested the relationship between spinal training and several known
molecular biomarkers of CNS plasticity. Quantitative RT-PCR
revealed that master rats have an increase in spinal mRNA levels
compared to naïve controls for several pro-plasticity biomarkers including brain-derived neurotrophic factor (BDNF), calcium/calmodulin activated kinase II (CaMKII), cAMP response
element binding protein (CREB), and the pre-synaptic terminal
protein synapsin I. Moreover, the degree of mRNA correlated
highly with performance on the spinal learning task. In contrast,
yoked animals demonstrated significant decreases in spinal levelsof BDNF, CaMKII, and CREB relative to naïve animals. Together
these data suggest that pro-plasticity markers may play a role inspinal cord learning.
BDNF appears to be particularly important for spinal learning. Intrathecal BDNF supplementation can promote spinal cordlearning when task difficulty is increased beyond a level thatnaïve rats can normally perform (Gomez-Pinilla et al., 2007).
In contrast the BDNF inhibitor TrkB-IgG can block the adaptive benefits of prior training reducing master animals to theperformance level of untrained rats. This suggests that BDNF,
a well-established modulator of synaptic plasticity in the brain,also has beneficial effects on adaptive spinal plasticity that promotes future spinal learning (reviewed in McAllister et al., 1999;
Fritsch et al., 2010). In contrast, the learning deficit following
yoked stimulation involves a down regulation of BDNF, suggesting that bidirectional modulation of synaptic plasticity mechanisms dictate spinal learning potential. A similar role for BDNF
in promoting adaptive spinal plasticity has also recently beenshown to translate to a model of locomotor recovery. Boyce et al.
demonstrated that in rats with a complete transection at the T10
thoracic spinal cord segment, treatment with adeno-associatedvirus expressing BDNF was able to induce weight-supported
hindlimb stepping without the assistance of step-training (Boyceet al., 2012).
Further work has indicated that uncontrollable/unpredictableintermittent nociceptive stimulation engages a maladaptive formof plasticity that involves its own signature of cellular molecular changes. Initial studies indicated that intrathecal lidocaine(Joynes et al., 2003) and protein synthesis inhibitors (Patton
et al., 2004; Baumbauer et al., 2006) protect learning potential
when delivered prior to intermittent nociceptive stimulation. Thissuggested that spinal cord circuitry actively encodes the maladaptive stimulation patterns through a form of activity-dependent
CNS plasticity. Indeed, intrathecal delivery of an NMDA receptor
antagonist (at doses that are known to block central sensitization of nociceptive systems) prior to intermittent nociceptive stimulation protected spinal learning potential (Ferguson
et al., 2006). This observation led to the hypothesis that central sensitization undermines spinal cord learning potential byengaging a generalized hyper-excitability that prevents adaptive
spinal learning (Ferguson et al., 2006). Several converging lines ofmolecular and cellular evidence have lent support for this concept. The key cellular and molecular mechanisms associated withboth long-term spinal learning deficits and central sensitization

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Nociception vs. spinal learning

are depicted in Figure 5. Intermittent nociceptive stimulation
has been found to engage several glutamate receptor systems,
as well as the proinflammatory cytokine TNFα and substance P(Baumbauer et al., 2007; Huie et al., 2012a). All of these systems
have been implicated in central nociceptive processing as well
(Sandkuhler and Gruber-Schoffnegger, 2012).
One of the conundrums outlined above is that both adaptive
learning and maladaptive plasticity could be blocked by NMDA
receptor antagonists (Joynes et al., 2004; Ferguson et al., 2006).
This suggested that NMDA receptors serve as executors of spinal
plasticity in the spinal learning preparation. The NMDA receptor in spinal motoneurons has been shown to be highly mobile,and can induce glutamatergic plasticity by rapidly trafficking
from extrasynaptic to synaptic sites in response to changes inglutamatergic input (Shanthanelson et al., 2009). Interestingly,
Shanthanelson et al. showed that recovery of NMDA-mediatedexcitatory tone was more pronounced at monosynaptic input sites
coming from segmental dorsal roots, as opposed to central inputs
coming from the ventrolateral funiculus. This finding suggeststhat NMDA-mediated plasticity is highly regulated by, and highly
susceptible to, peripheral input. As such, differences in the timing
and pattern of peripheral input (such as those seen in controllable
vs. uncontrollable stimulation) may induce differential NMDA
receptor trafficking and activation, leading to divergent forms ofspinal plasticity.
Critical systems for switching between maladaptive and adaptive plasticity may also lie upstream of NMDA receptor changes.
One of the well-established neuropharmacological modulatorsof NMDA receptor plasticity is group I mGluRs. The group I
mGluRs consist of two receptor subtypes (mGluR1 and mGluR5)
that are known to modulate plasticity in the CNS through downstream effects on iGluRs, including NMDA and AMPARs (Fisher
et al., 2002; Fundytus et al., 2002). In addition activation of group
I mGluRs in the spinal cord increases NMDA-dependent central
sensitization after intradermal formalin (Coderre and Melzack,1992), and central pain after SCI (Mills et al., 2002).
Therefore, mGluRs are a good candidate for a central role indictating spinal metaplasticity in the spinal learning paradigm.
We tested this hypothesis using a combination of pharmacological, biochemical, and behavioral methods. We found thatmGluR1 and mGluR5 antagonists protect spinal learning potential in the face of uncontrollable stimulation. On the other hand
the group I mGluR agonist DHPG can substitute for uncontrollable stimulation to produce long-term impairments in spinal
cord learning (Ferguson et al., 2008b). Group I mGluRs were thefirst receptor system identified to be both necessary and sufficientfor inducing persistent maladaptive alterations in spinal learning potential. Maladaptive mGluR effects depend on downstream
activation of protein kinase C (PKC), a molecule that has been
implicated in hippocampal plasticity (Akers et al., 1986; Malinow
and Malenka, 2002; Ferguson et al., 2008b). Activation of mGluRs
and PKC has previously been implicated in maladaptive plasticity
within spinal pain pathways, once again suggesting an interaction
between spinal learning deficits and nociceptive systems (Munro
et al., 1994; Young et al., 1995; Ferguson et al., 2008b).
One of the major downstream effects of mGluR and PKC
activation is post-translational modification of the ionotropic

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FIGURE 5 | Proposed neurobiological model for maladaptive spinal
plasticity. The uncontrollable stimulation-induced spinal learning deficit
requires the activation of group I metabotropic glutamate receptors and thesubstance P receptor NK1R which liberate intracellular calcium (Baumbauer
et al., 2008; Ferguson et al., 2008a). This in turn activates downstream protein
kinases PKC and CamKII, (Ferguson et al., 2006, 2008a; Baumbauer et al.,2007). These kinases are known to produce long-term alterations in ionotropic
glutamate receptor (iGluR) function; however, the specific role of thissignaling cascade in spinal learning remains an open question (“?”; dashedlines). Altered iGluR activation is known to further increase post-synaptic
calcium levels through the NMDA receptor channel and calcium-permeable
AMPA receptors, which may provide a mechanism for altered associative
learning in the spinal cord. Increases in intracellular calcium can induce further
protein kinase activity and de novo protein synthesis, all of which have all
been shown necessary for the development of the stimulation-induced spinal
learning deficit (Patton et al., 2004; Baumbauer et al., 2006; Huie et al.,2012a). Well-characterized features are shown in black. Areas of ongoingstudy are shown in red. Adapted from Ferguson et al. (2008a).

AMPA receptor (Ugolini et al., 1997; Xiao et al., 2001). AMPA
receptors are thought to mediate the majority of rapid excitatory neurotransmission in the CNS, and their post-translational
modification can have major effects on synaptic plasticity. For
example, phosphorylation of AMPARs can increase their open
channel time, resulting in enhanced post-synaptic currents and
LTP (Derkach et al., 1999; Lee et al., 2000). In addition rapid trafficking of AMPA receptors to the plasma membrane can have amajor effect on CNS plasticity (Malinow and Malenka, 2002).
In the spinal cord, AMPAR phosphorylation and trafficking tosynapses have been implicated in central sensitization and otherforms of maladaptive plasticity (Galan et al., 2004; Ferguson et al.,2008a; Drdla-Schutting et al., 2012).
Pharmacological evidence has recently linked AMPAR
over-activation to spinal learning deficits after intermittent
nociceptive stimulation. Intrathecal delivery of a general AMPA
receptor antagonist prevents induction of learning deficits byintermittent nociceptive stimulation (Hoy et al., 2012). However,this protective effect can only be observed at 24 h post-drugbecause general AMPAR antagonism reduces performance of thelearned flexion response in the Horridge paradigm. A specificantagonist to AMPA receptors lacking the GluA2 subunit,
however, selectively reverses the spinal learning deficit with nomeasurable side-effect on performance of the flexion response(Huie et al., 2012a). This is particularly relevant from a plasticity
perspective because the GluA2 subunit renders AMPA receptors
impermeable to Ca++ and GluA2-lacking receptors increase
intracellular Ca++ levels which then, in turn, can activate aseries of intracellular changes that can lead to a feedback loopof ever increasing excitatory plasticity and ultimately cellular
dysfunction (Figure 6). Therefore, by engaging GluA2-lacking
AMPARs intermittent nociceptive stimulation may produce
lasting maladaptive plasticity that is characterized by spinal
hyper-activity and reduced capacity for future spinal cordwww.frontiersin.org

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FIGURE 6 | AMPA receptor positive feedback-loop hypothesis forspinal metaplasticity. Spinal AMPARs are hypothesized to rapidly traffic to
the plasma membrane in response to uncontrollable nociceptive
stimulation in the periphery (box). Because GluA2-lacking AMPARs function
as calcium ionophores, their localization to the membrane generates acascade of increased intracellular calcium followed by activation of
intracellular calcium detectors such as PKC that can then produce further
increases in trafficking of AMPARs to the plasma membrane. This feedback
loop (oval) of increasing AMPA receptor numbers may account for theobserved pattern of saturation of spinal learning plasticity, spinal learning
deficits, and nociceptive hyper-responsiveness that is observed after
yoked/uncontrollable stimulation training.

learning. However, the specific mechanisms by which intermittent nociceptive stimulation engages AMPAR receptors remains a
topic of intensive ongoing study.
One prevailing hypothesis is that proinflammatory cytokine
TNFα contributes to maladaptive spinal plasticity mediated by
AMPA receptors. Prior work has shown that the glial TNFαincreases trafficking of GluA2-lacking AMPA receptors to theneuronal plasma membrane, thereby increasing synaptic receptor
levels (Beattie et al., 2002; Stellwagen et al., 2005; Stellwagen andMalenka, 2006; Leonoudakis et al., 2008). A series of studies havelinked TNFα modulation of AMPARs to altered synaptic plasticity
in the cortex (Leonoudakis et al., 2004; Jia et al., 2007), hippocampus (Furukawa and Mattson, 1998; Beattie et al., 2002; Ogoshi
et al., 2005), and spinal cord (Hermann et al., 2001; Ferguson
et al., 2008a). In addition, TNFα induced AMPAR trafficking has
recently been implicated in maladaptive plasticity in pain pathways (Choi et al., 2010). We have recently undertaken a seriesof experiments to test whether TNFα plays a role in maladaptive plasticity in the spinal learning paradigm (Huie et al., 2012a).
Results suggest that glial TNFα does indeed play a critical rolein undermining spinal learning potential (Huie et al., 2012a).
Intrathecal delivery of TNFα was found to be sufficient to inducea spinal learning deficit for at least 24 h. In addition, uncontrollable stimulation produces TNF release in the spinal cord,

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providing a link to stimulation-induced maladaptive plasticity.
The maladaptive effects of uncontrollable stimulation and TNFα
are reversible with glial inhibitors and TNFα sequestering agents,
providing strong evidence that glial TNF plays a central role inmodulation of synaptic mechanisms of spinal cord learning. We
also found that specifically blocking GluA2-lacking AMPARs protected against both the TNF- and stimulation-induced learning
deficits (Vichaya et al., 2009; Huie et al., 2012a). The specificmechanisms of these effects remain a topic of intensive study(Garraway et al., 2012; Stuck et al., 2012). However, several
converging lines of evidence suggest that TNFα may play animportant role in tipping spinal plasticity toward a maladaptive
form that undermines future spinal cord training and promotes
nociception. This crucial role for TNFα in mediating maladaptive spinal plasticity caudal to a complete transection may also
provide insight into the recovery of function after spinal contusion injury. TNF mRNA is significantly increased following spinal
contusion, peaking within hours, but remaining elevated for days
(Wang et al., 1996). Likewise, others have shown that TNF protein signaling at the site of injury may not peak until 2 days after
injury and remain elevated up to one week (Gorio et al., 2005).
Given our findings that increased TNFa expression can undermine adaptive plasticity, it is possible TNFa may also contributeto limiting behavioral recovery after contusion injury by altering
plasticity.
Taken together, these findings provide strong evidence that themaladaptive effect of intermittent stimulation on spinal learning
is a distinct form of plasticity that shares many mechanistic similarities with central sensitization. Ongoing research into thesemolecular mechanisms may have great potential for improving
rehabilitation therapies. The final section explores how the findings from the spinal learning work has been extended to spinal
contusion injury, and how our work on maladaptive spinal plasticity may provide insights toward improved rehabilitation after
injury.

IMPLICATIONS FOR REHABILITATION AFTER SPINAL CORD
INJURYWe have shown how uncontrollable nociceptive stimulation canundermine adaptive spinal modifications below a SCI. Althoughmuch of this work was done in an isolated spinal system, theimplications of these findings on recovery of function after
incomplete SCI are profound. In the present section we will firstshow how our instrumental spinal training paradigm can beapplied to a more general spinal injury model, and then discuss
the broader implications of spinal training as means to overcome
maladaptive plasticity, and promote functional recovery.
Knowing that the spinal cord is capable of exhibiting varying types of spinal plasticity in response to subtle changes instimulation, we reasoned that spinal instrumental training could
provide a window into how these divergent forms of spinal plasticity may dictate functional recovery after SCI. To test the relationship between instrumental training and recovery of function
after SCI we evaluated the long-term effects of acute master/yokedtraining in a T12 contusion model of SCI (Grau et al., 2004).
We delivered two 30 min sessions of master/yoked training to rats
24 and 48 h post-contusion injury and then monitored recovery

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Ferguson et al.

Nociception vs. spinal learningof locomotor function over 42 days using the Basso, Beattie,
Bresnahan (BBB; Basso et al., 1995) locomotor scale with behavioral raters who were blind to instrumental training condition.
Yoked training produced persistent impairments in recovery of
locomotor function (Figure 7A) as well as measures of sensory
and autonomic recovery (Grau et al., 2004). Surprisingly, masterrats did not show significant impairments. The yoked stimulation
effect was further replicated, as just a single 6-min bout of uncontrollable stimulation to the tail, given 1 day post-injury, produced
a deficit in locomotor recovery that was still apparent 6 weeks after
injury (Figure 7B).
Such a finding illustrates just how vulnerable the spinal cord is
to nociceptive input after injury, and how important the spinal
cord is in processing nociceptive signals. This has clear translational relevance to human SCI, given that acute nociceptive
input is a common feature of polytraumatic automobile accidents, the most common etiology of human SCI (Marino et al.,1999). Pain is a prevalent feature in SCI, affecting between 65–
85% of the patient population (Siddall et al., 2003; Siddall, 2009).

Although the mechanisms for neuropathic pain after SCI are notfully understood, the work reviewed in the present paper strongly
suggests that co-morbid peripheral injuries may play a role indictating both functional recovery and nociceptive sensitization.
One of the most clinically difficult forms of pain following SCI involves pain below the injury site. This phenomenon,
known as dysesthetic pain syndrome, may represent an exampleof plasticity within spinal pain systems following SCI (Davidoff
et al., 1987; Yezierski, 1996; Bennett et al., 2000; Hains et al.,
2001; Bruce et al., 2002; Mills et al., 2002; Finnerup et al., 2003;
Andersen et al., 2004; Carlton et al., 2009; Gwak et al., 2009;
Hulsebosch et al., 2009; Leem et al., 2010). It has been argued thatdysesthesia involves dysregulation of descending pain inhibitory
mechanisms that affect spinal nociceptive circuitry. Two observations provide support for this. First, dysesthetic pain syndrome ismost prevalent when there is damage specific to the spinal andmesencephalic trajectories of the ascending pain transmission
pathways (Beric et al., 1988). These pathways are thought to be
involved in activating segmental and descending pain inhibitory

FIGURE 7 | The spinal learning deficit is associated with other forms of
maladaptive plasticity such as impaired recovery of function after SCI. (A)Rats were given 2 days of spinal training in the acute phase after a thoracic
contusive SCI delivered with the NYU/MASCIS impactor (Gruner, 1992).
(B) Varying amounts (in seconds, s) of intermittent stimulation (INT. STIM.) wereadministered to the tail one day following contusive SCI. Data show as little as
6 min (360 s) of intermittent stimulation to the tail is sufficient to undermine
recovery of function. Y-axes represent a 12-point modified version of the Basso,
Beattie, Bresnahan (BBB) locomotor scale, over 3 weeks (A) or 6 weeks (B)(Basso et al., 1995; Ferguson et al., 2004). Modified from Grau et al. (2004).

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Ferguson et al.

mechanisms. In contrast, most studies have shown that complete
injury to the anterolateral ascending pain transmission pathways
does not produce dysesthetic pain (Beric, 1993; Yezierski, 1996;
Finnerup et al., 2003; Wasner and Brock, 2008). Second, thereis evidence that many of the descending fibers damaged by SCI
have a net inhibitory effect in uninjured subjects. Under nonpathological conditions, nociceptive plasticity in the spinal cord istightly controlled by descending modulation from the brain, preventing spontaneous emergence of maladaptive pain syndromes.
Following SCI there is significant alteration of reflexes below thelesion (Hubscher and Johnson, 2000; Grau and Patterson (eds.),
2001). Nociceptive reflexes demonstrate increased excitability
accompanied by a loss of GABAergic inhibition (Zhang et al.,
1994; Yezierski, 1996), as well as loss of descending inhibition
through noradrenergic and serotonergic fibers located in the dorsolateral funiculus (Watkins et al., 1984; Faden et al., 1988; Liuet al., 1990). This increased excitability can be reduced by administration of the GABAB agonist baclofen (Hao et al., 1992) andserotonergic/noradrenergic drugs (Barbeau and Norman, 2003;
Hains et al., 2003).
Interestingly, the expression of spinal LTP is normally inhibited by descending pathways (Sandkuhler and Liu, 1998; Gjerstad
et al., 2001). Using our spinal training paradigm, we showed thatintermittent stimulation given prior to complete transection was
not sufficient to produce a learning deficit, indicating a brainmediated descending protection against the deleterious effects ofintermittent stimulation. Further, we showed the necessity for the
DLF in this effect. We lesioned the DLF at T2, then gave intermittent stimulation followed by a complete transection at T8, andfound that by removing the protection of this descending system,
rats exhibited a spinal learning deficit (Crown and Grau, 2005).
Similarly, as SCI may disrupt these fibers, it is possible that thevulnerability to nociceptive plasticity after injury reflects a lossof descending inhibition (Hains et al., 2002). Thus, spinal injury
may create a predisposition toward the lasting maladaptive effects
of nociceptive input. This notion has even greater clinical impact,when one considers the potential blockade of descending inhibition conferred by surgical anesthesia. To test this, Washburn et al.
(2007) assessed the effect of the anesthetic pentobarbital on thestimulus-induced spinal learning deficit. We first delivered 6 minof intermittent uncontrollable stimulation (AC 60 Hz, 1.5 mA)
to rats that were under pentobarbital anesthesia, 24 h after complete T2 transection. The next day these rats were tested for spinal
instrumental learning. These rats failed to learn, indicating that
pentobarbital anesthesia does not protect against the spinal mechanisms responsible for the induction of the stimulation-induced
learning deficit. We next assessed whether pentobarbital anesthesia could protect against the induction of the learning deficit
if intact rats were given intermittent uncontrollable stimulation
under anesthesia. Intact rats were given an injection of either
pentobarbital or saline vehicle, followed by 6 min of uncontrollable intermittent stimulation to the tail and the next day all rats
were given a complete transection, followed 24 h later with spinal
instrumental testing. Rats that were not under anesthesia during the intermittent uncontrollable stimulation (saline-treated),
did not exhibit a learning deficit, replicating the earlier finding from Crown and Grau (2005) that descending supraspinal
input provides protection against the stimulation-induced deficit.
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Interestingly, those rats that were under pentobarbital anesthesia
during the intermittent uncontrollable stimulation did exhibit alearning deficit when later tested, indicating that the descending
protection was undermined by anesthesia, leaving the spinal cordsusceptible to the induction of maladaptive nociceptive plasticity.
These findings highlight how important it is to be cognizant of
the capacity of the spinal cord for nociceptive plasticity, particularly when supraspinal controls are removed under anesthesia.
The pain memory that can be formed during surgical procedures
could contribute to the development of neuropathic pain, and in
the instance of SCI, could undermine functional recovery.
From our studies detailing the varying stimulation parameters that produce divergent effects on adaptive and maladaptive
forms of spinal plasticity, it is clear that the timing and controllability of stimulation are very important predictors of recovery offunction. Harnessing the specific capacity for spinal cord learning may improve rehabilitative training of limb position after SCI.
The neurobiological basis of training-induced plasticity within
the spinal cord has been studied in some detail. For example,
following chronic complete SCI there is an increase in glycinergic (de Leon et al., 1999; Cantoria et al., 2012) and GABAergic
inhibitory tone (Edgerton et al., 2001; Tillakaratne et al., 2002)
that has been shown to hinder locomotor performance. Systemic
administration of the glycinergic antagonist strychnine improves
locomotion in untrained animals, whereas animals with previous step training do not require strychnine (de Leon et al., 1999).
Moreover, strychnine does not yield further improvement beyond
step-training alone, suggesting that spinal training has the capacity to modulate inhibitory neurotransmitter levels in the spinal
cord. However, the type of training used has a profound influence on glycinergic tone. If animals are re-trained to stand after
treadmill step training, there is a reemergence of glycinergic inhibition, resulting in poor treadmill performance that was reversible
by strychnine.
Indeed the locomotor physiology literature has produced substantial evidence that following complete transection the spinal
cord can be trained to elicit stepping (for review see Edgerton
et al., 1997). For example, Lovely et al. (1990) found that treadmill
training can improve stepping in spinally transected cats. A similar improvement can be quantified through the use of kinematics
and electromyography (EMG) in rats and mice, and consistentdifferences have been observed between untrained and trained
animals in a variety of different contexts (Drew and Rossignol,
1987; Roy et al., 1998; Courtine et al., 2009; van den Brand
et al., 2012). Importantly, motor training after SCI has beenshown to be exquisitely task-specific; training on one task caninterfere with training on other tasks (Garcia-Alias et al., 2009;de Leon et al., 2011). Collaborative work has revealed that ratsthat are trained to stand on a treadmill have impaired instrumental learning (Bigbee et al., 2007). Interestingly, stand trainingis also known to interfere with locomotor training after SCI (deLeon et al., 1999), suggesting that instrumental training in the
Horridge paradigm may be able to predict locomotor recovery.
These findings illustrate how critical it is to control the types of
input that are received after SCI. A study from Petruska et al.
(2007) highlighted this importance. They trained transected rats
to walk on a treadmill, and found that this training regimen
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The existing literature indicates many similarities between central sensitization within spinal pain pathways and stimulusinduced deficits in spinal learning after SCI. Taken together
the findings indicate that central nociceptive sensitization andadaptive spinal learning are opposing forms of spinal plasticity (Figure 8). Adaptive training of the spinal cord undermines
the development of central sensitization, and conversely central
nociceptive stimulation undermines the capacity for spinal
learning.

While studies of spinal cord plasticity after SCI have uncovereda remarkable degree of plasticity, it must also be remembered that
this plasticity is a two-edged sword; adaptive processes can foster
recovery and reduce neuropathic pain while maladaptive mechanisms have the opposite effect. This review has aimed to bringto light the ongoing struggle between nociceptive and adaptive
forms of spinal plasticity after injury. We have shown that certain
peripheral stimuli limit adaptive spinal learning and may actuallypromote maladaptive forms of spinal plasticity. This maladaptive
plasticity may include hyperexcitability of spinal nociceptive systems, leading to pain and spasticity. Maladaptive spinal plasticity
may ultimately lead to intractable pain in SCI, a common problem for SCI patients (for review see Yezierski, 1996, 2000, 2009;
Bruce et al., 2002; Weaver et al., 2002; Finnerup and Jensen, 2004;
Crown and Grau, 2005; Crown et al., 2006, 2008; Finnerup et al.,2007).
The present paper has focused on the negative side of spinal
plasticity: the mechanisms by which inappropriate spinal training(uncontrollable electrical stimulation) and persistent nociceptive
stimuli can impair spinal cord learning. In the companion paperin this issue Grau et al. (2012) discuss the positive side to spinal
training: the mechanisms by which specific types of spinal cord
training can protect against the development of nociceptive plasticity and may promote spinal adaptation and recovery of function after SCI. An effective rehabilitation strategy will integrate
the messages from both papers to maximize positive elementsof spinal cord training while limiting the negative consequencesof inappropriate stimulus timing and nociceptive input below
the injury. Ongoing work is focused on determining the specific

FIGURE 8 | Theoretical framework for understanding the relationshipbetween adaptive and maladaptive spinal cord plasticity. After spinal
cord injury peripheral stimulation can take a controllable form such as
instrumental training or step training that promotes adaptive plasticity andleads to further improvements in spinal learning and recovery of function. On

the other hand peripheral stimulation delivered in an uncontrollable form suchas random (position-independent) stimulation or peripheral inflammation
produces a maladaptive spinal plasticity that promotes central sensitizationand deficits in future spinal cord learning. Modified from Ferguson et al.
(2006).

trained animals. Interestingly, a subset of rats was found to havelesions on their hindpaws and the beneficial effects of training
were markedly diminished in these rats. This finding suggests thatthe noxious input that these animals were receiving may havebeen undermining their capacity for adaptive locomotor plasticity. Further, recent research indicates that even manipulations thatare considered relatively passive or innocuous may be inducing
unintended maladaptive plasticity, and doing untold damage torecovery of function. Studies in the human patient populationof the efficacy of relatively passive rehabilitative efforts after SCI(including stretching to increase range of motion) have revealed
that these interventions may have few beneficial effects on locomotor recovery (Harvey et al., 2002, 2009). It has been shownin rodents that peripheral input such as leg immobilization in awheelchair model, muscle stretching, or repeated tactile stimulation produce lasting changes in spinal circuitry that can impair
recovery (Hutchinson et al., 2004; Hoschouer et al., 2010; Caudle
et al., 2011).

SUMMARY

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Nociception vs. spinal learning

conditions that limit maladaptive plasticity, while promoting
adaptive spinal plasticity. This work will be critical in order totailor rehabilitative and restorative therapies toward maximizing
recovery of function after SCI.

ACKNOWLEDGMENTS
The authors wish to thank Jacqueline C. Bresnahan, PhD,
Michael S. Beattie, PhD, Vincent Degos, MD PhD, Ernesto

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A. Salegio, PhD, Jessica L. Nielson, PhD, Ellen D. Stuck,
Aiwen Liu, and Cristian Guandique for comments on an earlier version of this article. The work in this article was supported by grants from the National Institute of Neurological
Disorders and Stroke (NS063597 and NS067092 to Adam R.
Ferguson; NS041548 to James W. Grau) and the National Instituteof Child Health and Development (HD058412 to James W.
Grau).

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Conflict of Interest Statement: Dr.
Crown is currently employed by Abbott
Laboratories. The current research is
not affiliated with his current duties at
Abbott Laboratories. The other authors
declare that the research was conductedin the absence of any commercial or
financial relationships that could beconstrued as a potential conflict ofinterest.
Received: 26 June 2012; accepted: 20
September 2012; published online: 10
October 2012.
Citation: Ferguson AR, Huie JR, Crown
ED, Baumbauer KM, Hook MA,
Garraway SM, Lee KH, Hoy KC and
Grau JW (2012) Maladaptive spinal
plasticity opposes spinal learning andrecovery in spinal cord injury. Front.
Physio. 3:399. doi: 10.3389/fphys.
2012.00399
This article was submitted to Frontiersin Integrative Physiology, a specialty of
Frontiers in Physiology.
Copyright © 2012 Ferguson, Huie,
Crown, Baumbauer, Hook, Garraway,
Lee, Hoy and Grau. This is an openaccess article distributed under the termsof the Creative Commons Attribution
License, which permits use, distribution
and reproduction in other forums, provided the original authors and source
are credited and subject to any copyright notices concerning any third-party
graphics etc.

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