The challenges of respiratory motor system recovery following cervical spinal cord injury.

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The challenges of respiratory motor system recovery following cervical spinal cord injury

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Philippa M. Warren, Warren J. Alilain1 Department of Neurosciences, MetroHealth Medical Center, Case Western Reserve University School of Medicine, Cleveland, OH, USA 1 Corresponding author: Tel.: +01-216-778-8966; Fax: +01-216-778-8720, e-mail address: [email protected]

Abstract High cervical spinal cord injury (SCI) typically results in partial paralysis of the diaphragm due to intrusion of descending inspiratory drive at the level of the phrenic nucleus. The degree to which such paralysis occurs depends on the type, force, level, and extent of trauma produced. While endogenous recovery and plasticity may occur, the resulting respiratory complications can lead to morbidity and death. However, it has been shown that through modification of intrinsic motor neuron properties, or altering the environment localized at the site of SCI, functional recovery and plasticity of the respiratory motor system can be facilitated. The present review emphasizes these factors and correlates it to the treatment of SCI at the level of the somatic nervous system. Despite these promising therapies, functional respiratory motor system recovery following cervical SCI is often minimal. This review thus focuses on possible directions for the field, with emphasis on combinatorial treatment.

Keywords spinal cord injury, respiratory motor system, channelrhodopsin-2, chondroitinase

Abbreviations 5-HT A2A AIH BBB

serotonin adenosine 2A acute intermittent hypoxia blood-brain barrier

Progress in Brain Research, Volume 212, ISSN 0079-6123, http://dx.doi.org/10.1016/B978-0-444-63488-7.00010-0 © 2014 Elsevier B.V. All rights reserved.

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CHAPTER 10 The challenges of respiratory motor system recovery

BDNF cAMP C# ChABC ChR2 CIH CNP CNS CPP CSPG CST dAIH ECM EMG EPO ERK1/2 GABA GAG GDNF IH NADPH NGF NMDA NSCISC NT OEC PKA PKC pLTF PMF PMNs PNG PNS PSA PTEN rAIH Rho rVRG Sema SCI TrkB VEGF VRG a b g

brain-derived neurotrophic factor cyclic adenosine monophosphate cervical level of injury chondroitinase ABC channelrhodopsin-2 chronic intermittent hypoxia cyclic nucleotide phosphodiesterase central nervous system crossed phrenic pathway chondroitin sulfate proteoglycan corticospinal tract daily acute intermittent hypoxia extracellular matrix electromyography erythropoietin extracellular regulated kinases 1 and 2 g-aminobutyric acid glycosaminoglycan glial-derived neurotrophic factor intermittent hypoxia nicotinamide adenine dinucleotide phosphate nerve growth factor N-methyl-D-aspartic acid National Spinal Cord Injury and Statistics Center neurotrophin olfactory ensheathing cell protein kinase A protein kinase C phrenic long-term facilitation phrenic motor facilitation phrenic motor neurons peripheral nerve graft peripheral nervous system polysialic acid phosphatase and tensin homolog repetitive AIH Ras homolog gene family rostral VRG semaphorin spinal cord injury tropomyosin-related kinase B vascular endothelial growth factor ventral respiratory group alpha beta gamma

1 Cervical spinal cord injury and the deficit in respiratory motor function

1 CERVICAL SPINAL CORD INJURY AND THE DEFICIT IN RESPIRATORY MOTOR FUNCTION High cervical spinal cord injury (SCI) has both sensory and motor effects within the central nervous system (CNS). The consequences of such insult are largely described and studied in terms of the devastating consequences caused to voluntary movement and the somatic nervous system. However, it is well established that cervical SCI has annihilating effects upon other systems (clinically described by Nandoe Tewarie et al., 2010). Of particular significance are injuries that involve disruption to respiratory motor function. Indeed, despite meaningful advances, the life expectancy of ventilator-dependent SCI patients is substantially less than the uninjured population (NSCISC, 2012), with common causes of death including pneumonia and septicemia. More than half of all SCIs occur at the cervical level (NSCISC, 2012) and prominently feature the loss of inspiration. This is largely caused by disruption of the motor circuitry to the diaphragm, although injury additionally prevents innervation to the intercostal and abdominal muscles. Autonomic control of broncho-pulmonary functions is lost following cervical SCI resulting in abnormal secretions and airway hypersensitivity (Fein et al., 1998; Grimm et al., 2000; Singas et al., 1999). Spontaneous recovery has been reported within the respiratory motor system (Bluechardt et al., 1992; Linn et al., 2001; Loveridge et al., 1992; Oo et al., 1999), indicative of plasticity. However, this endogenous effect is often suboptimal and highly variable. It most likely represents an attempt to maintain or restore blood-gas homeostasis following SCI by means of an increase in respiratory drive. Compromised breathing, even in unventilated individuals, can make a SCI patient increasingly susceptible to pneumonia and atelectasis. Due to these complications, the search to find treatments and strategies to functionally improve respiratory motor activity following cervical SCIs are of great importance. In the present review, we first establish the organization of the respiratory motor system. We then describe how breathing has been experimentally modeled, the intrinsic and extrinsic mechanisms that drive respiratory motor function following SCI, and the treatment strategies that have been applied to enhance this activity. Discussion relates these findings back to spinal cord development and injury to alternative motor systems, highlighting universal themes for increasing functional recovery and regeneration. We define “functional” recovery as the restoration, compensation, or use of alternative/novel motor circuits to perform a task controlled through the respiratory motor system. Finally, we assess the use of combination treatment strategies to facilitate respiratory motor function following high cervical SCI, emphasizing the need for strategy development, the potential to incorporate currently unexamined treatment stratagems within the respiratory motor system, and the possibility of assessing multiple outcome measures.

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2 ORGANIZATION OF THE RESPIRATORY MOTOR CIRCUITRY AND THE CROSSED PHRENIC PHENOMENON The diaphragm is the major muscle used for inspiration. It is innovated by the phrenic nerve which originates at C3–C5 (cervical level 3–5) within the spinal cord. Patients with injuries at or above this level lose the ability to spontaneously breathe. The circuitry that controls the movement of the diaphragm during breathing was elucidated through electrophysiological and neuronal tracing studies in rodent and feline models (Ballanyi et al., 1999; Boulenguez et al., 2007; Dobbins and Feldman, 1994; Ellenberger and Feldman, 1988; Greer et al., 2006; Lipski et al., 1993, 1994; Onai et al., 1987; Tian and Duffin, 1996; Yamada et al., 1988). These models share significant homology with the primate respiratory motor system. This evolutionary conservation means that animal models of the respiratory motor system can provide meaningful data regarding the human response to SCI and treatment (Holstege et al., 1988). The inspiratory premotor neurons that project down through the phrenic nucleus to the diaphragm originate within the ventral respiratory group (VRG; Fig. 1A). Located in the ventral lateral medulla, the neurons of the supraspinal centers, in particular, the pre-Bo¨tzinger complex, control the frequency and rhythm of respiration (Gray et al., 2001; Onimaru and Homma, 2003; Tan et al., 2008). These neurons are connected to the propriobulbar and premotor neurons of the VRG in the ventral lateral medulla (Chitravanshi and Sapru, 1996; Dobbins and Feldman, 1994; Moreno et al., 1992; Onai et al., 1987). The bulbospinal projections from the left and right VRG descend through the lateral and ventromedial funiculi of the cervical spinal cord to innervate the phrenic nucleus (Fig. 1A; Boulenguez et al., 2007; Dobbins and Feldman, 1994; Ellenberger and Feldman, 1988; Juvin and Morin, 2005; Lipski et al., 1994; Yamada et al., 1988). Some bulbospinal projections cross the midline in the medulla (Fig. 1A). In both primates and rodents, bulbospinal neurons from the most rostral part of the VRG (rVRG) facilitate the glutamatergic inspiratory drive, while those from the caudal end facilitate expiration (Bianchi et al., 1995). The phrenic motor neurons (PMNs) of the phrenic nucleus are located in the ventral horn between C3 and C6 (Fig. 1A; Goshgarian and Rafols, 1984; Routal and Pal, 1999). Inputs to the intact PMNs can be glutamatergic, GABAergic (g-aminobutyric acid), serotonergic or from norepinephrine neurons (Chitravanshi and Sapru, 1996; Liu et al., 1990; McCrimmon et al., 1989). However, PMN activity is principally controlled by excitatory glutamatergic projections from the rVRG in both rodent and primate models (Chitravanshi and Sapru, 1996; Howard et al., 1992; Nathan et al., 1996; Vinit et al., 2007). Similarly, PMNs are innervated by cervical spinal cord interneurons located bilaterally between the brain and spinal cord (Fig. 1A; Juvin and Morin, 2005; Lane et al., 2008; Lipski et al., 1993, 1994; Lu et al., 2004a). These interneurons do not mediate respiratory motor system drive in the uninjured spinal cord, as occurs in the CST (corticospinal tract; Gauthier et al., 2006; Rossignol et al., 2008; Vinit et al., 2006). A number of the bulbospinal projections from the rVRG to the PMNs cross the midline at the level of the phrenic nucleus (C3–C6; Fig. 1A; Vinit et al., 2007). These

FIGURE 1 Schematic of the cervical spinal cord respiratory network before and after C2 hemisection. (A) Basic anatomy of the intact respiratory motor system detailing the bilateral connections from the rostral ventral respiratory group (rVRG, glutamatergic; blue; dark grey in print version) and caudal raphe nucleus (serotonergic; yellow; light gray in print version) to those of the phrenic nucleus (PN; red (medium grey in print version)). Dissociations of these pathways occur in the medulla and spinal cord, the latter comprising the crossed phrenic pathway (CPP), which is retained from development but latent in the adult. Interneurons (green; light grey in print version) are disbursed through the system creating polysynaptic connections. (B) Following subacute C2 hemisection, connections to the ipsilateral phrenic nucleus and hemidiaphragm are broken causing paralysis. Further to this, axons dieback forming dystrophic end bulbs, a glial scar develops, and the cells of the immune system invade. (C) However, with an appropriate stimulus generate drive, the latent CPP may be activated by-passing the site of injury and facilitating activity through the phrenic nucleus to generate activity in the hemidiaphragm ipsilateral to the hemisection. Stimulus may be varied; the schematic shows the transection phrenic nerve contralateral phrenic to the C2 hemisection and stimulates ipsilateral hemidiaphragm activity. This is known as the crossed phrenic phenomenon.

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spinal decussating pathways do not typically drive PMNs but can be activated under conditions of stress (Lewis and Brookheart, 1951). The classic example of this effect involves hemisection of the C2 bulbospinal pathways, causing paralysis of the ipsilateral hemidiaphragm (Fig. 1C). When followed by transection of the contralateral phrenic nerve below C6, the originally paralyzed hemidiaphragm becomes active, while the hemidiaphragm ipsilateral to the phrenicotomy is inactivated (Chatfield and Mead, 1948; Goshgarian, 1981; O’Hara and Goshgarian, 1991; Porter, 1895; Seligman and Davis, 1941). This is termed the “crossed phrenic phenomenon” as it involves activation of the crossed phrenic pathway (CPP; defined as the decussating tract and postsynaptic target; Fig. 1A). This injury archetype has been extensively used to model recovery of breathing following cervical SCI. Of course, the diaphragm is not the only musculature involved in breathing. The respiratory intercostals and abdominal muscles are innervated within the thoracolumbar region of the spinal cord at T1–T11 and T7–L2, respectively. Similar to the diaphragm, autonomic premotor neurons projecting from the rVRG modulate the activity of these muscles through innovation of motor neuron pools. However, while the inputs to the phrenic nucleus are primarily monosynaptic (Ellenberger and Feldman, 1988; Tian and Duffin, 1996, 1998; Tian et al., 1998), evidence suggests that activation of the intercostals is polysynaptic and relies upon spinal interneurons (Davies et al., 1985; Kirkwood, 1995; Merrill and Lipski, 1987). The occurrence of these interneurons may act to modulate intercostal activity or drive independent of the phrenic nerve (Davies et al., 1985; Qin et al., 2002). Due to the organization of these respiratory motor pathways, patients with incomplete C3–C5 or lower C6–C8 injuries may have the ability to breathe spontaneously. However, vital capacity is reduced and respiration impaired due to paralysis of the external and parasternal intercostals, scalene, and abdominal musculature.

3 MODELING RESPIRATORY MOTOR FUNCTION FOLLOWING CERVICAL SPINAL CORD INJURY 3.1 CERVICAL SPINAL CORD INJURY SCI is a heterogeneous condition where pathological changes can be broadly defined by location, severity, and the length of time following injury (Fig. 1B; Young and Koreh, 1986). Briefly, the acute injury is typified by the immediate affect of the mechanical trauma. The result is direct damage, loss of the blood-brain barrier (BBB), ischemia, edema, and electrolytic changes (Sandler and Tator, 1976; Young and Koreh, 1986). These effects cause excitotoxicity and cellular necrosis within the gray and then white matter during the first 24 h after injury. Glial cells migrate to the site of SCI and are involved in beneficial phagocytosis of neuronal debris, conservation of the remaining tissue, and proinflammatory responses (Bouhy et al., 2006; Davalos et al., 2005; Ha et al., 2005; Rapalino et al., 1998). However, several days following SCI a process of secondary cell loss occurs due to Wallerian degeneration (Guth et al., 1999) and apoptotic mechanisms in

3 Modeling respiratory motor function following cervical spinal cord injury

oligodendrocytes, oligodendrocyte precursor cells, astrocytes, microglia, and neurons. This is caused by ionic disruption, the expression of free radicals, and inflammatory cytokines. The post-acute/chronic stage of injury typically starts days following the initial insult and persists over time. The acute affects described initiate inflammatory and cytotoxic events that cause the formation of fluid filled cysts (Poon et al., 2007), demyelination (Totoiu and Keirstead, 2005), deposition of myelin debris (Buss et al., 2004), and axonal loss (Bjartmar et al., 2001). In addition, glial cells are activated and form a protective barrier around the injury site by reactive gliosis. This is primarily composed of chondroitin sulfate proteoglycans (CSPGs) and is known as the “glial scar” (McKeon et al., 1999; Tang et al., 2003). Acutely, this scar limits damage and preserves function within the damaged cord ( Jones et al., 2003; reviewed in Rolls et al., 2009). However, in the chronic stages of SCI, the glial scar acts as both a physical (Windle et al., 1952) and chemical (Snow and Letourneau, 1992) barrier to endogenous growth and regeneration (Windle et al., 1952). Similarly, the immune cells of the CNS, microglia, and macrophages, are activated following SCI, and have been shown to promote regeneration through the secretion of neurotrophic factors (Bessis et al., 2007; Coull et al., 2005). However, microglia are also associated with an increase in neuropathic pain (Coull et al., 2005; Hulsebosch, 2008) and thus have detrimental effects, particularly in chronic SCI.

3.2 ACUTE MODELS OF CERVICAL SCI AND THE EFFECT UPON THE RESPIRATORY MOTOR SYSTEM Rat models are widely employed to study the effect of SCI on breathing with the activation of the CPP being the classic paradigm (Goshgarian, 1981; Goshgarian et al., 1991; O’Hara and Goshgarian, 1991; Porter, 1895). The mechanism behind the crossed phrenic phenomenon is an increase in respiratory drive due to the asphyxia caused by the contralateral phrenicotomy following complete ipsilateral hemisection (Fig. 1C; Goshgarian and Guth, 1977). Of course, the aim of most studies is to induce an increase in respiratory drive that activates the CPP without performing the contralateral phrenicotomy. For this reason, complete high cervical hemisection is used as an acute model to assess functional recovery within the respiratory motor system following injury (Fig. 1B). This lesion causes ipsilateral hemidiaphragm paralysis, but the animal survives as breathing is maintained through intact pathways to the contralateral phrenic nucleus (Decherchi and Gauthier, 2002). Inspiratory volume is diminished and frequency of breathing enhanced, following this lesion (Fuller et al., 2006). However, minute ventilation in rodents is unaffected (Fuller et al., 2006) and is only apparent upon variation in levels of carbon dioxide (Fuller et al., 2008). Of course, the cervical hemisection additionally affects locomotor and sensory systems. It is suggested that an incomplete lesion may transiently produce the same effect as a complete hemisection while saving other motor systems (Goshgarian, 1981; Vinit et al., 2007). However, such injuries spare bulbospinal axons innervating the phrenic nucleus resulting in more favorable

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respiratory outcomes (Fuller et al., 2009; Lipski et al., 1994; Schucht et al., 2002; Vinit et al., 2006). Nonetheless, such studies clearly demonstrate how spared pathways may contribute to post-lesion plasticity. The CPP can activate spontaneously following acute SCI in the absence of respiratory drive resulting in partial restoration of PMN activity (Fuller et al., 2008; Golder and Mitchell, 2005; Vinit et al., 2007). However, similar to locomotor and sensory motor systems, assessment of hemidiaphragm electromyography (EMG) activity shows spontaneous recovery within the phrenic nucleus to be modest (Alilain and Goshgarian, 2008; Fuller et al., 2008; Mantilla et al., 2007; Miyata et al., 1995; Nantwi et al., 1999) despite the improvement in neuromuscular transmission (Mantilla et al., 2007; Prakash et al., 1999). Nonetheless, the potential for endogenous recovery is certainly present and the reasons why it fails to be functionally significant has yet to be fully understood.

3.3 CONTUSION AND CHRONIC MODELS OF CERVICAL SCI AND THE AFFECT UPON THE RESPIRATORY MOTOR SYSTEM Despite the wealth of information generated through the acute and chronic C2 hemisection injury model regarding the respiratory motor system, the translational relevance of these data can be questioned when one considers that analogous lacerations are rare in humans (NSCISC, 2012). For this reason, the effects of the more sever C2–C5 lateral or midline cervical contusion has been assessed (Fig. 2A). They yield a complementary system to the lateral C2 hemisection model; however, hold increased clinical relevance. These reproducible injuries do not require long-term post-injury ventilation for survival but cause PMN loss and degeneration, depressed diaphragm EMG recordings, reduced phrenic nerve activity, impaired response to respiratory challenge, and limited endogenous recovery (Awad et al., 2013; Baussart et al., 2006; Choi et al., 2005; El-Bohy et al., 1998; Lane et al., 2012; Nicaise et al., 2012). Golder et al. (2011) have recently shown that recovery of breathing patterns following contusion is, in part, dependent upon mechanisms of endogenous plasticity (Golder et al., 2011). Further to this, Lane et al. (2012) used a bilateral C3/C4 contusion model to show that damage to gray matter after injury could chronically impair hemidiaphragm activity under conditions of respiratory stress while ventilation remains constant. These data are suggestive of plasticity and remodeling within the contused animal (Alilain et al., 2008; Hayashi et al., 2003; White et al., 2010). Most recently, Awad et al. (2013) have developed a dual injury contusion model to certify the robustness of the respiratory motor deficit. Their moderate 150 kD C3 contusion causes extensive damage to white and gray matter. Nonetheless, the injured or spared bulbospinal fibers following trauma enable partial ipsilateral hemidiaphragmatic activity to be retained as is shown in other contusion models. However, Awad et al. (2013) combine the contusion injury with the elimination of modulatory decussating inputs from the non-injured side through a contralateral C2 hemisection, revealing the highly weakened state of the contused pathways at acute and chronic time points (Fig. 2B). The authors suggest that this

FIGURE 2 Schematic of the cervical spinal cord respiratory network after lateral C3 contusion. (A) Following lateral C3 contusion, connections to the ipsilateral phrenic nucleus and hemidiaphragm are weakened or injured causing reduced activity in the diaphragm. The functional deficit of this injury is not readily shown in many contusion models. A glial scar develops and the cells of the immune system invade. (B) The C3 contusion model produced by Awad et al. (2013). This model combines the initial injury with a delayed contralateral C2 hemisection to reveal the full extent of the functional deficit caused by the contusion injury. The application of treatment strategies for SCI may be applied between the initial contusion and the deferred contralateral C2 hemisection.

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new model of injury may enable further examination of the degree to which any SCI treatment strategy directs affects the pathways damaged in the initial injury. As such, this model holds substantial clinical relevance as it can highlight functional recovery within these pathways following treatment. The effect of SCI upon the respiratory motor system must also be assessed chronically to facilitate clinical applicability. Similar to human studies (Oo et al., 1999), rodent models of high cervical injury have shown an increase in ipsilateral PMN activity at chronic time points following injury (Fuller et al., 2006; Golder and Mitchell, 2005; Nantwi et al., 1999; Vinit et al., 2006, 2008). Whether this results in a functional improvement to diaphragmatic function is variable (Alilain and Goshgarian, 2008; Goshgarian, 1981; Nantwi et al., 1999; Polentes et al., 2004). The CPP can still activate in a chronic injury model (Vinit et al., 2006, 2008) although it is possible that endogenous functional recovery at these time points can be a result of CPP remodeling (Vinit et al., 2008) and is likely reinforced by the sparing of ventromedial tissue (Darlot et al., 2012; Minor et al., 2006). This has been shown to occur within the CST (Fouad et al., 2001; Ghosh et al., 2010) and may suggest that the mechanisms to respiratory motor system recovery in a chronic model are divergent from that of an acute injury.

3.4 ENDOGENOUS RESPIRATORY MOTOR SYSTEM RECOVERY FOLLOWING SUBACUTE/CHRONIC CERVICAL SPINAL CORD INJURY Endogenous remodeling and activation of the CPP following subacute/chronic C2 hemisection produces a modest return of function (Fuller et al., 2008; Nantwi et al., 1999; Pitts, 1940) but may hold significant implications for treatment strategies. This return of function correlates with synaptic and receptor changes around the PMNs and involves receptor and synaptic plasticity. For example, there is an increase in presynaptic serotonin (5-HT) terminals and their corresponding receptors, including 5-HT2A around PMNs ipsilateral to the C2 hemisection (Fuller et al., 2005; Golder and Mitchell, 2005; Tai et al., 1997). This endogenous response facilitates induction of the crossed phrenic phenomenon, which is dependent on 5-HT (Hadley et al., 1999a,b). In fact, infusion of 5-HT receptor agonists is sufficient to promote functional recovery of respiratory motor function (Choi et al., 2005; Ling et al., 1994; Zhou and Goshgarian, 1999, 2000; Zhou et al., 2001; Zimmer and Goshgarian, 2006). Alilain and Goshgarian (2008) demonstrated that spontaneous activity within the PMNs is correlated with an increase in the 2A subunit of the NMDA (N-methyl-D-aspartic acid) receptor and a decrease in the AMPA (2-amino-3-(3hydroxy-5-methyl-isoxazol-4-yl)propanoic acid) glutamate receptor 1 subunit on motor neurons. These studies are important because, while 5-HT may modulate respiratory motor output, glutamate is an excitatory neurotransmitter that causes the neuron to fire (Chitravanshi and Sapru, 1996). Additionally, GABAergic signaling has been shown to decrease at chronic stages of cervical SCI by reducing inhibition ( James and Nantwi, 2006; Zimmer and Goshgarian, 2007). These spontaneous changes in the 5-HT, glutamatergic and GABAergic systems following SCI indicate an endogenous mechanism to facilitate respiratory motor system recovery.

4 Intrinsic factors

The interneuron population present at the site of the phrenic nucleus may confer some additional support to endogenous recovery following SCI, although evidence to this effect is limited. Following acute C2 hemisection, Lane et al. (2008) have shown the number of interneurons at the level of the PMNs is unaltered from uninjured controls, although motor neuron numbers significantly decrease. It is suggested that these interneurons integrate with phrenic circuits on opposite sides of the cord and facilitate synchronized activity after injury (Alilain et al., 2008; Lane et al., 2008; Sandhu et al., 2009). Indeed, an increase in the number of interneurons at C2 post hemisection suggest a pool of recruited cells positioned to mediate an increase in drive contralateral to the site of injury and may facilitate intercostal or abdominal motor circuits (Fig. 1B; Lipski et al., 1994). However, in the chronic setting, both interneuron and motor neuron numbers are diminished. This suggests that these cells alone are insufficient to facilitate robust endogenous recovery. Indeed more information is required to establish the role of the interneuron population in respiratory recovery following cervical SCI.

3.5 THE LIMITATIONS OF SPINAL CORD INJURY MODELS Functional recovery following SCI is typically deemed the most clinically relevant outcome measure when assessing the efficacy of a treatment strategy. However, such measures are difficult to assess due to the high variability inherent within CNS injuries. This variability cannot be extinguished even when they are mechanically produced through the same processes. One reason for this is that the hormone, blood sugar, and hydration levels of each animal vary when surgery is performed as well as vascularity at the site of injury and level of anesthesia (Gruner, 1992; Kwo et al., 1989). Furthermore, animal behavior following injury may be altered depending on their circadian rhythm and the time of year (Dauchy et al., 2010; O’Bryant et al., 2011). Additionally, different strains of rodents are known to demonstrate wide differences in motor control (Webb et al., 2003), indeed the sex of rodent has been shown to have variation on respiratory motor activity following cervical SCI (Doperalski et al., 2008). Further, long-lasting increase in respiratory motor drive (see Section 4.2) is effected by the rodents age, gender, and substrain (Fuller et al., 2001a; Zabka et al., 1985, 2001). These variations inherent within models of SCI mean that the anatomical and functional assessment of the effect and treatment of any trauma is potentially problematic and must be considered when assessing the outcome of any one study.

4 INTRINSIC FACTORS CONTROLLING RESPIRATORY MOTOR RECOVERY FOLLOWING CERVICAL SCI 4.1 ADENOSINE A1 AND CAMP Levels of adenosine within the neonatal CNS are characteristically high due to fetal ischemic or hypoxic conditions (Rudolphi et al., 1992; Winn et al., 1981a,b). Adenosine acts as a neuroprotectant causing dilation of blood vessels in the

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CNS when flow is compromised (Phillis et al., 1985), a decrease in neurotransmitter release (Fredholm and Hedquist, 1980), and reduced oxygen consumption (Gross et al., 1976; Raberger et al., 1970). However, high levels of adenosine decrease neonatal respiration, an effect that may be counteracted though A1 receptor-mediated antagonism (reviewed in Herlenius and Lagercrantz, 2004). Similar effects occur to respiratory motor function following treatment of C2 hemisection with adenosine antagonism (Fig. 3A). Through administration of the methylxanthine theophylline, nonspecific antagonism of central and peripheral adenosine A1 receptors partially restored function to the paralyzed hemidiaphragm. This was caused by increased respiratory drive (Nantwi, 2009; Nantwi and Goshgarian, 1998; Nantwi et al., 1996). Further to this, Nantwi et al. (2003) demonstrated that chronic theophylline treatment could amplify respiratory motor function beyond the period of drug administration. This illustrates the pharmaceutical-induced plasticity of the respiratory motor circuitry. High levels of adenosine may be required in the acute phases of cervical SCI to act as a neuroprotectant when blood flow may be compromised. However, the antagonism of receptor-mediated transmission within subacute and chronic phases may generate the drive to increase functional respiratory motor activity. Alternatively, theophylline use could increase respiratory drive through the inhibition of cyclic nucleotide phosphodiesterase (CNP), which causes an increase in cyclic adenosine monophosphate (cAMP) independent of A1 receptor antagonism (Fig. 3A). cAMP is known to be a key intracellular signaling molecule and elevated amounts have facilitated axonal regeneration in numerous injury models (Cai et al., 1999; Chierzi et al., 2005; Lu et al., 2004b, 2012; Qiu et al., 2002a,b) including the increase in plasticity and functional recovery of the respiratory motor system (Kajana and Goshgarian, 2008a,b). This effect is likely caused by enhancing growth factor receptor translocation (Meyer-Franke et al., 1998). Alternatively, it may be mediated through activation of protein kinase A (PKA) and the cAMP response elementbinding protein (CREB) transcription factor (Gao et al., 2004; Sands and Palmer, 2008) which arbitrates the neurogenic effects of neurotrophic factors (Gao et al., 2003).

4.2 GQ PROTEIN SIGNALING CASCADES: INTERMITTENT HYPOXIA, 5-HT2, AND PHRENIC LTF Originally described by Millhorn et al. (1980a,b), the induction of phrenic long-term facilitation (pLTF) is the long-lasting increase in respiratory motor drive. This phenomenon is typically observed as an increase in nerve burst amplitude that similarly effects inspiratory motor output (Bocchiaro and Feldman, 2004; Fuller et al., 2001a,b, 2002) and is elicited by repeated carotid sinus nerve stimulation or intermittent hypoxia (IH; Hayashi et al., 1993). pLTF is hypothesized to facilitate plasticity following cervical SCI. The most studied paradigm of IH is acute intermittent hypoxia (AIH), which describes 5-min exposure to the hypoxic environment, repeated three to five times (Hayashi et al., 1993). Interestingly, Golder and

FIGURE 3 Current models of intrinsic pathways to facilitate phrenic motor activity and drive. (A) Adenosine A1 and cAMP (red; dark gray in print version). Theophylline acts to inhibit adenosine A1 activity and/or increase intracellular concentrations of cAMP via the inhibition of CNP. These processes may act to increase PMN drive. The latter pathway acts through an increase in growth factor translocation or through the activation of protein kinase A (PKA) and the cAMP response element-binding protein (CREB) transcription factor. (B) Intermittent hypoxia, 5-HT2 and phrenic longterm facilitation (pLTF; green (gray in print version)). Induced through intermittent hypoxia, Gq-coupled metabotropic receptors 5-HT2, or a1 are activated, stimulating the activity of protein kinase C (PKC) which causes BDNF synthesis and NADPH oxidase (NOX) activity. The release of BDNF activates TrkB and, subsequently, the ERK kinase (pERK). The pathway is regulated through the action of NOX-dependent reactive oxygen species and protein phosphatases (PP2/5). (C) Adenosine and 5-HT7 (blue; light gray in print version). Following stimulation of Gs-coupled metabotropic receptors 5-HT7 and A2A, PKA is activated and induces the synthesis of immature TrkB. The TrkB dimerizes, autophosphorylates and signals via Akt activation. The figure also demonstrates how downstream of intermittent hypoxia PTEN may be inhibited leading to the increase in mTOR which may act intrinsic to the neuron to facilitate plasticity and regeneration. Parts of schematic modified from Dale et al. (2014).

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Mitchell (2005) demonstrated that a program of AIH in the chronically injured (4–8 weeks) C2 hemisected animal could produce a functionally relevant increase in respiratory drive to aid recovery. This indicated that, if harnessed, AIH treatment could be effective regardless of time post-injury. Of course, there are many other protocols used to induce pLTF through IH including chronic IH (CIH; IH for 5–10 min intervals lasting 4 days to 4 weeks; Fletcher et al., 1992; Gozal et al., 2001), daily AIH (dAIH; 10 AIH episodes lasting 7 days; Lovett-Barr et al., 2012; Wilkerson and Mitchell, 2009), repetitive AIH (rAIH; AIH repeated over days to weeks; Golan et al., 2009), repeated AIH (10 AIH episodes 3 days a week for 4–10 weeks; Satriotomo et al., 2012), and sustained hypoxic exposure (Powell et al., 1998). These protocols produce contrasting effects, although they operate in a mechanistically similar fashion. 5-HT receptor activation is required for the induction of pLTF (Fig. 3B; Millhorn et al., 1980a,b). Exposure to IH activates the serotonergic medullary raphe neurons causing the release of 5-HT at the level of the phrenic nucleus and subsequent activation of Gq protein-coupled 5-HT receptor subtypes (Erickson and Millhorn, 1994). Specifically, Kinkead and Mitchell (1999) identified the 5-HT2A/B/C receptor activation is necessary for pLTF initiation (MacFarlane et al., 2011). MacFarlane and Mitchell (2008, 2009) showed that 5-HT receptor activation was sufficient to cause long-lasting facilitation in the motor output of the phrenic nerve (phrenic motor facilitation; PMF) using periodic intraspinal injections of the neurotransmitter and 5-HT receptor agonists without AIH. However, 5-HT receptor activation is not required to maintain the response in either acute or chronic models (Fuller et al., 2001a,b, 2002). As the CPP shows an increase in 5-HT2A receptor activation following C2 hemisection in subchronic animals (Fuller et al., 2003), an effect exacerbated following CIH (Fuller et al., 2005), the pathway is believed to be activated following the increase in drive caused by pLTF. Baker-Herman and Mitchell (2002) demonstrated that the intermittent activation of 5-HT receptors causes protein synthesis required for pLTF through the activation of PKC (protein kinase C). Of particular note is the synthesis of brain-derived neurotrophic factor (BDNF; Fig. 3B; Baker-Herman et al., 2004). The subsequent activation of tropomyosin-related kinase B (TrkB; the high-affinity receptor for BDNF) has been shown both necessary and sufficient for induction of pLTF (Baker-Herman et al., 2004). The significance of BDNF and TrkB has recently been confirmed in the chronic C2 hemisected model using immunohistochemistry following dAIH (LovettBarr et al., 2012). However, while the exogenous application of BDNF can produce PMF, it has a short half-life and poor BBB penetration (Poduslo and Curran, 1996), limiting its use as a treatment for SCI. Kishino and Nakayama (2003) and Wilkerson and Mitchell (2009) have respectively shown that BDNF increases extracellular regulated kinases 1 and 2 (ERK1/2) phosphorylation in PMNs. This suggests that these kinases are involved downstream of TrkB (Fig. 3B). The events which occur downstream of ERK are less clear. NMDA receptor antagonism is known to prevent pLTF in the anesthetized and

4 Intrinsic factors

unanesthetized animal (McGuire et al., 2005, 2008). Further to this, Slack et al. (2004) demonstrated that BDNF modulates the phosphorylation of the NR1 subunit on NMDA receptors though the ERK pathway. This suggests that glutamate receptor phosphorylation, or membrane insertion, may account for NMDA-mediated induction and maintenance of pLTF in the phrenic nucleus (Fig. 3B; Bocchiaro and Feldman, 2004). pLTF is regulated by serine/threonine protein phosphatases PP2A and PP5 (Wilkerson et al., 2008); which are, in turn, regulated by the formation of reactive oxygen species by NADPH (nicotinamide adenine dinucleotide phosphate) oxidase activity (Abramov et al., 2007; MacFarlane et al., 2008, 2009; Wilkerson et al., 2008). Wilkerson et al. (2007) and MacFarlane et al. (2008) suggest that this regulatory mechanism facilitates sensitivity of pLTF expression (Fig. 3B). However, MacFarlane et al. (2011) have recently shown that NADPH oxidase inhibitors block PMF only when induced through 5-HT2B not 5-HT2A receptors. These findings suggest that the multiple receptors capable of eliciting this activity may have distinct pathways through which they are regulated. The insight these studies give into the mechanism through which IH induces respiratory drive is, perhaps, not surprising when the development of the respiratory motor system is considered. During critical periods of CNS development 5-HT levels increase to affect neuronal proliferation, differentiation, migration, and synaptogenesis (reviewed in Lauder, 1993; Levitt et al., 1997; Lipton and Kater, 1989) although knocking out receptors and genes does not cause marked alteration in brain histology (Gaspar et al., 2003). Further to this, the effect of neurotrophins (including nerve growth factor (NGF), BDNF, neurotrophin-3 (NT-3) and NT-4), and their corresponding Trk receptors, has been extensively studied during development (Erickson et al., 1996; Funakoshi et al., 1993; Griesbeck et al., 1995; Ip et al., 2001). BDNF and NT-3 are known to be present in large neurons, like PMNs, in the ventral cervical spinal cord during development ( Johnson et al., 2000). In the adult, CNS neurons may continue to express neurotrophic receptors, a fact which is exploited following SCI. Altered expression of neurotrophic factors has been shown within multiple models of SCI. NGF, BDNF, NT-3, and glialderived neurotrophic factor (GDNF) are known to promote axon regeneration or sprouting postinjury (Blesch and Tuszynski, 2003; Grill et al., 1997; Jin et al., 2002; Liu et al., 1999), while an endogenous or exogenous increase in NT concentration at the site of injury significantly enhances regeneration within both the peripheral and CNSs (Blesch and Tuszynski, 2003; Kobayashi et al., 1997; Park and Hong, 2006; Schnell et al., 1994). BDNF specifically has been shown to facilitate the regeneration of raphe, reticilospinal, rubrospinal, and vestibulospinal neurons following lateral hemisection ( Jin et al., 2002; Liu et al., 1999). The use of trophic factors to support axon growth following SCI increases the likelihood that the micro-environment at the site of injury will be permissible for functional recovery. The fact that IH endogenously produces these effects to enhance spinal plasticity, and specifically respiratory motor function, highlights the importance of this treatment strategy.

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4.3 GS PROTEIN SIGNALING CASCADE: ADENOSINE AND 5-HT7 The model described for pLTF induced by IH requires activation of spinal Gq protein-coupled 5-HT2 receptors and the synthesis of BDNF to activate TrkB (Baker-Herman et al., 2004; Fuller et al., 2001a,b, 2002). However, Golder et al. (2008) and Hoffman and Mitchell (2011) report a BDNF-independent mechanism to achieve PMF without the need for IH (Fig. 3C). Activation of either Gs protein-coupled adenosine 2A (A2A) or 5-HT7 receptors induces the synthesis of immature TrkB receptors that autodimerize and autophosphorylate. Once activated, intracellular TrkB (Golder et al., 2008) signals via PI3 kinase, which increases the phosphorylation of protein kinase B or Akt, and is believed to mediate the effects of PMF (Fig. 3C; Chao, 2003; Golder et al., 2008). This pathway is thus independent of BDNF and ERK signaling. The ability to initiate PMF without the use of IH could be useful in the clinical setting where patients’ respiratory motor output is often impaired. However, A2A receptor activation has been shown to cause neural and cardiovascular morbidity (Minghetti et al., 2007; Mojsilovic-Petrovic et al., 2006; Pedata et al., 2001). 5-HT7 receptor antagonism may be the only means of clinically mediating this response. The relationship between the two G-coupled protein-mediated methods to induce PMF is interesting. Hoffman and Mitchell (2011) demonstrated that inhibition of ERK delayed, but did not block, 5-HT7-induced PMF. Similarly, Hoffman et al. (2007) describe that the application of A2A receptor antagonists following AIH increased pLTF. Satriotomo et al. (2012) have recently described that rAIH showed upregulation of molecules known to be involved in PMN plasticity including both phosphorylated ERK and phosphorylated Akt. These data suggest that both the G protein-signaling cascades described are initiated following AIH, but each mutually inhibit the other. The growth/trophic factors vascular endothelial growth factor (VEGF) and spinal erythropoietin (EPO) have both been shown to induce PMF through an ERK- and Akt-dependent mechanism (Dale et al., 2012; Dale-Nagle et al., 2011) and are known to be hypoxia sensitive (Liu et al., 1995; Stohlman, 1959). However, Dale and Mitchell (2013) have recently shown that PMF induced by injection of these growth factors into the spinal cord is not amplified following rAIH pre-conditioning. The implications of this study are intriguing as they imply that the functional changes evoked by VEGF and EPO are independent of hypoxia despite the latter causing similar plastic changes at the level of the phrenic nucleus (Dale et al., 2012; Dale-Nagle et al., 2011; Satriotomo et al., 2012). CNS axon regeneration is known to involve multifaceted signaling mechanisms that are typically upregulated following injury including the kinases ERK (Atwal et al., 2000; Liu and Snider, 2001) and Akt (Atwal et al., 2000; Chierzi et al., 2005; Gallo and Letourneau, 1998; Markus et al., 2002). Through further understanding of these pathways, treatment strategies to enhance PMF may be elucidated to aid functional respiratory motor activity following cervical SCI. However, modulation in the expression of 5-HT, BDNF, and adenosine might not be the only mechanism through which IH treatment can facilitate functional recovery of the respiratory motor system following cervical SCI. Gutierrez et al. (2013) have

5 Extrinsic factors

recently shown that following acute C2 hemisection, PMNs show decreased expression of PTEN (phosphatase and tensin homolog) and increased levels of mTOR (mammalian target of rapamycin) and S6 (Fig. 3B). Recent studies inhibiting PTEN in the CNS have demonstrated significant regeneration in the spinal cord and visual system (Kwon et al., 2006; Liu et al., 2010; Park et al., 2008). While in need of further examination and the mechanism of action fully elucidated, these data suggest that IH may mediate functional regeneration and plasticity following SCI through a multitude of mechanisms.

4.4 OPTOGENETICS Perhaps the most impressive mechanism though which functional recovery of the respiratory motor system occurs is the use of optogenetics. Neuronal depolarization and action potentials can be specifically stimulated and controlled using photostimulation of the light-sensitive cation channel channelrhodopsin-2 (ChR2; Zheng et al., 2007), following its expression in motor neurons. Such a tool is advantageous following SCI, where neuronal loss and denervation is extensive. For example, following C2 hemisection Alilain et al. (2008) were able to achieve near complete restoration of respiratory motor activity using photostimulation of ChR2 expressed in motor neurons, interneurons and spinal glial cells at the level of the PMNs under a CMV promoter (Fig. 4A). Significantly, this activity was retained in absence of stimulation (lasting for at least 24 h) and was synchronized to the endogenous activity of the hemidiaphragm contralateral to the hemisection and not light stimulation. Use of the NMDA receptor antagonist MK-801 abolished this activity. These data indicate both the importance of NMDA receptors to the activity of the respiratory motor system after injury and increasing sensitivity of motor neurons and interneurons to weak, but spared tracts. Nonetheless, while the use of optogenetics can provide substantial functional results and illustrate the mechanism of motor system recovery, direct translation of this technique to the clinic would be challenging. While modern surgical techniques could facilitate a minimally invasive method to introduce a potential light source within the human spinal cord, the viral methods currently employed to express ChR2 within motor neurons would need substantial modification before clinical trial. For example, it would be necessary to determine the length of time ChR2 is expressed and the specific cell type within which this occurs. However, this technique remains a valuable tool for the study of respiratory motor function following cervical SCI.

5 EXTRINSIC FACTORS CONTROLLING RESPIRATORY MOTOR RECOVERY FOLLOWING CERVICAL SCI 5.1 INFLAMMATION In response to SCI, both macrophages and microglia are activated each producing both neuroprotective and proinflammatory effects likely to be caused by cells of distinct lineages (Kigerl et al., 2009). Augmenting macrophage and microglia activation

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FIGURE 4 Intrinsic and extrinsic modification of the cervical spinal cord following C2 hemisection (see Fig. 1) to facilitate the functional regeneration of the respiratory motor system. (A) Infection of cells at the site of the phrenic motor nucleus with ChR2 can, following light stimulation, case neuronal depolarization/action potentials that will transiently enable activity of the paralyzed hemidiaphragm. The cells mediating such activity are possibly spared motor neurons, such as the CPP, or more likely interneurons. (B) Implantation of a peripheral nerve graft (PNG) facilitates the growth of regenerating neurons which can by-pass the site of injury and form functional synapses with spared tissue at the phrenic nucleus enabling activity of the paralyzed hemidiaphragm. (C) Application of exogenous chondroitinase ABC (ChABC) breaks down major components of the glial scar to facilitate the endogenous growth of neurons through the site of injury. The enzyme additionally promotes neuroprotection, plasticity, and reduces the size of the lesion cavity. This restores minimal activity to the paralyzed hemidiaphragm although whether this is through regenerated fibers or spared tissue is unknown.

5 Extrinsic factors

has been shown to enhance axon regeneration (Schwartz et al., 1999). This occurs through enhanced phagocytosis, the production of cytokines and growth factors, remyelination, angiogenesis, oligodendrogenesis, prevention of excitotoxicity, and secretion of NTs (Kerschensteiner et al., 1999; Li et al., 2005). Such responses are likely produced by M2 macrophages, although this has not been proven in SCI models (Kigerl et al., 2009). Conversely, preclinical models of SCI have shown that blocking the actions of macrophage and microglia facilitates functional recovery by preventing axonal dieback and the death of neurons and oligodendrocytes (Blight, 1994; Kaushal et al., 2007; Lopez-Vales et al., 2005; Popovich et al., 1999; Stirling et al., 2004; Wong et al., 2010). Additionally, inhibition of integrins that mediate the immune response following injury have been shown to facilitate neuroprotection and functional recovery (Fleming et al., 2008, 2009; Gris et al., 2004), although aspects of these studies have been hard to replicate (Hurtado et al., 2012). Macrophage of the M1 lineage are believed to produce this neurotoxic effect causing the retraction of axons, secretion of inhibitory CSPGs, and the breakdown of growth promoting ECM (extracellular matrix) substrates, such as laminin (Busch et al., 2009; Horn et al., 2008; Martinez et al., 2006). The effect of the activated immune system upon the functional recovery of the respiratory motor system following cervical SCI has only recently been assessed. In a preliminary study, Windelborn and Mitchell (2012) have shown, following incomplete C2 hemisection, microglia and astrocytes are activated in the phrenic nucleus caudal to the site of injury, peaking at 3 days postlesion but remaining 28 days following injury. Activation of these cells is retained up to 180 days following SCI in alternative areas of the cord (Gwak et al., 2012). This suggests that these glial cells facilitate in the recovery or deficit of the respiratory PMNs following SCI. Indeed the importance of glia to the correct functioning of the respiratory system has been widely reported (Gourine et al., 2010; Huckstepp et al., 2010; Parsons and Hirasawa, 2010; Shimizu et al., 2007; Young et al., 2000). Adding to this hypothesis is the recent work conducted by Vinit et al. (2011) demonstrating that the initiation of inflammation through a single injection of lipopolysaccharide can prevent the induction of pLTF. Whether this response is mediated by activated microglia is not yet determined (Huxtable et al., 2011). However, such effects have been exhibited elsewhere in the CNS (Bessis et al., 2007; Hennigan et al., 2007).

5.2 GRAFTING TISSUE Unlike the CNS, the peripheral nervous system (PNS) exhibits an exceptional facility for regeneration following injury. PNS cells mediating growth have historically been prime targets for transplantation into the injured CNS to facilitate functional regeneration (David and Aguayo, 1981; Richardson et al., 1980). One of the most successful uses of peripheral nerve grafts (PNGs) to achieve functional recovery of axonal pathways has been demonstrated in the respiratory motor system (Fig. 4B; Gauthier and Rasminsky, 1988). Using a model where the proximal end of a peritoneal nerve was placed in close proximity to the rVRG or into the funiculi of the descending

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respiratory tracts, Gauthier and colleagues were able to demonstrate growth of respiratory bulbospinal axons into the graft (Decherchi et al., 1996; Gauthier and Lammari-Barreault, 1992; Gauthier and Rasminsky, 1988; Lammari-Barreault et al., 1991). Specifically, respiratory-related axons within the graft showed spontaneous, respiratory-related activity (Gauthier and Rasminsky, 1988; LammariBarreault et al., 1994). This was only maintained in chronic animals if a functional reconnection with an appropriate target could be established. Further studies included implantation of the PNGs distal end at the level of the phrenic nucleus following C3 hemisection (Decherchi and Gauthier, 2002; Gauthier et al., 2002). These data demonstrated the success of PNGs at acute/subacute time points indicating that regenerated axons from central respiratory neurons can remain in graft tissue for 3 weeks and make functional connections with a denervated target. However, PNGs have minimal impact on the restoration of phrenic nerve activity following SCI (Gauthier et al., 2002). This result is typical of bridge-graft studies where anatomical repair does not reflect functional regeneration. This is likely caused by poor entry of the growing axon from graft tissue into the host spinal cord due to the inhibitory nature of the glial scar. A multitude of literature demonstrates that high concentrations of either endogenous or synthetic CSPGs at cellular interfaces create a barrier to axon regeneration (Petersen et al., 1996; Pindzola et al., 1993; Plant et al., 2001; Snow et al., 1990, 2002). While acutely this scar tissue preserves function, chronically it negatively regulates the outgrowth of regenerating axons whether from graft tissue or endogenous plasticity (McKeon et al., 1995; Snow et al., 1990, 2002). Due to the presence of this scar tissue, the use of PNS grafts following cervical SCI, may be functionally limited.

5.3 REDUCTION OF THE GLIAL SCAR The neuroprotective glial scar, in chronic injuries, has been shown to inhibit the regeneration and plasticity of the CNS. Part of this inhibition can be attributed to the ephrins and semaphorin 2A (Sema2A) released from the cells of the spinal cord following injury (De Winter et al., 2002). Sema3A is constitutively expressed on motor neurons and, through repellant signaling, acts to guide descending supraspinal and reflex pathways from sensory afferents expressing the Sema receptor (Gavazzi et al., 2000; Giger et al., 1998). A series of recent experiments have demonstrated that inhibition or suppression of Sema3A facilitates neuronal growth (Castellani et al., 2004; Minor et al., 2011). However, this may not be sufficient to cause functional regeneration (Mire et al., 2008) perhaps indicating that other factors in the scar, for example, CSPGs, are more significant mediators of inhibition. It has been demonstrated both in vitro (Dou and Levine, 1994; Fidler et al., 1999; Smith-Thomas et al., 1994, 1995; Snow et al, 1990; Tom et al., 2004) and in vivo (Borisoff et al., 2003; Davies et al., 1997, 1999; Dou and Levine, 1994; Friedlander et al., 1994; Snow et al., 1990; Tang et al., 2003) that CSPGs limit axon growth and regeneration, and that these molecules are intensely upregulated following SCI (Iaci et al., 2007; Jones et al., 2003; Tang et al., 2003). During development,

5 Extrinsic factors

the occurrence of CSPGs within the ECM coincides with a cessation of developmental plasticity (Pizzorusso et al., 2002, 2006). The major inhibitory component of CSPGs are the individual disaccharide moieties present on the glycosaminoglycan (GAG) chains (Rolls et al., 2004). Several methods have been employed to inhibit or reduce the expression of CSPGs following injury (Laabs et al., 2007; Larsen et al., 2003; Lemke et al., 2010; Nigro et al., 2009; Schwartz et al., 1974). An important example of which is the use of chondroitinase ABC (ChABC; Bradbury et al., 2002; Campbell et al., 1990). ChABC is a bacterial enzyme isolated from Proteus vulgaris (Yamagata et al., 1968) that acts to cleave GAG polymers into their component tetrasaccharides and disaccharides preventing matrix–glycoprotein interactions (Huang et al., 2000, 2003; Prabhakar et al., 2005; Yamagata et al., 1968). Over the last decade, ChABC application has been used to stimulate the growth of axons due to the breakdown of CSPGs both in vitro (Asher et al., 2002; McKeon et al., 1991, 1995; Nakamae et al., 2009; Rudge and Silver, 1990; Vahidi et al., 2008; Zou et al., 1998) and in vivo (Barritt et al., 2006; Bradbury et al., 2002; Cafferty et al., 2008; Garcia-Alias et al., 2009; Houle et al., 2006; Jefferson et al., 2011; Lemons et al., 1999; Moon et al., 2001; Tom et al., 2009a). A wealth of evidence has shown that the mode and mechanism though which ChABC operates causes axonal regeneration, plasticity, and neuroprotection (Barritt et al., 2006; Bradbury et al., 2002; Cafferty et al., 2007; Carter et al., 2008; Massey et al., 2006). Recently, Alilain et al. (2011) have demonstrated the presence of the CSPG composed glia scar at the level of the phrenic nucleus following C2 hemisection (Fig. 4C). ChABC treatment increased 5-HT fibers about the PMNs indicative of functional respiratory plasticity. However, while ChABC alone-treated animals may have demonstrated an increase in functional recovery quicker than controls, the ultimate result was insubstantial as inspiratory bursts did not exceed 10–20% of the peak amplitude displayed by controls at 12 weeks postinjury (Alilain et al., 2011). The reason ChABC failed to induce a significant functional effect in this instance could be due to the quantity and time frame of enzyme administration. Our laboratory is currently pursuing the assessment of optimized ChABC treatment within the respiratory motor system following acute and chronic cervical SCI. Further, the advent of virally delivered or thermostabilized chondroitinase could solve these issues (Curinga et al., 2007; Jin et al., 2011; Lee et al., 2010; Muir et al., 2010; Zhao et al., 2011). Nevertheless, the efficacy and safety of these modified enzymes has not yet been established. Further, it is known that the effects of ChABC on longdistance axon regeneration are relatively modest (Bradbury et al., 2002; Cafferty et al., 2007; Iseda et al., 2008; Shields et al., 2008). The main functional consequence of using the enzyme is the increase in sprouting and plasticity. Indeed, two recent studies in divergent models of the CNS have shown that the neuronal plasticity induced by ChABC application does not uniformly result in functional recovery (Harris et al., 2010; Vorobyov et al., 2013). Alilain and colleagues (2011) sought to overcome the lack of functional recovery in the ipsilateral hemidiaphragm following ChABC treatment by combining it with a

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PNG. The removal of CSPGs about the bridge graft enhanced the entry and exit of axons from host tissue while facilitating axonal sprouting. The use of ChABC upregulated the expression of 5-HT and retrograde labeling showed a small proportion of the neurons that projected through the graft were from the raphe nuclei and rVRG. Interestingly, the use of ChABC with the PNG caused the alignment of glial fibrillary acidic protein positive astrocytes to the regenerating axons. At 12 weeks post-injury, it was the combined treatment group that showed the maximal return of functional diaphragmatic muscle activity with both peak inspiratory amplitude and phrenic nerve activity of the lesioned side often surpassing controls. Significantly, transection of the graft caused the transient increase in EMG of the ipsilateral hemidiaphragm and suggested that this treatment combination was able to significantly rewire the cervical spinal cord leading to functional restoration of respiratory motor activity. The combined use of PNGs and ChABC has been used previously to establish functional regeneration of the locomotor system following acute and chronic SCI. The degradation of CSPGs in the lesion and graft (Lemons et al., 1999) allows axons to grow through graft tissue and form functional synaptic connections (Houle et al., 2006; Tom and Houle, 2008; Tom et al., 2009b, 2013). Similar data have been achieved by combining ChABC with grafts of Schwann or neural stem/progenitor cells (Chau et al., 2004; Fouad et al., 2005, 2009; Karimi-Abdolrezaee et al., 2010; Vavrek et al., 2007).

6 FUTURE DIRECTIONS: INTEGRATION OF TREATMENT STRATEGIES AND OUTCOME MEASURES 6.1 INTEGRATION OF TREATMENT STRATEGIES The success of the Alilain et al. (2011) study has shown that a combinatorial approach to treating respiratory function after SCI is a promising method to achieve maximal functional recovery. Recent experiments in the treatment of locomotor function using some of the therapeutic strategies known to have functional effects for the recovery of the respiratory motor system lend support to this idea. For example, Bai et al. (2010) combined the use of ChABC and the b2-adrenoceptor agonist, clenbuterol, to increase cAMP levels following a chronic thoracic transection of the spinal cord. Only with the combined treatment was significant anatomical and partial functional recovery observed. Similarly, Tropea et al. (2003) described how combined BDNF and ChABC treatment worked synergistically to promote plasticity, regeneration, and synaptogenesis of retinal afferents in a model of acute partial retinal lesion. The combination of BDNF with an olfactory ensheathing cell (OEC) graft following subacute C5/6 over-hemisection showed significant anatomical regeneration and substantial functional recovery of skilled motor function (Iarikov et al., 2007; Lynskey et al., 2006). However, it is important to cast the correct treatment combination spatially and temporally post-injury. Bretzner et al. (2008, 2010) have shown that the combination of an OEC bridge graft and increase in cAMP (through the application of the phosphodiesterase inhibitor rolipram) but not BDNF,

6 Future directions

was able to promote anatomical and functional plasticity of rubrospinal axons, reduce lesion size, and attenuate thermal sensitivity following cervical crush. Lu et al. (2012) have recently described the application of cAMP and BDNF following either partial midcervical or complete upper thoracic spinal cord transections. The combined treatment generated significant axon regeneration and synaptogenesis beyond both the C5 hemisection and the T3 transection. However, both locomotor function and spasticity worsened. These data highlight the need not only for an optimized treatment combination but also additional control in shaping the process of axonal regeneration. This idea was emphasized through the work of Garcia-Alias et al. (2009). Following acute dorsal column injury, the combination of ChABC with task-specific physical rehabilitation enhanced functional recovery of forepaw motor function further than either treatment strategy alone or ChABC combined with a nonspecific rehabilitation program (Garcia-Alias et al., 2009). These data suggest, following SCI, driving plasticity through specific rehabilitation to form functional neuronal connections can enhance the benefit attained. These data were furthered by Wang et al. (2011) whom showed similar effects following a chronic crush injury model, highlighting the clinical applicability of this strategy. Furthermore, Weishaupt et al. (2013) used a C3/4 dorsal quadrant spinal lesion to demonstrate that viral administration of BDNF combined with task-specific rehabilitation provides a beneficial synergistic effect on functional recovery of forepaw motor function than either strategy alone. Significantly, the anatomical regeneration of the corticospinal and rubrospinal tracts was not different between treatment groups. This indicates that, following cervical SCI, rehabilitation directs the plasticity induced by specific treatment strategies into a functional rather than maladaptive response, shaping the outcome of recovery (Ferguson et al., 2012). The functional use of rehabilitation following SCI is not unusual. It has long been known that locomotor training enhances messenger ribonucleic acid and protein expression of neuronal growth and plasticity factors including BDNF, NT-3, fibroblast growth factor-2, and insulin-like growth factor (Hutchinson et al., 2004; Ying et al., 2005). In particular, the level of BDNF and its receptor TrkB are specifically regulated in subpopulations of motor neurons following SCI rehabilitation and may modulate the efficacy of synaptic functions (Gomez-Pinilla et al., 2002; Macias et al., 2007, 2009; Skup et al., 2002; Ying et al., 2005, 2008). Exercise has also been shown to restore levels of glycine and GAD-67, a synthetic enzyme for GABA, to postinjury levels facilitating neuronal functioning (Edgerton et al., 2001; Khristy et al., 2009; Tillakaratne et al., 2000). However, locomotor training post-SCI acts to increase plasticity, but is not sufficient to mediate gross structural reorganization (De Leon and Acosta, 2006; De Leon et al., 2002; Dietz et al., 1994; Leblond et al., 2003; Petruska et al., 2007). It is the combination of task-specific rehabilitation and the induction of neural plasticity that mediates these effects. In the case of respiratory motor function following cervical SCI, such rehabilitation could take the form of IH or the use of ChR2 transfection in the C4 ventral horn with light stimulation. Both treatment strategies induce functional effects upon respiratory motor function in their own right and are known to specifically drive respiratory activity. However, this

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effect could be amplified if neural plasticity was further induced through the application of ChABC, cAMP, or neurotrophic factors. Such strategies may result in a rapid or higher level of functional recovery than that previously demonstrated and are currently being pursued in our laboratory.

6.2 ASSESSMENT OF TREATMENT STRATEGIES CURRENTLY OVERLOOKED IN THE RESPIRATORY MOTOR SYSTEM MODEL There exists a significant body of research into the intrinsic and extrinsic mechanisms that can facilitate functional respiratory motor system recovery following cervical SCI. However, a number of other highly successful treatment strategies have been identified in alternative injury models that have yet to be assessed within the respiratory motor system. For example, the transmembrane Eph receptors (EphA3, EphA4, EphA6, EphA8, and EphB3) and ephrins (ephrin-B2) are upregulated in astrocytes, oligodendrocytes, motor neurons, and meningeal fibroblasts following SCI (Bundesen et al., 2003; Goldshmit et al., 2004; Miranda et al., 1999; Willson et al., 2002, 2003) some of which have been shown to facilitate regeneration failure (Fabes et al., 2007). The down-regulation of these receptors has been shown to promote functional recovery by mediating inflammation and facilitating neuronal extension (Benson et al., 2005; Goldshmit et al., 2004). A similar intrinsic factor, specific integrin receptors have been implicated in facilitating axonal regeneration. For example, a7-deficient animals exhibit impaired axon regeneration (Ekstro¨m et al., 2003), while lentivirus-mediated overexpression of a9 facilitated axonal regeneration in vivo (Andrews et al., 2009). Similarly, inhibition of RhoA (Ras homolog gene family A), or its downstream effector Rho-associated kinase, have generated significant neuronal regeneration following CNS injury (Dergham et al., 2002; Lehmann et al., 1999). This treatment has exhibited promising results during initial clinical trial (Fehlings et al., 2011). Additionally, it has recently been shown that taxol (the clinically approved anticancer drug Paclitaxel) can facilitate axon regeneration and neurite outgrowth in the adult spinal cord and visual system through the stabilization of microtubules (Erturk et al., 2007; Hellal et al., 2011; Sengottuvel et al., 2011). Our laboratory is currently pursuing the assessment of taxol within the respiratory motor system following cervical SCI. In terms of extrinsic factors not currently assessed within the respiratory motor system, myelin-derived molecules express a multitude of inhibitory factors including NogoA (Caroni and Schwab, 1988, 1989), myelin-associated glycoprotein (McKerracher et al., 1994; Mukhopadhyay et al., 1994), and oligodendrocyte– myelin glycoprotein (Kottis et al., 2002). Through the use of antibodies, knockout models, and enzyme-related inhibition to NogoA (Brosamle et al., 2000; Caroni and Schwab, 1988; GrandPre et al., 2002; Schnell and Schwab, 1990) long-distance functional regeneration and plasticity of motor neurons following SCI has been achieved (Fouad et al., 2004; Freund et al., 2007; Maier et al., 2009; Schnell and Schwab, 1990). The proven efficacy of anti-NogoA antibody treatment in nonhuman primate models of SCI (Fouad et al., 2004; Freund et al., 2006, 2007) have lead to

7 Concluding remarks

Phase 1 clinical trials as an acute treatment for human SCI patients (Abel et al., 2011). Alternatively, application of molecules such as polysialic acid (PSA) could aid functional regeneration of the injured respiratory motor system. PSA is a cell-surface glycan added to glycoproteins during post-translational modification (Rutishauser, 2008) which, when attached to the cellular surface, prevents adhesion due to the large hydrated volume (Rutishauser, 2008). Following injury, axonal growth occurs in close proximity to astrocytes expressing PSA (Dusart et al., 1999), possibly facilitating regeneration by shielding axons from inhibitory cues. Expression of the molecule, or mimetic peptides, in vivo facilitates functional regeneration (El Maarouf et al., 2006; Marino et al., 2009; Zhang et al., 2007). None of these factors alone have caused complete functional regeneration of the somatic motor system following injury. However, neglecting to assess them in the context of the respiratory motor system is imprudent as it represents a significant gap in our understanding and knowledge base.

6.3 ASSESSMENT OF MULTIPLE OUTCOME MEASURES Throughout the course of this review, it has been demonstrated how the advent of cervical SCI has multiple affects including impairing both the respiratory and locomotor systems. However, the strategies employed to treat this injury have universal effects on all systems. These often involve the induction of plasticity, neuroprotection, axonal growth, stimulation of drive, and the construction of a permissive environment in which functional regeneration can occur. Trumbower et al. (2012) described the use of 15 episodes of dAIH in a cohort of 13 patients with chronic, incomplete SCI that caused a functional increase in voluntary ankle movement. Further, Hayes et al. (2014) used a similar protocol of dAIH on a cohort of 19 patients with chronic, incomplete SCI to show that combining this treatment with rehabilitation could increase the speed and endurance of overground walking. LovettBarr et al. (2012) described the use of dAIH following chronic C2 hemisection in a rodent model of SCI to facilitate plasticity and functional recovery of the respiratory motor system. However, without somatic motor rehabilitation, the authors additionally report a functional improvement in forelimb motor function and seemed to be related to the anatomical increase in BDNF and TrkB generated within the relevant motor neurons. While further research is required, collectively, these studies suggest that the treatment strategy applied following cervical SCI may be effective at improving function in multiple motor systems simultaneously. Subsequently, when combined, our current methods of repairing the spinal cord following injury may be more effective then we imagine.

7 CONCLUDING REMARKS Complete functional recovery of the respiratory motor system following cervical SCI is, at present, unattainable. Attempts to enhance endogenous functional activity involve modifying the pharmaceutical profile of the spinal cord, stimulating or

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enhancing endogenous activity, and transforming the microenvironment of the injury site. It is clear that both intrinsic and extrinsic factors play significant roles in the function of the respiratory motor system. Through manipulation of these systems, recovery and plasticity can be achieved. However, these accomplishments are incomplete as functional restoration of activity seldom approaches that demonstrated before injury. Further to this, the models we use to assess treatment outcomes are often disparate from that observed clinically being acute lesions and not the more relevant and severe chronic contusion. Nonetheless, the advent of new models and investigations of combinatorial treatment strategies provides expectation for the achievement of functional activity which mirrors that of the uninjured animal. Additionally, we must learn and remember that cervical SCI is not a series of individually damaged motor and sensory systems but as a holistic, coordinated scheme.

ACKNOWLEDGMENTS This work was supported by funding to W. J. A. from the International Spinal Research Trust in the UK, the Craig H. Neilsen Foundation, and the MetroHealth Medical Center in Cleveland, Ohio, USA. We thank Drs. B. Awad, D. Gutierrez, and K. Hoy for their constructive comments. The authors also acknowledge Drs. Gert Holstege, Mathias Dutschmann, and Hari Subramanian, the organizers of the XIIth Oxford Conference on “Breathing, Emotion, and Evolution,” and Dr. Gordon Mitchell, the Chair of the Spinal Cord Mechanisms session, for their kind invitation and oversight.

REFERENCES Abel, R., Baron, H.-C., Casha, S., Harms, J., Hurlbert, J., Kucher, K., Maier, D., Thietje, R., Weidner, N., Curt, A., 2011. Therapeutic anti-Nogo-A antibodies in acute spinal cord injury: safety and pharmacokinetic data from an ongoing first-in-human trial. In: The International Spinal Cord Society (ISCoS) (Ed.), International Conference on Spinal Cord Medicine and Rehabilitation, Washington, D.C., USA, p. 16. Abramov, A.Y., Scorziello, A., Duchen, M.R., 2007. Three distinct mechanisms generate oxygen free radicals in neurons and contribute to cell death during anoxia and reoxygenation. J. Neurosci. 27, 1129–1138. Alilain, W.J., Goshgarian, H.G., 2008. Glutamate receptor plasticity and activity regulated cytoskeletal associated protein regulation in the phrenic motor nucleus may mediate spontaneous recovery of the hemidiaphragm following chronic cervical spinal cord injury. Exp. Neurol. 212, 348–357. Alilain, W.J., Li, X., Horn, K.P., Dhingra, R., Dick, T.E., Herlitze, S., Silver, J., 2008. Light induced rescue of breathing after spinal cord injury. J. Neurosci. 28, 11862–11870. Alilain, W.J., Horn, K.P., Hu, H., Dick, T.E., Silver, J., 2011. Functional regeneration of respiratory pathways after spinal cord injury. Nature 475, 196–200. Andrews, M.R., Czvitkovich, S., Dassie, E., Vogelaar, C.F., Faissner, A., Blits, B., Gage, F.H., ffrench-Constant, C., Fawcett, J.W., 2009. Alpha9 integrin promotes neurite outgrowth on tenascin-C and enhances sensory axon regeneration. J. Neurosci. 29, 5546–5557.

References

Asher, R.A., Morgenstern, D.A., Shearer, K.H., Adcock, K.H., Pesheva, P., Fawcett, J.W., 2002. Versican is upregulated in CNS injury and is a product of oligodendrocyte lineage cells. J. Neurosci. 22, 2225–2236. Atwal, J.K., Massie, B., Miller, F.D., Kaplan, D.R., 2000. The TrkB-Shc site signals neuronal survival and local axon growth via MEK and P13-kinase. Neuron 27, 265–277. Awad, B.I., Warren, P.M., Steinmetz, M.P., Alilain, W.J., 2013. The role of the crossed phrenic pathway after cervical contusion injury and a new model to evaluate therapeutic interventions. Exp. Neurol. 248, 398–405. Bai, F., Peng, H., Etlinger, J.D., Zeman, R.J., 2010. Partial recovery after complete spinal cord transection by combined chondroitinase and clenbuterol treatment. Pflugers Arch. 460, 657–666. Baker-Herman, T.L., Mitchell, G.S., 2002. Phrenic long-term facilitation requires spinal serotonin receptor activation and protein synthesis. J. Neurosci. 22, 6239–6246. Baker-Herman, T.L., Fuller, D.D., Bavis, R.W., Zabka, A.G., Golder, F.J., Doperalski, N.J., Johnson, R.A., Watters, J.J., Mitchell, G.S., 2004. BDNF is necessary and sufficient for spinal respiratory plasticity following intermittent hypoxia. Nat. Neurosci. 7, 48–55. Ballanyi, K., Onimaru, H., Homma, I., 1999. Respiratory network function in the isolated brainstem-spinal cord of newborn rats. Prog. Neurobiol. 59, 583–634. Barritt, A.W., Davies, M., Marchand, F., Hartley, R., Grist, J., Yip, P., McMahon, S.B., Bradbury, E.J., 2006. Chondroitinase ABC promotes sprouting of intact and injured spinal systems after spinal cord injury. J. Neurosci. 26, 10856–10867. Baussart, B., Stamegna, J.C., Polentes, J., Tadie, M., Gauthier, P., 2006. A new model of upper cervical spinal contusion inducing a persistent unilateral diaphragmatic deficit in the adult rat. Neurobiol. Dis. 22, 562–574. Benson, M.D., Romero, M.I., Lush, M.E., Lu, Q.R., Henkemeyer, M., Parada, L.F., 2005. Ephrin-B3 is a myelin-based inhibitor of neurite outgrowth. Proc. Natl. Acad. Sci. U.S.A 102, 10694–10699. Bessis, A., Be´chade, C., Bernard, D., Roumier, A., 2007. Microglial control of neuronal death and synaptic properties. Glia 55, 233–238. Bianchi, A.L., Denavit-Saubie, M., Champagnat, J., 1995. Central control of breathing in mammals: neuronal circuitry, membrane properties, and neurotransmitters. Physiol. Rev. 75, 1–45. Bjartmar, C., Kinkel, R.P., Kidd, G., Rudick, R.A., Trapp, B.D., 2001. Axonal loss in normal appearing white matter in a patient with acute MS. Neurology 57, 1248–1252. Blesch, A., Tuszynski, M.H., 2003. Cellular GDNF delivery promotes growth of motor and dorsal column sensory axons after partial and complete spinal cord transections and induces remyelination. J. Comp. Neurol. 467, 403–417. Blight, A.R., 1994. Effects of silica on the outcome from experimental spinal cord injury: implication of macrophages in secondary tissue damage. Neuroscience 60, 263–273. Bluechardt, M.H., Wiens, M., Thomas, S.G., Plyley, M.J., 1992. Repeated measurements of pulmonary function following spinal cord injury. Paraplegia 30, 479–488. Bocchiaro, C.M., Feldman, J.L., 2004. Synaptic activity-dependent persistent plasticity in endogenously active mammalian motoneurons. Proc. Natl. Acad. Sci. U.S.A 101, 4292–4295. Borisoff, J.F., Chan, C.C., Hiebert, G.W., Oschipok, L., Robertson, G.S., Zamboni, R., Steeves, J.D., Tetzlaff, W., 2003. Suppression of Rho kinase activity promotes axonal growth on inhibitory CNS substrates. Mol. Cell. Neurosci. 22, 405–416.

199

200


Bouhy, D., Malgrange, B., Multon, S., Poirrier, A.L., Scholtes, F., Schoenen, J., Franzen, R., 2006. Delayed GM-CSF treatment stimulates axonal regeneration and functional recovery in paraplegic rats via an increased BDNF expression by endogenous macrophages. FASEB J. 20, 1239–1241. Boulenguez, P., Gauthier, P., Kastner, A., 2007. Respiratory neuron subpopulations and pathways potentially involved in the reactiviation of phrenic motorneurons after C2 hemisection. Brain Res. 1148, 96–104. Bradbury, E.J., Moon, L.D., Popat, R.J., King, V.R., Bennett, G.S., Patel, P.N., Fawcett, J.W., McMahon, S.B., 2002. Chondroitinase ABC promotes functional recovery after spinal cord injury. Nature 416, 636–640. Bretzner, F., Liu, J., Currie, E., Roskams, A.J., Tetzlaff, W., 2008. Undesired effects of a combinatorial treatment for spinal cord injury-transplantation of olfactory ensheathing cells and BDNF infusion into the red nucleus. J. Neurosci. Res. 88, 2833–2846. Bretzner, F., Plemel, J.R., Liu, J., Richter, M., Roskams, A.J., Tetzlaff, W., 2010. Combination of olfactory ensheathing cells with local versus systemic cAMP treatment after a cervical rubospinal tract injury. J. Neurosci. Res. 88, 2833–2846. Brosamle, C., Huber, A.B., Fiedler, M., Skerra, A., Schwab, M.E., 2000. Regeneration of lesioned corticospinal tract fibers in the adult rat induced by a recombinant, humanized IN-1 antibody fragment. J. Neurosci. 20, 8061–8068. Bundesen, L.Q., Scheel, T.A., Bregman, B.S., Kromer, L.F., 2003. Ephrin-B2 and EphB2 regulation of astrocyte-meningeal fibroblast interactions in response to spinal cord lesions in adult rats. J. Neurosci. 23, 7789–7800. Busch, S.A., Horn, K.P., Silver, D.J., Silver, J., 2009. Overcoming macrophage-mediated axonal dieback following CNS injury. J. Neurosci. 29, 9967–9976. Buss, A., Brook, G.A., Kakulas, B., Martin, D., Franzen, R., Schoenen, J., Noth, J., Schmitt, A.B., 2004. Gradual loss of myelin and formation of an astrocytic scar during Wallerian degeneration in the human spinal cord. Brain 127, 34–44. Cafferty, W.B., Yang, S.H., Duffy, P.J., Li, S., Strittmatter, S.M., 2007. Functional axonal regeneration through astrocytic scar genetically modified to digest chondroitin sulfate proteoglycans. J. Neurosci. 27, 2176–2185. Cafferty, W.B., Bradbury, E.J., Lidierth, M., Jones, M., Duffy, P.J., Pezet, S., McMahon, S.B., 2008. Chondroitinase ABC-mediated plasticity of spinal sensory function. J. Neurosci. 28, 11998–12009. Cai, D., Shen, Y., De Bellard, M., Tang, S., Filbin, M.T., 1999. Prior exposure to neurotrophins blocks inhibition of axonal regeneration by MAG and myelin via a cAMP-dependent mechanism. Neuron 22, 89–101. Campbell, S.C., Krueger, R.C., Schwartz, N.B., 1990. Deglycosylation of chondroitin sulfate proteoglycan and derived peptides. Biochemistry 29, 907–914. Caroni, P., Schwab, M.E., 1988. Antibody against myelin-associated inhibitor of neurite growth neutralizes nonpermissive substrate properties of CNS white matter. Neuron 1, 85–96. Caroni, P., Schwab, M.E., 1989. Codistribution of neurite growth inhibitors and oligodendrocytes in rat CNS: appearance follows nerve fiber growth and precedes myelination. Dev. Biol. 136, 287–295. Carter, L.M., Starkey, M.L., Akrimi, S.F., Davies, M., McMahon, S.B., Bradbury, E.J., 2008. The yellow fluorescent protein (YFP-H) mouse reveals neuroprotection as a novel mechanism underlying chondroitinase ABC-mediated repair after spinal cord injury. J. Neurosci. 28, 14107–14120.

References

Castellani, V., Falk, J., Rougon, G., 2004. Semaphorin3A-induced receptor endocytosis during axon guidance responses is mediated by L1 CAM. Mol. Cell. Neurosci. 26, 89–100. Chao, M.V., 2003. Neurotrophins and their receptors: a convergence point for many signalling pathways. Nat. Rev. Neurosci. 4, 299–309. Chatfield, P.O., Mead, S., 1948. Role of the vagi in the crossed phrenic phenomenon. Am. J. Physiol. 54, 417–422. Chau, C.H., Shum, D.K., Li, H., Pei, J., Lui, Y.Y., Wirthlin, L., Chan, Y.S., Xu, X.M., 2004. Chondroitinase ABC enhances axonal regrowth through Schwann cell-seeded guidance channels after spinal cord injury. FASEB J. 18, 194–196. Chierzi, S., Ratto, G.M., Verma, P., Fawcett, J.W., 2005. The ability of axons to regenerate their growth cones depends on axonal type and age, and is regulated by calcium, cAMP and ERK. Eur. J. Neurosci. 21, 2051–2062. Chitravanshi, V.C., Sapru, H.N., 1996. NMDA as well as non-NMDA receptors mediate the neurotransmission of inspiratory drive to phrenic motoneurons in the adult rat. Brain Res. 715, 104–112. Choi, H., Liao, W.-L., Newton, K.W., Onario, R.C., King, A.M., Desilets, F.C., Woodard, E.J., Eichler, M.E., Frontera, W.R., Subharwal, S., Teng, Y.D., 2005. Respiratory abnormalities resulting from midcervical spinal cord injury and their reversal by serotonin 1A agonists in conscious rats. J. Neurosci. 25, 4550–4559. Coull, J., Beggs, S., Boudreau, D., Boivin, D., Tsuda, M., Inoue, K., Gravel, C., Salter, M., De Koninck, Y., 2005. BDNF from microglia causes the shift in neuronal anion gradient underlying neuropathic pain. Nature 438, 1017–1021. Curinga, G.M., Snow, D.M., Mashburn, C., Kohler, K., Thobaben, R., Caggiano, A.O., Smith, G.M., 2007. Mammalian-produced chondroitinase AC mitigates axon inhibition by chondroitin sulfate proteoglycans. J. Neurochem. 102, 275–288. Dale, E.A., Mabrouk, R.B., Mitchell, G.S., 2014. Unexpected benefits of intermittent hypoxia: enhanced respiratory and nonrespiratory motor function. Physiology 29, 39–48. Dale, E.A., Mitchell, G.S., 2013. Spinal vascular endothelial growth factor (VEGF) and erythropoietin (EPO) induced phrenic motor facilitation after repetitive acute intermitant hypoxia. Respir. Physiol. Neurobiol. 185, 481–488. Dale, E.A., Satriotomo, I., Mitchell, G.S., 2012. Cervical spinal erythropoietin induces phrenic motor facilitation via ERK and Akt signaling? J. Neurosci. 32, 5973–5983. Dale-Nagle, E.A., Satriotomo, I., Mitchell, G.S., 2011. Spinal vascular endothelial growth factor induces phrenic motor facilitation via ERK and Akt signaling. J. Neurosci. 31, 7682–7690. Darlot, F., Cayetanot, F., Gauthier, P., Matarazzo, V., Kastner, A., 2012. Extensive respiratory plasticity after cervical spinal cord injury in rats: axonal sprouting and rerouting of ventrolateral bulbospinal pathways. Exp. Neurol. 236, 88–102. Dauchy, R.T., Dauchy, E.M., Tirrell, R.P., Hill, C.R., Davidson, L.K., Greene, M.W., Tirrell, P.C., Wu, J., Sauer, L.A., Blask, D.E., 2010. Dark-phase light contamination disrupts circadian rhythms in plasma measures of endocrine physiology and metabolism in rats. Comp. Med. 60, 348–356. Davalos, D., Grutzendler, J., Yang, G., Kim, J.V., Zuo, Y., Jung, S., Littman, D.R., Dustin, M.L., Gan, W.B., 2005. ATP mediates rapid microglial response to local brain injury in vivo. Nat. Neurosci. 8, 752–758. David, S., Aguayo, A.J., 1981. Axonal elongation into peripheral nervous system bridges after central nervous system injury in adult rats. Science 241, 931–933.

201

202


Davies, J.G., Kirkwood, P.A., Sears, T.A., 1985. The distribution of monosynaptic connexions from inspiratory bulbospinal neurons to inspiratory motorneurones in the cat. J. Physiol. 368, 63–87. Davies, S.J., Fitch, M.T., Memberg, S.P., Hall, A.K., Raisman, G., Silver, J., 1997. Regeneration of adult axons in white matter tracts of the central nervous system. Nature 390, 680–683. Davies, S.J., Goucher, D.R., Doller, C., Silver, J., 1999. Robust regeneration of adult sensory axons in degenerating white matter of the adult rat spinal cord. J. Neurosci. 19, 5810–5822. De Leon, R.D., Acosta, C.N., 2006. Effect of robotic-assisted treadmill training and chronic quipazine treatment on hindlimb stepping in spinally transected rats. J. Neurotrauma 23, 1147–1163. De Leon, R.D., Reinkensmeyer, D.J., Timoszyk, W.K., London, N.J., Roy, R.R., Edgerton, V.R., 2002. Use of robotics in assessing the adaptive capacity of the rat lumbar spinal cord. Prog. Brain Res. 137, 141–149. De Winter, F., Oudega, M., Lankhorst, A.J., Hamers, F.P., Blits, B., Ruitenberg, M.J., Pasterkamp, R.J., Gispen, W.H., Verhaagen, J., 2002. Injury-induced class 3 semaphorin expression in the rat spinal cord. Exp. Neurol. 175, 61–75. Decherchi, P., Gauthier, P., 2002. Regeneration of acutely and chronically injured descending respiratory pathways within post-traumatic nerve grafts. Neuroscience 112, 141–152. Decherchi, P., Lammari-Barreault, N., Gauthier, P., 1996. Regeneration of respiratory pathways within spinal peripheral nerve grafts. Exp. Neurol. 137, 1–14. Dergham, P., Ellezam, B., Essagian, C., Avedissian, H., Lubell, W.D., McKerracher, L., 2002. Rho signaling pathway targeted to promote spinal cord repair. J. Neurosci. 22, 6570–6577. Dietz, V., Colombo, G., Jensen, L., 1994. Locomotor activity in spinal man. Lancet 344, 1260–1263. Dobbins, E.G., Feldman, J.L., 1994. Brainstem network controlling descending drive to phrenic motorneurons in rat. J. Comp. Neurol. 347, 64–86. Doperalski, N.J., Sandhu, M.S., Bavis, R.W., Reier, P.J., Fuller, D.D., 2008. Ventilation and phrenic output following high cervical spinal hemisection in male vs. female rats. Respir. Physiol. Neurobiol. 162 (2), 160–167. Dou, C.L., Levine, J.M., 1994. Inhibition of neurite growth by the NG2 chondroitin sulphate proteoglycan. J. Neurosci. 19, 8778–8788. Dusart, I., Morel, M.P., Wehrle, R., Sotelo, C., 1999. Late axonal sprouting of injured Purkinje cells and its temporal correlation with permissive changes in the glial scar. J. Comp. Neurol. 408, 399–418. Edgerton, V.R., McCall, G.E., Hodgson, J.A., Gotto, J., Goulet, C., Fleischmann, K., Roy, R.R., 2001. Sensorimotor adaptations to microgravity in humans. J. Exp. Biol. 204, 3217–3224. Ekstro¨m, P.A., Mayer, U., Panjwani, A., Pountney, D., Pizzey, J., Tonge, D.A., 2003. Involvement of alpha7beta1 integrin in the conditioning-lesion effect on sensory axon regeneration. Mol. Cell. Neurosci. 22, 383–395. El Maarouf, A., Petridis, A.K., Rutishauser, U., 2006. Use of polysialic acid in repair of the central nervous system. Proc. Natl. Acad. Sci. U.S.A 103, 16989–16994. El-Bohy, A.A., Schrimsher, G.W., Reier, P.J., Goshgarian, H.G., 1998. Quantitative assessment of respiratory function following contusion injury of the cervical spinal cord. Exp. Neurol. 150, 143–152. Ellenberger, H.H., Feldman, J.L., 1988. Monosynaptic transmission of respiratory drive to phrenic motorneurons from brainstem bulbospinal neurons in rats. J. Comp. Neurol. 269, 47–57.

References

Erickson, J.T., Millhorn, D.E., 1994. Hypoxia and electrical stimulation of the carotid sinus nerve induce Fos-like immunoreactivity with catecholaminergic and serotonergic neurons of the rat brainstem. J. Comp. Neurol. 348, 161–182. Erickson, J.T., Conover, J.C., Borday, V., Champagnat, J., Barbacid, M., Yancopoulos, G., Katz, D.M., 1996. Mice lacking brain-derived neurotrophic factor exhibit visceral sensory neuron losses distinct from mice lacking NT4 and display a severe developmental deficit in control of breathing. J. Neurosci. 16, 5361–5371. Erturk, A., Hellal, F., Enes, J., Bradke, F., 2007. Disorganized microtubules underlie the formation of retraction bulbs and the failure of axonal regeneration. J. Neurosci. 27, 9169–9180. Fabes, J., Anderson, P., Brennan, C., Bolsover, S., 2007. Regeneration enhancing effects of EphA4 blocking peptide following corticospinal tract injury in adult rat spinal cord. Eur. J. Neurosci. 26, 2496–2505. Fehlings, M.G., Theodore, N., Harrop, J., Maurais, G., Kuntz, C., Shaffrey, C.I., Kwon, B.K., Chapman, J., Yee, A., Tighe, A., McKerracher, L., 2011. A phase I/IIa clinical trial of a recombinant Rho protein antagonist in acute spinal cord injury. J. Neurotrauma 28, 787–796. Fein, E.D., Grimm, D.R., Lesser, M., Bauman, W.A., Almenoff, P.L., 1998. The effects of ipratropium bromide on histamine-induced bronchoconstriction in subjects with cervical spinal cord injury. J. Asthma 35, 49–55. Ferguson, A.R., Huie, J.R., Crown, E.D., Baumbauer, K.M., Hook, M.A., Garraway, S.M., Lee, K.H., Hoy, K.C., Grau, J.W., 2012. Maladaptive spinal plasticity opposes spinal learning and recovery in spinal cord injury. Front. Physiol. 3, 1–17. Fidler, P.S., Schuette, K., Asher, R.A., Dobbertin, A., Thornton, S.R., Calle-Patino, Y., Muir, E., Levine, J.M., Geller, H.M., Rogers, J.H., Faissner, A., Fawcett, J.W., 1999. Comparing astrocytic cell lines that are inhibitory or permissive for axon growth: the major axon-inhibitory proteoglycan is NG2. J. Neurosci. 19, 877–8788. Fleming, J.C., Bao, F., Chen, Y., Hamilton, E.F., Relton, J.K., Weaver, L.C., 2008. Alpha4beta1 integrin blockade after spinal cord injury decreases damage and improves neurological function. Exp. Neurol. 214, 147–159. Fleming, J.C., Bao, F., Chen, Y., Hamilton, E.F., Gonzalez-Lara, L.E., Foster, P.J., Weaver, L.C., 2009. Timing and duration of anti-alpha4beta1 integrin treatment after spinal cord injury: effect on therapeutic efficacy. J. Neurosurg. Spine 11, 575–587. Fletcher, E.X., Lesske, J., Qian, W., Miller 3rd., C.C., Unger, T., 1992. Repetitive, episodic hypoxia causes diurnal elevation of blood pressure in rats. Hypertension 19, 555–561. Fouad, K., Pedersen, V., Schwab, M.E., Brosamle, C., 2001. Cervical sprouting of corticospinal fibers after thoracic spinal cord injury accompanies shifts in evoked motor responses. Curr. Biol. 11, 1766–1770. Fouad, K., Klusman, I., Schwab, M.E., 2004. Regenerating corticospinal fibers in the Marmoset (Callitrix jacchus) after spinal cord lesion and treatment with the anti-Nogo-A antibody IN-1. Eur. J. Neurosci. 20, 2479–2482. Fouad, K., Schnell, L., Bunge, M.B., Schwab, M.E., Liebscher, T., Pearse, D.D., 2005. Combining Schwann cell bridges and olfactory-ensheathing glia grafts with chondroitinase promotes locomotor recovery after complete transection of the spinal cord. J. Neurosci. 25, 1169–1178. Fouad, K., Pearse, D.D., Tetzlaff, W., Vavrek, R., 2009. Transplantation and repair: combined cell implantation and chondroitinase delivery prevents deterioration of bladder function in rats with complete spinal cord injury. Spinal Cord 47, 727–732.

203

204


Fredholm, B.B., Hedquist, P., 1980. Modulation of neurotransmission by purine nucleotides and nucleosides. Biochem. Pharmacol. 29, 1635–1643. Freund, P., Schmidlin, E., Wannier, T., Bloch, J., Mir, A., Schwab, M.E., Rouiller, E.M., 2006. Nogo-A-specific antibody treatment enhances sprouting and functional recovery after cervical lesion in adult primates. Nat. Med. 12, 790–792. Freund, P., Wannier, T., Schmidlin, E., Bloch, J., Mir, A., Schwab, M.E., Rouiller, E.M., 2007. Anti-Nogo-Aantibody treatment enhances sprouting of corticospinal axons rostral to a unilateral cervical spinal cord lesion in adult macaque monkey. J. Comp. Neurol. 502, 644–659. Friedlander, D.R., Milev, P., Karthikeyan, L., Margolis, R.K., Margolis, R.U., Grumet, M., 1994. The neuronal chondroitin sulfate proteoglycan neurocan binds to the neural cell adhesion molecules Ng-CAM/L1/NILE and N-CAM, and inhibits neuronal adhesion and neurite outgrowth. J. Cell Biol. 125, 669–680. Fuller, D.D., Baker, T.L., Behan, M., Mitchell, G.S., 2001a. Expression of hypoglossal longterm facilitation differs between substrains of Sprague-Dawley rat. Physiol. Genomics 4 (3), 175–181. Fuller, D.D., Zabka, A.G., Baker, T.L., Mitchell, G.S., 2001b. Phrenic long-term facilitation requires 5-HT receptor activation during but not following episodic hypoxia. J. Appl. Physiol. 90, 2001–2006. Fuller, D.D., Johnson, S.M., Johnson, R.A., Mitchell, G.S., 2002. Chronic cervical spinal sensory denervation reveals ineffective spinal pathways to phrenic motor neurons in the rat. Neurosci. Lett. 323, 25–28. Fuller, D.D., Johnson, S.M., Olson Jr., E.B., Mitchell, G.S., 2003. Synaptic pathways to phrenic motorneurons are enhanced by chronic intermittent hypoxia after cervical spinal cord injury. J. Neurosci. 23, 2993–3000. Fuller, D.D., Baker-Herman, T.L., Golder, F.J., Doperalski, N.J., Watters, J.J., Mitchell, G.S., 2005. Cervical spinal cord injury upregulates ventral spinal 5-HT2A receptors. J. Neurotrauma 22, 203–213. Fuller, D.D., Golder, F.J., Olson, E.B., Mitchell, G.S., 2006. Recovery of phrenic activity and ventilation after cervical spinal hemisection in rats. J. Appl. Physiol. 100, 800–806. Fuller, D.D., Doperalki, N.J., Dougherty, B.J., Sandhu, M.S., Bolser, D.C., Reier, P.J., 2008. Modest spontaneous recovery of ventilation following chronic high cervical hemisection in rats. Exp. Neurol. 21, 97–106. Fuller, D.D., Sandhu, M.S., Doperalski, N.J., Lane, M.A., White, T.E., Bishop, M.D., Reier, P.J., 2009. Graded unilateral cervical spinal cord injury and respiratory motor recovery. Respir. Physiol. Neurobiol. 165, 245–253. Funakoshi, H., Frisen, J., Barbany, G., Timmusk, T., Zachrisson, O., Verge, V.M., Persson, H., 1993. Differential expression of mRNAs for neurotrophins and their receptors after axotomy of the sciatic nerve. J. Cell Biol. 123, 455–465. Gallo, G., Letourneau, P.C., 1998. Localized sources of neurotrophins initiate axon collateral sprouting. J. Neurosci. 18, 5403–5414. Gao, C., Che, L.W., Chen, J., Xu, X.J., Chi, Z.Q., 2003. Ohmefentanyl stereoisomers induce changes of CREB phosphorylation in hippocampus of mice in conditioned place preference paradigm. Cell Res. 13, 29–34. Gao, Y., Deng, K., Hou, J., Bryson, J.B., Barco, A., Nikulina, E., Spencer, T., Mellado, W., Kandel, E.R., Filbin, M.T., 2004. Activated CREB is sufficient to overcome inhibitors in myelin and promote spinal axon regeneration in vivo. Neuron 44, 609–621.

References

Garcia-Alias, G., Barkhuysen, S., Buckle, M., Fawcett, J.W., 2009. Chondroitinase ABC treatment opens a window of opportunity for task-specific rehabilitation. Nat. Neurosci. 12, 1145–1151. Gaspar, P., Cases, O., Maroteaux, L., 2003. The developmental role of serotonin: news from mouse molecular genetics. Nat. Rev. Neurosci. 4, 1002–1012. Gauthier, P., Lammari-Barreault, N., 1992. Central respiratory neurons of the adult rat regrow axons preferentially into peripheral nerve autografts implanted within ventral rather than within dorsal parts of the medulla oblongata. Neurosci. Lett. 137, 33–36. Gauthier, P., Rasminsky, M., 1988. Activity of medullary respiratory neurons regenerating axons into peripheral nerve grafts in the adult rat. Brain Res. 438, 225–236. Gauthier, P., Rega, P., Lammari-Barreault, N., Polentes, J., 2002. Functional reconnections established by central respiratory neurons regenerating axons into a nerve graft bridging the respiratory centers to the cervical spinal cord. J. Neurosci. Res. 70, 65–81. Gauthier, P., Baussart, B., Stamegna, J.C., Tadie, M., Vinit, S., 2006. Diaphragm recovery by laryngeal innervation after bilareral phrenicotomy or complete C2 spinal section in rats. Neurobiol. Dis. 24, 53–66. Gavazzi, I., Stonehouse, J., Sandvig, A., Reza, J.N., Appiah-Kubi, L.S., Keynes, R., Cohen, J., 2000. Peripheral, but not central, axotomy induces neuropilin-1 mRNA expression in adult large diameter primary sensory neurons. J. Comp. Neurol. 423, 492–499. Ghosh, A., Haiss, F., Sydekum, E., Schneider, R., Gullo, M., Wyss, M.T., Mueggler, T., Baltes, C., Rudin, M., Weber, B., Schwab, M.E., 2010. Rewiring of hindlimb corticospinal neurons after spinal cord injury. Nat. Neurosci. 13, 97–104. Giger, R.J., Urquhart, E.R., Gillespie, S.K., Levengood, D.V., Ginty, D.D., Kolodkin, A.L., 1998. Neuropilin-2 is a receptor for semaphorin IV: insight into the structural basis of receptor function and specificity. Neuron 21, 1079–1092. Golan, M.H., Mane, R., Molczadzki, G., Zuckerman, M., Kaplan-Louson, V., Huleihel, M., Perez-Polo, J.R., 2009. Impaired migration signaling in the hippocampus following prenatal hypoxia. Neuropharmacology 57, 511–522. Golder, F.J., Mitchell, G.S., 2005. Spinal synaptic enhancement with acute intermittent hypoxia improves respiratory function after chronic cervical spinal cord injury. J. Neurosci. 25, 2925–2932. Golder, F.J., Ranganathan, L., Satriotomo, I., Hoffman, M., Lovett-Barr, M.R., Watters, J.J., Baker-Herman, T.L., Mitchell, G.S., 2008. Spinal adenosine A2a receptor activation elicits long-lasting phrenic motor facilitation. J. Neurosci. 28, 2033–2042. Golder, F.J., Fuller, D.D., Lovett-Barr, M.R., Vinit, S., Resnick, D.K., Mitchell, G.S., 2011. Breathing patterns after mid-cervical spinal contusion in rats. Exp. Neurol. 231, 97–103. Goldshmit, Y., Galea, M.P., Wise, G., Bartlett, P.F., Turnley, A.M., 2004. Axonal regeneration and lack of astrocytic gliosis in EphA4-deficient mice. J. Neurosci. 24, 10064–10073. Gomez-Pinilla, F., Ying, Z., Roy, R.R., Molteni, R., Edgerton, V.R., 2002. Voluntary exercise induces a BDNF-mediated mechanism that promotes neuroplasticity. J. Neurophysiol. 88, 2187–2195. Goshgarian, H.G., 1981. The role of cervical afferent nerve fiber inhibition of the crossed phrenic phenomenon. Exp. Neurol. 72, 211–225. Goshgarian, H.G., Guth, L., 1977. Demonstration of functionally ineffective synapses in the guinea pig spinal cord. Exp. Neurol. 57, 613–621. Goshgarian, H.G., Rafols, J.A., 1984. The ultrastructure and synaptic architecture of phrenic motor neurons in the spinal cord of the adult rat. J. Neurocytol. 13, 85–109.

205

206


Goshgarian, H.G., Ellenberger, H.H., Feldman, J.L., 1991. Decussation of bulbospinal respiratory axons at the phrenic level of the phrenic nuclei in adult rats: a possible substrate for the crossed phrenic phenomenon. Exp. Neurol. 111, 135–139. Gourine, A.V., Kasymov, V., Marina, N., Tang, F., Figueiredo, M.F., Lane, S., Teschemacher, A.G., Spyer, K.M., Deisseroth, K., Kasparov, S., 2010. Astrocytes control breathing through pH-dependent release of ATP. Science 329, 571–575. Gozal, D., Daniel, J.M., Dohanich, G.P., 2001. Behavioral and anatomical correlates for chronic episodic hypoxia during sleep in the rat. J. Neurosci. 21, 2442–2450. GrandPre, T., Li, S., Strittmatter, S.M., 2002. Nogo-66 receptor antagonist peptide promotes axonal regeneration. Nature 417, 547–551. Gray, P.A., Janczewski, W.A., Mellen, N., McCrimmon, D.R., Felman, J.L., 2001. Normal breathing requires preBotzinger complex neurokinin-1 receptor-expressing neurons. Nat. Neurosci. 4, 927–930. Greer, J.J., Funk, G.D., Ballanyi, K., 2006. Preparing for the first breath: prenatal maturation of respiratory neural control. J. Physiol. 570, 437–444. Griesbeck, O., Parsadanian, A.S., Sendtner, M., Thoenen, H., 1995. Expression of neurotrophins in skeletal muscle: quantitative comparison and significance for motoneuron survival and maintenance of function. J. Neurosci. Res. 42, 21–33. Grill, R., Murai, K., Blesch, A., Gage, F.H., Tuszynski, M.H., 1997. Cellular delivery of neurotrophin-3 promotes corticospinal axonal growth and partial functional recovery after spinal cord injury. J. Neurosci. 17, 5560–5572. Grimm, D.R., Chandy, D., Almenoff, P.L., Schilero, G., Lesser, M., 2000. Airway hyperreactivity in subjects with tetraplegia is associated with reduced baseline airway caliber. Chest 118, 1397–1404. Gris, D., Marsh, D.R., Oatway, M.A., Chen, Y., Hamilton, E.F., Dekaban, G.A., Weaver, L.C., 2004. Transient blockade of the CD11d/CD18 integrin reduces secondary damage after spinal cord injury, improving sensory, autonomic, and motor function. J. Neurosci. 24, 4043–4051. Gross, G.J., Hardman, H.F., Warltier, D.C., 1976. Adenosine on myocardinal oxygen consumption. Br. J. Pharmacol. 57, 409–412. Gruner, J.A., 1992. A monitored contusion model of spinal cord injury in the rat. J. Neurotrauma 9, 123–126. Guth, L., Zhang, Z., Steward, O., 1999. The unique histopathological responses of the injured spinal cord. Implications for neuroprotective therapy. Ann. N. Y. Acad. Sci. 890, 366–384. Gutierrez, D.V., Clark, M., Nawanna, O., Alilain, W.J., 2013. Intermittent hypoxia training after C2 hemisection modifies the expression of PTEN and mTOR. Exp. Neurol. 248, 45–52. Gwak, Y.S., Kong, J., Unabia, G.C., Hulsebosch, C.E., 2012. Spatial and temporal activation of spinal glial cells: role of gliopathy in central neuropathic pain following spinal cord injury in rats. Exp. Neurol. 234, 362–372. Ha, Y., Kim, Y.S., Cho, J.M., Yoon, S.H., Park, S.R., Yoon, D.H., Kim, E.Y., Park, H.C., 2005. Role of granulocyte-macrophage colony-stimulating factor in preventing apoptosis and improving functional outcome in experimental spinal cord contusion injury. J. Neurosurg. Spine 2, 55–61. Hadley, S.D., Walker, P.D., Goshgarian, H.G., 1999a. Effects of serotonin inhibition on neuronal and astrocyte plasticity in the phrenic nucleus 4h following C2 spinal cord hemisection. Exp. Neurol. 160, 433–445.

References

Hadley, S.D., Walker, P.D., Goshgarian, H.G., 1999b. Effects of the serotonin synthesis inhibitor p-CPA on the expression of the crossed phrenic phenomenon 4h following C2 spinal cord hemisection. Exp. Neurol. 160, 479–488. Harris, N.G., Mironova, Y.A., Hovda, D.A., Sutton, R.L., 2010. Chondroitinase ABC enhances pericontusion axonal sprouting but does not confer robust improvements in behavioral recovery. J. Neurotrauma 27, 1971–1982. Hayashi, F., Coles, S.K., Bach, K.B., Mitchell, G.S., McCrimmon, D.R., 1993. Timedependent phrenic nerve responses to carotid afferent activation: intact vs. decerebellate rats. Am. J. Physiol. 265, R811–R819. Hayashi, F., Hinrichsen, C.F., McCrimmon, D.R., 2003. Short-term plasticity of descending synaptic input to phrenic motorneurons in rats. J. Appl. Physiol. 94, 1421–1430. Hayes, H.B., Jayaraman, A., Herrmann, M., Mitchell, G.S., Rymer, W.Z., Trumbower, R.D., 2014. Daily intermittent hypoxia enhances walking after chronic spinal cord injury: a randomized trial. Neurology 82, 104–113. Hellal, F., Hurtado, A., Ruschel, J., Flynn, K.C., Laskowski, C.J., Umlauf, M., Kapitein, L.C., Strikis, D., Lemmon, V., Bixby, J., Hoogenraad, C.C., Bradke, F., 2011. Microtubule stabilization reduces scarring and causes axon regeneration after spinal cord injury. Science 331, 928–931. Hennigan, A., Trotter, C., Kelly, A.M., 2007. Lipopolysaccharide impairs long-term potentiation and recognition memory and increases p75NTR expression in the rat dentate gyrus. Brain Res. 1130, 158–166. Herlenius, E., Lagercrantz, H., 2004. Development of neurotransmitter systems during critical periods. Exp. Neurol. 190 (Suppl. 1), S8–S21. Hoffman, M.S., Mitchell, G.S., 2011. Spinal 5-HT7 receptor activation induces long-lasting phrenic motor facilitation. J. Physiol. 589, 1397–1407. Hoffman, M.S., Mahamed, S., Golder, F.J., Mitchell, G.S., 2007. Adenosine A2A receptors con-strain phrenic long term facilitation following acute intermittent hypoxia. FASEB J. 918, 12. Holstege, G., Blok, B.F., Ralston, D.D., 1988. Anatomical evidence for red nucleus projections to motorneuronal cell groups in the spinal cord of the monkey. Neurosci. Lett. 95, 97–101. Horn, K.P., Busch, S.A., Hawthorne, A.L., van Rooijen, N., Silver, J., 2008. Another barrier to regeneration in the CNS: activated macrophages induce extensive retraction of dystrophicaxons through direct physical interactions. J. Neurosci. 28, 9330–9341. Houle, J.D., Tom, V.J., Mayes, D., Wagoner, G., Phillips, N., Silver, J., 2006. Combining an autologous peripheral nervous system "bridge" and matrix modification by chondroitinase allows robust, functional regeneration beyond a hemisection lesion of the adult rat spinal cord. J. Neurosci. 26, 7405–7415. Howard, R.S., Wiles, C.M., Hirsch, N.P., Loh, L., Spencer, G.T., Newsom-Davis, J., 1992. Respiratory involvement in multiple sclerosis. Brain 115, 479–494. Huang, W., Matte, A., Suzuki, S., Sugiura, N., Miyazono, H., Cygler, M., 2000. Crystallization and preliminary X-ray analysis of chondroitin sulphate ABC lyases I and II from Proteus vulgaris. Acta Crystallogr. 56, 904–906. Huang, W., Lunin, V.V., Li, Y., Suzuki, S., Sugiura, N., Miyazono, H., Cygler, M., 2003. Crystal structure of Proteus vulgaris chondroitin sulfate ABC lyase 1 at 1.9A resolution. J. Mol. Biol. 328, 623–634. Huckstepp, R.T., id Bihi, R., Eason, R., Spyer, K.M., Dicke, N., Willecke, K., Marina, N., Gourine, A.V., Dale, N., 2010. Connexin hemichannel-mediated CO2-dependent release

207

208


of ATP in the medulla oblongata contributes to central respiratory chemosensitivity. J. Physiol. 588, 3901–3920. Hulsebosch, C., 2008. Gliopathy ensures persistent inflammation and chronic pain after spinal cord injury. Exp. Neurol. 214, 6–9. Hurtado, A., Marcillo, A., Frydel, B., Bunge, M.B., Bramlett, H.M., Dietrich, W.D., 2012. Anti-CD11d monoclonal antibody treatment for rat spinal cord compression injury. Exp. Neurol. 233, 606–611. Hutchinson, K.J., Gomez-Pinilla, F., Crowe, M.J., Ying, Z., Basso, D.M., 2004. Three exercise paradigms differentially improve sensory recovery after spinal cord contusion in rats. Brain 127, 1403–1414. Huxtable, A.G., Vinit, S., Windelborn, J.A., Crader, S.M., Guenther, C.H., Watters, J.J., Mitchell, G.S., 2011. System inflammation improve respiratory chemoreflexes and plasticity. Respir. Physiol. Neurobiol. 178, 482–489. Iaci, J.F., Vecchione, A.M., Zimber, M.P., Caggiano, A.O., 2007. Chondroitin sulfate proteoglycans in spinal cord contusion injury and the effects of chondroitinase treatment. J. Neurotrauma 24, 1743–1759. Iarikov, D.E., Kim, B.G., Dai, H.N., McAtee, M., Kuhn, P.L., Bregman, B.S., 2007. Delayed transplantation with exogenous neurotrophin administration enhances plasticity of corticofugal projections after spinal cord injury. J. Neurotrauma 24, 690–702. Ip, F.C., Cheung, J., Ip, N.Y., 2001. The expression profiles of neurotrophins and their receptors in rat and chicken tissues during development. Neurosci. Lett. 301, 107–110. Iseda, T., Okuda, T., Kane-Goldsmith, N., Mathew, M., Ahmed, S., Chang, Y.W., Young, W., Grumet, M., 2008. Single, high-dose intraspinal injection of chondroitinase reduces glycosaminoglycans in injured spinal cord and promotes corticospinal axonal regrowth after hemisection but not contusion. J. Neurotrauma 25, 334–349. James, E., Nantwi, K.D., 2006. Involvement of peripheral adenosine A2 receptors in adenosine A1 receptor-mediated recovery of respiratory motor function after upper cervical spinal cord hemisection. J. Spinal Cord Med. 29, 57–66. Jefferson, S.C., Tester, N.J., Howland, D.R., 2011. Chondroitinase ABC promotes recovery of adaptive limb movements and enhances axonal growth caudal to a spinal hemisection. J. Neurosci. 31, 5710–5720. Jin, Y., Fischer, I., Tessler, A., Houle, J.D., 2002. Transplants of fibroblasts genetically modified to express BDNF promote axonal regeneration from supraspinal neurons following chronic spinal cord injury. Exp. Neurol. 177, 265–275. Jin, Y., Ketschek, A., Jiang, Z., Smith, G., Fischer, I., 2011. Chondroitinase activity can be transduced by a lentiviral vector in vitro and in vivo. J. Neurosci. Methods 199, 208–213. Johnson, R.A., Okragly, A.J., Haak-Frendscho, M., Mitchell, G.S., 2000. Cervical dorsal rhizotomy increases brain-derived neurotrophic factor and neurotrophin-3 expression in the ventral spinal cord. J. Neurosci. 20, RC77. Jones, L.L., Margolis, R.U., Tuszynski, M.H., 2003. The chondroitin sulfate proteoglycans neurocan, brevican, phosphacan, and versican are differentially regulated following spinal cord injury. Exp. Neurol. 182, 399–411. Juvin, L., Morin, D., 2005. Descending respiratory polysynaptic inputs to cervical and thoracic motorneurons diminish during early postnatal maturation in rat spinal cord. Eur. J. Neurosci. 21, 808–813. Kajana, S., Goshgarian, H.G., 2008a. Administration of phosphodiesterase inhibitors and an adenosine A1 receptor antagonist induces phrenic nerve recovery in high cervical spinal cord injured rats. Exp. Neurol. 210, 671–680.

References

Kajana, S., Goshgarian, H.G., 2008b. Spinal activation of the cAMP-PKA pathway induces respiratory motor recovery following high cervical spinal cord injury. Brain Res. 1232, 206–213. Karimi-Abdolrezaee, S., Eftekharpour, E., Wang, J., Schut, D., Fehlings, M.G., 2010. Synergistic effects of transplanted adult neural stem/progrnitor cells, chondroitinase, and growth factors promote functional repair and plasticity of the chronically injured spinal cord. J. Neurosci. 30, 1657–1676. Kaushal, V., Koeberle, P.D., Wang, Y., Schlichter, L.C., 2007. The Ca2+-activated K+ channel KCNN4/KCa3.1 contributes to microglia activation and nitric oxide-dependent neurodegeneration. J. Neurosci. 27, 234–244. Kerschensteiner, M., Gallmeier, E., Behrens, S., Leal, V.V., Misgeld, T., Klinkert, W.E., Kolbeck, R., Hoppe, E., Oropeza-Wekerle, R.L., Bartke, I., Stadelmann, C., Lassmann, H., Wekerle, H., Hohlfeld, R., 1999. Activated human T cells, B cells, and monocytes produce brain-derived neurotrophic factor in vitro and in inflammatory brain lesions: a neuroprotective role of inflammation? J. Exp. Med. 189, 865–870. Khristy, W., Ali, N.J., Bravo, A.B., de Leon, R., Roy, R.R., Zhong, H., London, N.J., Edgerton, V.R., Tillakaratne, N.J., 2009. Changes in GABA(A) receptor subunit gamma 2 in extensor and flexor motoneurons and astrocytes after spinal cord transection and motor training. Brain Res. 1273, 9–17. Kigerl, K.A., Gensel, J.C., Ankeny, D.P., Alexander, J.K., Donnelly, D.J., Popovich, P.G., 2009. Identification of two distinct macrophage subsets with divergent effects causing either neurotoxicity or regeneration in the injured mouse spinal cord. J. Neurosci. 29, 13435–13444. Kinkead, R., Mitchell, G.S., 1999. Time-dependent hypoxic ventilatory responses in rats: effects of ketanserin and 5-carboxamidotryptamine. Am. J. Physiol. 277, R658–R666. Kirkwood, P.A., 1995. Synaptic excitation in the thoracic spinal cord from expiratory bulbospinal neurones in the cat. J. Physiol. 484, 201–225. Kishino, A., Nakayama, C., 2003. Enhancement of BDNF and activated-ERK immunoreactivity in spinal motor neurons after peripheral administration of BDNF. Brain Res. 964, 56–66. Kobayashi, N.R., Fan, D.P., Giehl, K.M., Bedard, A.M., Wiegand, S.J., Tetzlaff, W., 1997. BDNF and NT-4/5 prevent atrophy of rat rubrospinal neurons after cervical axotomy, stimulate GAP-43 and Talpha1-tubulin mRNA expression, and promote axonal regeneration. J. Neurosci. 17, 9583–9595. Kottis, V., Thibault, P., Mikol, D., Xiao, Z.C., Zhang, R., Dergham, P., Braun, P.E., 2002. Oligodendrocyte-myelin glycoprotein (OMgp) is an inhibitor of neurite outgrowth. J. Neurochem. 82, 1566–1569. Kwo, S., Young, W., Decrescito, V., 1989. Spinal cord sodium, potassium, calcium, and water concentration changes in rats after graded contusion injury. J. Neurotrauma 6, 13–24. Kwon, C.H., Luikart, B.W., Powell, C.M., Zhou, J., Matheny, S.A., Zhang, W., Li, Y., Baker, S.J., Parada, L.F., 2006. Pten regulates neuronal arborization and social interaction in mice. Neuron 50, 377–388. Laabs, T.L., Wang, H., Katagiri, Y., McCann, T., Fawcett, J.W., Geller, H.M., 2007. Inhibiting glycosaminoglycan chain polymerization decreases the inhibitory activity of astrocytederived chondroitin sulfate proteoglycans. J. Neurosci. 27, 14494–14501. Lammari-Barreault, N., Rega, P., Gauthier, P., 1991. Axonal regeneration from central respiratory neurons of the adult rat into peripheral nerve autografts: effects of graft location within the medulla. Neurosci. Lett. 125, 121–124.

209

210


Lammari-Barreault, N., Rega, P., Gauthier, P., 1994. Central respiratory neuronal activity after axonal regeneration within blind-ended peripheral nerve grafts: time course of recovery and loss of functional neurons. Exp. Brain Res. 98, 238–244. Lane, M.A., White, T.E., Coutts, M.A., Jones, A.L., Sandhu, M.S., Bloom, D.C., Bolser, D.C., Yates, B.J., Fuller, D.D., Reier, P.J., 2008. Cervical prephrenic interneurons in the normal and lesioned spinal cord of the adult rat. J. Comp. Neurol. 511, 692–709. Lane, M.A., Lee, K.-Z., Salazar, K., O’Steen, B.E., Bloom, D.C., Fuller, D.D., Reier, P.J., 2012. Respiratory function following bilateral mid-cervical contusion injury in the adult rat. Exp. Neurol. 235, 197–210. Larsen, P.H., Wells, J.E., Stallcup, W.B., Opdenakker, G., Yong, V.W., 2003. Matrix metalloproteinase-9 facilitates remyelination in part by processing the inhibitory NG2 proteoglycan. J. Neurosci. 23, 11127–11135. Lauder, J.M., 1993. Neurotransmitters as growth regulatory signals: role of receptors and second messengers. Trends Neurosci. 16, 233–239. Leblond, H., L’Esperance, M., Orsal, D., Rossignol, S., 2003. Treadmill locomotion in the intact and spinal mouse. J. Neurosci. 23, 11411–11419. Lee, J.K., Geoffroy, C.G., Chan, A.F., Tolentino, K.E., Crawford, M.J., Leal, M.A., Kang, B., Zheng, B., 2010. Assessing spinal axon regeneration and sprouting in Nogo-, MAG-, and OMgp-deficient mice. Neuron 66, 663–670. Lehmann, M., Fournier, A., Selles-Navarro, I., Dergham, P., Sebok, A., Leclerc, N., Tigyi, G., McKerracher, L., 1999. Inactivation of Rho signaling pathway promotes CNS axon regeneration. J. Neurosci. 19, 7537–7547. Lemke, A.K., Sandy, J.D., Voigt, H., Dreier, R., Lee, J.H., Grodzinsky, A.J., Mentlein, R., Fay, J., Schunke, M., Kurz, B., 2010. Interleukin-1alpha treatment of meniscal explants stimulates the production and release of aggrecanase-generated, GAG-substituted aggrecan products and also the release of pre-formed, aggrecanase-generated G1 and mcalpaingenerated G1–G2. Cell Tissue Res. 340, 179–188. Lemons, M.L., Howland, D.R., Anderson, D.K., 1999. Chondroitin sulfate proteoglycan immunoreactivity increases following spinal cord injury and transplantation. Exp. Neurol. 160, 51–65. Levitt, P., Harvey, J.A., Friedman, E., Simansky, K., Murphy, E.H., 1997. New evidence for neurotransmitter influences on brain development. Trends Neurosci. 20, 269–274. Lewis, L.J., Brookheart, J.M., 1951. Significance of the crossed phrenic phenomenon. Am. J. Physiol. 166, 241–254. Li, W.W., Setzu, A., Zhao, C., Franklin, R.J., 2005. Minocycline-mediated inhibition of microglia activation impairs oligodendrocyte progenitor cell responses and remyelination in a non-immune model of demyelination. J. Neuroimmunol. 158, 58–66. Ling, L., Bach, K.B., Mitchell, G.S., 1994. Serotonin reveals ineffective spinal pathways to contralateral phrenic motor neurons in spinally hemisected rats. Exp. Brain Res. 101, 35–43. Linn, W.S., Spungen, A.M., Gong Jr., H., Adkins, R.H., Bauman, W.A., Waters, R.L., 2001. Forced vital capacity in two large outpatient populations with chronic spinal cord injury. Spinal Cord 39, 263–268. Lipski, J., Duffin, J., Kruszewska, B., Zhang, X., 1993. Upper cervical inspiratory neurons in the rat: and electophysiological and morphological study. Exp. Brain Res. 95, 477–487. Lipski, J.X., Duffin, J., Kruszewska, B., Kanjhan, R., 1994. Morphological study of long axonal projections of ventral medullary inspiratory neurons in the rat. Brain Res. 640, 171–184.

References

Lipton, S.A., Kater, S.B., 1989. Neurotransmitter regulation of neuronal outgrowth, plasticity and survival. Trends Neurosci. 12, 265–270. Liu, R.Y., Snider, W.D., 2001. Different signaling pathways mediate regenerative versus developmental sensory axon growth. J. Neurosci. 21, RC164. Liu, G., Feldman, J.L., Smith, J.C., 1990. Excitatory amino acid-mediated transmission of intraspiratory drive to phrenic motorneurons. J. Neurophysiol. 64, 423–436. Liu, Y., Cox, S.R., Morita, T., Kourembanas, S., 1995. Hypoxia regulates vascular endothelial factor gene expression in endothelial cells. Identification of a 50 enhancer. Circ. Res. 77, 638–643. Liu, Y., Kim, D., Himes, B.T., Chow, S.Y., Schallert, T., Murray, M., Tessler, A., Fischer, I., 1999. Transplants of fibroblasts genetically modified to express BDNF promote regeneration of adult rat rubrospinal axons and recovery of forelimb function. J. Neurosci. 19, 4370–4387. Liu, K., Lu, Y., Lee, J.K., Samara, R., Willenberg, R., Sears-Kraxberger, I., Tedeschi, A., Park, K.K., Jin, D., Cai, B., Xu, B., Connolly, L., Steward, O., Zheng, B., He, Z., 2010. PTEN deletion enhances the regenerative ability of adult corticospinal neurons. Nat. Neurosci. 13, 1075–1081. Lopez-Vales, R., Garcia-Alias, G., Fores, J., Udina, E., Gold, B.G., Navarro, X., Verdu, E., 2005. FK 506 reduces tissue damage and prevents functional deficit after spinal cord injury in the rat. J. Neurosci. Res. 81, 827–836. Loveridge, B., Sanii, R., Dubo, H.I., 1992. Breathing pattern adjustments during the first year following spinal cord injury. Paraplegia 30, 479–488. Lovett-Barr, M.R., Satriotomo, I., Muir, G.D., Wilkerson, J.E.R., Hoffman, M.S., Vinit, S., Mitchell, G.S., 2012. Repetitive intermittent hypoxia induces respiratory and somatic motor recovery after chronic cervical spinal injury. J. Neurosci. 32, 3591–3600. Lu, F., Qin, C., Foreman, R.D., Farber, J.P., 2004a. Chemical activation of C1-C2 spinal neurons modulates intercostals and phrenic nerve activity in rats. Am. J. Physiol. Regul. Integr. Comp. Physiol. 286, R1069–R1076. Lu, P., Yang, H., Jones, L.L., Filbin, M.T., Tuszynski, M.H., 2004b. Combinatorial therapy with neurotrophins and cAMP promotes axonal regeneration beyond sites of spinal cord injury. J. Neurosci. 24, 6402–6409. Lu, P., Blesch, A., Graham, L., Wang, Y., Samara, R., Banos, K., Haringer, V., Havton, L., Weishaupt, N., Bennett, D., Faouad, K., Tuszynski, M.H., 2012. Motor axonal regeneration after partial and complete spinal cord transection. J. Neurosci. 32, 8208–8218. Lynskey, J.V., Sandhu, F.A., Dai, H.N., McAtee, M., Slotkin, J.R., MacArthur, L., Bregman, B.S., 2006. Delayed intervention with transplants and neurotrophic factors supports recovery of forelimb function after cervical spinal cord injury in adult rats. J. Neurotrauma 23, 617–634. MacFarlane, P.M., Mitchell, G.S., 2008. Respiratory long-term facilitation following intermittent hypoxia requires reactive oxygen species formation. Neuroscience 152, 189–197. MacFarlane, P.M., Mitchell, G.S., 2009. Episodic spinal serotonin receptor activation elicits long-lasting phrenic motor facilitation by an NADPH oxidase-dependent mechanism. J. Physiol. 587, 5469–5481. MacFarlane, P.M., Wilkerson, J.E., Lovett-Barr, M.R., Mitchell, G.S., 2008. Reactive oxygen species and respiratory plasticity following intermittent hypoxia. Respir. Physiol. Neurobiol. 164, 263–271. MacFarlane, P.M., Satriotomo, I., Windelborn, J.A., Mitchell, G.S., 2009. NADPH oxidase activity is necessary for acute intermittent hypoxia-induced phrenic long-term facilitation. J. Physiol. 587, 1931–1942.

211

212


MacFarlane, P.M., Vinit, S., Mitchell, G.S., 2011. Serotonin 2A and 2B receptor-induced phrenic motor facilitation: differential requirement for spinal NADPH oxidase activity. Neuroscience 178, 45–55. Macias, M., Dwornik, A., Ziemlinska, E., Fehr, S., Schachner, M., Czarkowska-Bauch, J., Skup, M., 2007. Locomotor exercise alters expression of pro-brain-derived neurotrophic factor, brain-derived neurotrophic factor and its receptor TrkB in the spinal cord of adult rats. Eur. J. Neurosci. 25, 2425–2444. Macias, M., Nowicka, D., Czupryn, A., Sulejczak, D., Skup, M., Skangiel-Kramska, J., Czarkowska-Bauch, J., 2009. Exercise-induced motor improvement after complete spinal cord transection and its relation to expression of brain-derived neurotrophic factor and presynaptic markers. BMC Neurosci. 10, 144–169. Maier, I.C., Ichiyama, R.M., Courtine, G., Schnell, L., Lavrov, I., Edgerton, V.R., Schwab, M.E., 2009. Differential effects of anti-Nogo-A antibody treatment and treadmill training in rats with incomplete spinal cord injury. Brain 132, 1426–1440. Mantilla, C.B., Rowley, K.L., Zhan, W.Z., Fahim, M.A., Sieck, G.C., 2007. Synaptic vesicle pools at diaphragm neuromuscular junctions vary with motoneuron soma, not axon terminal inactivity. J. Neurosci. 146, 178–189. Marino, P., Norreel, J.C., Schachner, M., Rougon, G., Amoureux, M.C., 2009. A polysialic acid mimetic peptide promotes functional recovery in a mouse model of spinal cord injury. Exp. Neurol. 219, 163–174. Markus, A., Zhong, J., Snider, W.D., 2002. Raf and akt mediate distinct aspects of sensory axon growth. Neuron 35, 65–76. Martinez, F.O., Gordon, S., Locati, M., Mantovani, A., 2006. Transcriptional profiling of the human monocyte-to-macrophage differentiation and polarization: new molecules and patterns of gene expression. J. Immunol. 177, 7303–7311. Massey, J.M., Hubscher, C.H., Wagoner, M.R., Decker, J.A., Amps, J., Silver, J., Onifer, S.M., 2006. Chondroitinase ABC digestion of the perineuronal net promotes functional collateral sprouting in the cuneate nucleus after cervical spinal cord injury. J. Neurosci. 26, 4406–4414. McCrimmon, D.R., Smith, J.C., Feldman, J.L., 1989. Involvement of excitatory amino acids in neurotransmission of inspiratory drive to spinal respiratory motorneurons. J. Neurosci. 9, 1910–1921. McGuire, M., Zhang, Y., White, D.P., Ling, L., 2005. Phrenic long-term facilitation requires NMDA receptors in the phrenic motornucleus in rats. J. Physiol. 576, 599–611. McGuire, M., Liu, C., Cao, Y., Ling, L., 2008. Formation and maintenance of ventilatory longterm facilitation require NMDA but not non-NMDA receptors in awake rats. J. Appl. Physiol. 105, 942–950. McKeon, R.J., Schreiber, R.C., Rudge, J.S., Silver, J., 1991. Reduction of neurite outgrowth in a model of glial scarring following CNS injury is correlated with the expression of inhibitory molecules on reactive astrocytes. J. Neurosci. 11, 3398–3411. McKeon, R.J., Hoke, A., Silver, J., 1995. Injury-induced proteoglycans inhibit the potential for laminin-mediated axon growth on astrocytic scars. Exp. Neurol. 136, 32–43. McKeon, R.J., Jurynec, M.J., Buck, C.R., 1999. The chondroitin sulfate proteoglycans neurocan and phosphacan are expressed by reactive astrocytes in the chronic CNS glial scar. J. Neurosci. 19, 10778–10788. McKerracher, L., David, S., Jackson, D.L., Kottis, V., Dunn, R.J., Braun, P.E., 1994. Identification of myelin associated glycoprotein as a major myelin-derived inhibitor of neurite growth. Neuron 13, 805–811.

References

Merrill, E.G., Lipski, J., 1987. Inputs to intercostal motoneurons from ventrolateral medullary respiratory neurons in the cat. J. Neurophysiol. 57, 1837–1853. Meyer-Franke, A., Wilkinson, G.A., Kruttgen, A., Hu, M., Munro, E., Hanson Jr., M.G., Reichardt, L.F., Barres, B.A., 1998. Depolarization and cAMP elevation rapidly recruit TrkB to the plasma membrane of CNS neurons. Neuron 21, 681–693. Millhorn, D.E., Eldridge, F.L., Waldrop, T.G., 1980a. Prolonged stimulation of respiration by a new central neural mechanism. Respir. Physiol. 41, 87–103. Millhorn, D.E., Eldridge, F.L., Waldrop, T.G., 1980b. Prolonged stimulation of respiration by endogenous central serotonin. Respir. Physiol. 42, 171–188. Minghetti, L., Greco, A., Potenza, R.L., Pezzola, A., Blum, D., Bantubungi, K., Popoli, P., 2007. Effects of the adenosine A2A receptor antagonist SCH 58621 on cyclooxygenase-2 expression, glial activation, and brain-derived neurotrophic factor availability in a rat model of striatal neurodegeneration. J. Neuropathol. Exp. Neurol. 66, 363–371. Minor, K.H., Akison, L.K., Goshgarian, H.G., Seeds, N.W., 2006. Spinal cord injuryinduced plasticity in the mouse—the crossed phrenic phenomenon. Exp. Neurol. 200, 486–495. Minor, K.H., Bournat, J.C., Toscano, N., Giger, R.J., Davies, S.J., 2011. Decorin, erythroblastic leukaemia viral oncogene homologue B4 and signal transducer and activator of transcription 3 regulation of semaphorin 3A in central nervous system scar tissue. Brain 134, 1140–1155. Miranda, J.D., White, L.A., Marcillo, A.E., Willson, C.A., Jaquid, J., Whittemore, S.R., 1999. Induction of Eph B3 after spinal cord injury. Exp. Neurol. 156, 218–222. Mire, E., Thomasset, N., Jakeman, L.B., Rougon, G., 2008. Modulating Sema3A signal with a L1 mimetic peptide is not sufficient to promote motor recovery and axon regeneration after spinal cord injury. Mol. Cell. Neurosci. 37, 222–235. Miyata, H., Zhan, W.Z., Prakash, Y.S., Sieck, G.C., 1995. Myoneural interactions affect diaphragm muscle adaptations to inactivity. J. Appl. Physiol. 79, 1640–1649. Mojsilovic-Petrovic, J., Jeong, G.B., Crocker, A., Arneja, A., David, S., Russell, D.S., Kalb, R.G., 2006. Protecting motor neurons from toxic insult by antagonism of adenosine A2a and Trk receptors. J. Neurosci. 26, 9250–9263. Moon, L.D., Asher, R.A., Rhodes, K.E., Fawcett, J.W., 2001. Regeneration of CNS axons back to their target following treatment of adult rat brain with chondroitinase ABC. Nat. Neurosci. 4, 465–466. Moreno, D.E., Yu, X.J., Goshgarian, H.G., 1992. Identification of the axon pathways which mediate functional recovery of a paralysed hemidiaphragm following spinal cord hemisection in the adult rat. Exp. Neurol. 182, 232–239. Muir, E.M., Fyfe, I., Gardiner, S., Li, L., Warren, P., Fawcett, J.W., Keynes, R.J., Rogers, J.H., 2010. Modification of N-glycosylation sites allows secretion of bacterial chondroitinase ABC from mammalian cells. J. Biotechnol. 145, 103–110. Mukhopadhyay, G., Doherty, P., Walsh, F.S., Crocker, P.R., Filbin, M.T., 1994. A novel role for myelin-associated glycoprotein as an inhibitor of axonal regeneration. Neuron 13, 757–767. Nakamae, T., Tanaka, N., Nakanishi, K., Kamei, N., Sadaki, H., Hamasaki, T., Yamada, K., Yamamoto, R., Mochizuki, Y., Ochi, M., 2009. Chondroitinase ABC promotes corticospinal axon growth in organotypic cocultures. Spinal Cord 47, 161–165. Nandoe Tewarie, R.D., Hurtado, A., Bartels, R.H., Grotenhuis, J.A., Oudega, M., 2010. A clinical perspective of spinal cord injury. NeuroRehabilitation 27 (2), 129–139.

213

214


Nantwi, K.D., 2009. Recovery of respiratory activity after C2 hemisection (C2HS): involvement of adenosinergic mechanisms. Respir. Physiol. Neurobiol. 169, 102–114. Nantwi, K.D., Goshgarian, H.G., 1998. Theophylline-induced recovery in a hemidiaphragm paralyzed by hemisection in rats: contribution of adenosine receptors. Neuropharmacology 37, 113–121. Nantwi, K.D., El-Bohy, A., Goshgarian, H.G., 1996. Actions of systemic theophylline on hemidiaphragmatic recovery in rats following cervical spinal cord hemisection. Exp. Neurol. 140, 53–59. Nantwi, K.D., El-Bohy, A.A., Schrimsher, G.W., Reier, P.J., Goshgarian, H.G., 1999. Spontaneous functional recovery in a paralyzed hemidiaphragm following upper cervical spinal cord injury in adult rats. Neurorehabil. Neural Repair 13, 225–234. Nantwi, K.D., Basura, G.J., Goshgarian, H.G., 2003. Effects of long-term theophylline exposure on recovery of respiratory function and expression of adenosine A1 mRNA in cervical spinal cord hemisected adult rats. Exp. Neurol. 182, 232–239. Nathan, P.W., Smith, M., Deacon, P., 1996. Vestibulospinal, reticulospinal and descending propriospinal nerve fibres in man. Brain 119, 1809–1833. Nicaise, C., Hala, T.J., Frank, D.M., Parker, J.L., Authelet, M., Leroy, K., Brion, J.-P., Wright, M.C., Lepore, A.C., 2012. Phrenic motor neuron degeneration compromises phrenic axonal circultry and diaphragm activity in a unilateral cervical contusion model of spinal cord injury. Exp. Neurol. 235, 539–552. Nigro, J., Wang, A., Mukhopadhyay, D., Lauer, M., Midura, R.J., Sackstein, R., Hascall, V.C., 2009. Regulation of heparin sulfate and chondroitin sulfate glycosaminoglycan biosynthesis by 4-fluoroglucosamine in murine airway smooth muscle cells. J. Biol. Chem. 284, 16832–16839. NSCISC, 2012. Spinal Cord Injury. Facts and Figures at a Glance. National Spinal Cord Injury Statistical Center, Birmingham, University of Alabama at Birmingham, National Spinal Cord Injury Statistical Center. Available at http://www.spinalcord.uab.edu. Assessed November 2012. O’Bryant, A.J., Allred, R.P., Maldonado, M.A., Cormack, L.K., Jones, T.A., 2011. Breeder and batch-dependent variability in the acquisition and performance of a motor skill in adult Long-Evans rats. Behav. Brain Res. 224, 112–120. O’Hara Jr., T.E., Goshgarian, H.G., 1991. Quantitative assessment of phrenic nerve functional recovery mediated by the crossed phrenic reflex at various time intervals after spinal cord injury. Exp. Neurol. 111, 224–250. Onai, T., Saji, M., Miura, M., 1987. Projections of supraspinal structures to the phrenic motor nucleus in rats studied by horseradish peroxidase microinjection method. J. Auton. Nerv. Syst. 21, 233–240. Onimaru, H., Homma, I., 2003. A novel functional neuron group for respiratory rhythm generation in the ventral medulla. J. Neurosci. 23, 1478–1486. Oo, T., Watt, J.W., Soni, B.M., Sett, P.K., 1999. Delayed diaphragm recovery in 12 patients after high cervical spinal cord injury. A retrospective review of the diaphragm status of 107 patients ventilated after acute spinal cord injury. Spinal Cord 37, 117–122. Park, S., Hong, Y.W., 2006. Transcriptional regulation of artemin is related to neurite outgrowth and actin polymerization in mature DRG neurons. Neurosci. Lett. 404, 61–66. Park, K.K., Liu, K., Hu, Y., Smith, P.D., Wang, C., Cai, B., Xu, B., Connolly, L., Kramvis, I., Sahin, M., He, Z., 2008. Promoting axon regeneration in the adult CNS by modulation of the PTEN/mTOR pathway. Science 322, 963–966. Parsons, M.P., Hirasawa, M., 2010. ATP-sensitive potassium channel-mediated lactate effect on orexin neurons: implications for brain energetics during arousal. J. Neurosci. 30, 8061–8070.

References

Pedata, F., Corsi, C., Melani, A., Bordoni, F., Latini, S., 2001. Adenosine extracellular brain concentrations and role of A2A receptors in ischemia. Ann. N. Y. Acad. Sci. 939, 74–84. Petersen, J., Russell, L., Andrus, K., MacKinnon, M., Silver, J., Kliot, M., 1996. Reduction of extra-neuronal scarring by ADCON-T/N after surgical intervention. Neurosurgery 38, 976–983. Petruska, J.C., Ichiyama, R.M., Jindrich, D.L., Crown, E.D., Tansey, K.E., Roy, R.R., Edgerton, V.R., Mendell, L.M., 2007. Changes in motoneuron properties and synaptic inputs related to step training after spinal cord transection in rats. J. Neurosci. 27, 4460–4471. Phillis, J.W., Delong, R.E., Towner, J.K., 1985. Adenosine and the regulation of cerebral blood flow during anoxia. In: Stefanovich, V., Rudolphi, K., Scubert, P. (Eds.), Adenosine: Receptors and Modulation of Cell Function. Oxford, United Kingdom, pp. 145–164. Pindzola, R.R., Doller, C., Silver, J., 1993. Putative inhibitory extracellular matrix molecules at the dorsal root entry zone of the spinal cord during development and after root and sciatic nerve lesions. Dev. Biol. 156, 34–48. Pitts, R.F., 1940. The respiratory center and its descending pathways. J. Comp. Neurol. 72, 605–625. Pizzorusso, T., Medini, P., Berardi, N., Chierzi, S., Fawcett, J.W., Maffei, L., 2002. Reactivation of ocular dominance plasticity in the adult visual cortex. Science 298, 1248–1251. Pizzorusso, T., Medini, P., Landi, S., Baldini, S., Berardi, N., Maffei, L., 2006. Structural and functional recovery from early monocular deprivation in adult rats. Proc. Natl. Acad. Sci. U.S.A 103, 8517–8522. Plant, G.W., Bates, M.L., Bunge, M.B., 2001. Inhibitory proteoglycan immunoreactivity is higher at the caudal than the rostral Schwann cell graft-transected spinal cord interface. Mol. Cell. Neurosci. 17, 471–487. Poduslo, J.F., Curran, G.L., 1996. Permeability at the blood-brain and blood-nerve barriers of the neurotrophic factors: NGF, CNTF, NT-3, BDNF. Brain Res. Mol. Brain Res. 36, 280–286. Polentes, J., Stamegna, J.C., Nieto-Sampedro, M., Gauthier, P., 2004. Phrenic rehabilitation and diaphragm recovery after cervical injury and transplantation of olfactory ensheathing cells. Neurobiol. Dis. 16, 638–653. Poon, P.C., Gupta, D., Shoichet, M.S., Tator, C.H., 2007. Clip compression model is useful for thoracic spinal cord injuries: histologic and functional correlates. Spine 32, 2853–2859. Popovich, P.G., Guan, Z., Wei, P., Huitinga, I., van Rooijen, N., Stokes, B.T., 1999. Depletion of hematogenous macrophages promotes partial hindlimb recovery and neuroanatomical repair after experimental spinal cord injury. Exp. Neurol. 158, 351–365. Porter, W.T., 1895. The path of the respiratory impulse from the bulb to the phrenic neucli. J. Physiol. Lond. 17, 455–485. Powell, F.L., Milsom, W.K., Mitchell, G.S., 1998. Time domains of the hypoxic ventilatory response. Respir. Physiol. 112, 123–134. Prabhakar, V., Capila, I., Bosques, C.J., Pojasek, K., Sasisekharan, R., 2005. Chondroitinase ABC 1 from Proteus vulgaris: cloning, recombinant expression and active site identification. Biochem. J. 386, 103–112. Prakash, Y.S., Miyata, H., Zhan, W.Z., Sieck, G.C., 1999. Inactivity-induced remodeling of neuromuscular junctions in rat diaphragmatic muscle. Muscle Nerve 22, 307–319. Qin, C., Chandler, M.J., Foreman, R.D., Farber, J.P., 2002. Upper thoracic respiratory interneurons integrate noxious somatic and visceral information in rats. J. Neurophysiol. 88, 2215–2223.

215

216


Qiu, J., Cai, D., Dai, H., McAtee, M., Hoffman, P.N., Bregman, B.S., Filbin, M.T., 2002a. Spinal axon regeneration induced by elevation of cyclic AMP. Neuron 34, 895–903. Qiu, J., Cai, D., Filbin, M.T., 2002b. A role for cAMP in regeneration during development and after injury. Prog. Brain Res. 137, 381–387. Raberger, G., Kraupp, O., Stuhlinger, W., Nell, G., Chirikdjian, J.J., 1970. The effects of an intracoronary infusion of adenosine on cardiac performance, blood supply and on myocardial metabolism in dogs. Pfluigers Arch. Gesamte. Physiol. 317, 20–34. Rapalino, O., Lazarov-Spiegler, O., Agranov, E., Velan, G.J., Yoles, E., Fraidakis, M., Solomon, A., Gepstein, R., Katz, A., Belkin, M., Hadani, M., Schwartz, M., 1998. Implantation of stimulated homologous macrophages results in partial recovery of paraplegic rats. Nat. Med. 4, 814–821. Richardson, P.M., McGuinness, U.M., Aguayo, A.J., 1980. Axons from CNS neurons regenerate into PNS grafts. Nature 284, 264–265. Rolls, A., Avidan, H., Cahalon, L., Schori, H., Bakalash, S., Litvak, V., Lev, S., Lider, O., Schwartz, M., 2004. A disaccharide derived from chondroitin sulphate proteoglycan promotes central nervous system repair in rats and mice. Eur. J. Neurosci. 20, 1973–1983. Rolls, A., Shechter, R., Schwartz, M., 2009. The bright side of the glial scar in CNS repair. Nat. Rev. Neurosci. 10, 235–241. Rossignol, S., Barriere, G., Frigon, A., Barthelemy, D., Bouyer, L., Provencher, J., Leblond, H., Bernard, G., 2008. Plasticity of locomotor sensorimotor interactions after peripheral and/or spinal lesions. Brain Res. Rev. 57, 228–240. Routal, R.V., Pal, G.P., 1999. Location of the phrenic nucleus in the human spinal cord. J. Anat. 195, 617–621. Rudge, J.S., Silver, J., 1990. Inhibition of neurite outgrowth on astroglial scars in vitro. J. Neurosci. 10, 3594–3603. Rudolphi, K.A., Schubert, P., Parkinson, F.E., Fredholm, B.B., 1992. Neuroprotective role of adenosine in cerebral ischaemia. Trends Pharmacol. Sci. 13, 439–445. Rutishauser, U., 2008. Polysialic acid in the plasticity of the developing and adult vertebrate nervous system. Nat. Rev. Neurosci. 9, 26–35. Sandhu, M.S., Dougherty, B.J., Lane, M.A., Bolser, D.C., Kirkwood, P.A., Reier, P.J., Fuller, D.D., 2009. Respiratory recovery following high cervical hemisection. Respir. Physiol. Neurobiol. 169, 94–101. Sandler, A.N., Tator, C.H., 1976. Effect of acute spinal cord compression injury on regional spinal cord blood flow in primates. J. Neurosurg. 45, 660–676. Sands, W.A., Palmer, T.M., 2008. Regulating gene transcription in response to cyclic AMP elevation. Cell. Signal. 20, 460–466. Satriotomo, I., Dale, E.A., Dahlberg, J.M., Mitchell, G.S., 2012. Repetitive actue intermittent hypoxia increases expression of proteins associated with plasticity in the phrenic motor nucleus. Exp. Neurol. 237, 103–115. Schnell, L., Schwab, M.E., 1990. Axonal regeneration in the rat spinal cord produced by an antibody against myelin-associated neurite growth inhibitors. Nature 343, 269–272. Schnell, L., Schneider, R., Kolbeck, R., Barde, Y.A., Schwab, M.E., 1994. Neurotrophin-3 enhances sprouting of corticospinal tract during development and after adult spinal cord lesion. Nature 367, 170–173. Schucht, P., Raineteau, O., Schwab, M.E., Fouad, K., 2002. Anatomical correlates of locomotor recovery following dorsal and ventral lesions of the rat spinal cord. Exp. Neurol. 176, 143–153.

References

Schwartz, N.B., Galligani, L., Ho, P.L., Dorfman, A., 1974. Stimulation of synthesis of free chondroitin sulfate chains by beta-D-xylosides in cultured cells. Proc. Natl. Acad. Sci. U.S. A 71, 4047–4051. Schwartz, M., Moalem, G., Leibowitz-Amit, R., Cohen, I.R., 1999. Innate and adaptive immune responses can be beneficial for CNS repair. Trends Neurosci. 22, 295–299. Seligman, A.M., Davis, W.A., 1941. The effects of some drugs on the crossed phrenic phenomenon. Am. J. Physiol. 143, 102–106. Sengottuvel, V., Leibinger, M., Pfreimer, M., Andreadaki, A., Fischer, D., 2011. Taxol facilitates axon regeneration in the mature CNS. J. Neurosci. 31, 2688–2699. Shields, L.B., Zhang, Y.P., Burke, D.A., Gray, R., Shields, C.B., 2008. Benefit of chondroitinase ABC on sensory axon regeneration in a laceration model of spinal cord injury in the rat. Surg. Neurol. 69, 568–577. Shimizu, H., Watanabe, E., Hiyama, T.Y., Nagakura, A., Fujikawa, A., Okado, H., Yanagawa, Y., Obata, K., Noda, M., 2007. Glial Nax channels control lactate signaling to neurons for brain [Na +] sensing. Neuron 54, 59–72. Singas, E., Grimm, D.R., Almenoff, P.L., Lesser, M., 1999. Inhibition of airway hyperreactivity by oxybutynin chloride in subjects with cervical spinal cord injury. Spinal Cord 37, 279–283. Skup, M., Dwornik, A., Macias, M., Sulejczak, D., Wiater, M., Czarkowska-Bauch, J., 2002. Long-term locotomotor training up-regulates TrkB(FL) receptor-like proteins, brain-derived neurotrophic factor, and neurotrophin 4 with different topographies of expression in oligodendroglia and neurons in the spinal cord. Exp. Neurol. 176, 289–307. Slack, S.E., Pezet, S., McMahon, S.B., Thompson, S.W., Malcangio, M., 2004. Brain derived neurotrophic factor induces NMDA receptor subunit one phosphorylation via ERK and PKC in the rat spinal cord. Eur. J. Neurosci. 20, 1769–1778. Smith-Thomas, L.C., Fok-Seang, J., Stevens, J., Du, J.-S., Muir, E., Faissner, A., Geller, H.M., Rogers, J.H., Fawcett, J.W., 1994. An inhibitor of neurite outgrowth produced by astrocytes. J. Cell Sci. 107, 1687–1695. Smith-Thomas, L., Stevens, J., Fok-Seang, J., Faissner, A., Rogers, J.H., Fawcett, J.W., 1995. Increased axon regeneration in astrocytes grown in the presence of proteoglycan synthesis inhibitors. J. Cell Sci. 108, 1307–1315. Snow, D.M., Letourneau, P.C., 1992. Neurite outgrowth on a step gradient of chondroitin sulfate proteoglycan (CS-PG). J. Neurobiol. 23, 322–336. Snow, D.M., Lemmon, V., Carrino, D.A., Caplan, A.I., Silver, J., 1990. Sulfated proteoglycans in astroglial barriers inhibit neurite outgrowth in vitro. Exp. Neurol. 109, 111–130. Snow, D.M., Smith, J.D., Gurwell, J.A., 2002. Binding characteristics of chondroitin sulfate proteoglycans and laminin-1, and correlative neurite outgrowth behaviors in a standard tissue culture choice assay. J. Neurobiol. 51, 285–301. Stirling, D.P., Khodarahmi, K., Liu, J., McPhail, L.T., McBride, C.B., Steeves, J.D., Ramer, M.S., Tetzlaff, W., 2004. Minocycline treatment reduces delayed oligodendrocyte death, attenuates axonal dieback, and improves functional outcome after spinal cord injury. J. Neurosci. 24, 2182–2190. Stohlman Jr., F., 1959. Observations on the physiology of erythropoietin and its role in the regulation of red cell production. Ann. N. Y. Acad. Sci. 77, 710–724. Tai, Q., Palazzolo, K.L., Goshgarian, H.G., 1997. Synaptic plasticity of 5-hydroxytryptamineimmunoreactive terminals in the phrenic nucleus following spinal cord injury: a quantitative electron microscopic analysis. J. Comp. Neurol. 386, 613–624.

217

218


Tan, W., Janczewski, W.A., Yang, P., Shao, X.M., Callaway, E.M., Feldman, J.L., 2008. Silencing preBotzinger Complex somatostatin-expressing neurons induces persistent apnea in awake rat. Nat. Neurosci. 11, 538–540. Tang, X., Davies, J.E., Davies, S.J., 2003. Changes in distribution, cell associations, and protein expression levels of NG2, neurocan, phosphacan, brevican, versican V2, and tenascinC during acute to chronic maturation of spinal cord scar tissue. J. Neurosci. Res. 71, 427–444. Tian, G.F., Duffin, J., 1996. Connections from upper cervical inspiratory neurons to phrenic and intercostals motoneurons studied with cross-correlation in the decerebrate rat. Exp. Brain Res. 110, 196–204. Tian, G.F., Duffin, J., 1998. The role of dorsal respiratory group neurons studied with crosscorrelation in the decerebrated rat. Exp. Brain Res. 121, 29–34. Tian, G.F., Peever, J.H., Duffin, J., 1998. Botzinger-complex expiratory neurons monosynaptically inhibit phrenic motoneurons in the decerebrated rat. Exp. Brain Res. 122, 149–156. Tillakaratne, N.J., Mouria, M., Ziv, N.B., Roy, R.R., Edgerton, V.R., Tobin, A.J., 2000. Increased expression of glutamate decarboxylase (GAD(67)) in feline lumbar spinal cord after complete thoracic spinal cord transection. J. Neurosci. Res. 60, 219–230. Tom, V.J., Houle, J.D., 2008. Intraspinal microinjection of chondroitinase ABC following injury promotes axonal regeneration out of a peripheral nerve bridge. Exp. Neurol. 211, 315–319. Tom, V.J., Steinmetz, M.P., Miller, J.H., Doller, C.M., Silver, J., 2004. Studies on the development and behaviour of the dystrophic growth cone, the hallmark of regeneration failure, in an in vitro model of the glial scar and after spinal cord injury. J. Neurosci. 24, 6531–6539. Tom, V.J., Kadakia, R., Santi, L., Houle, J.D., 2009a. Administration of chondroitinase ABC rostral or caudal to a spinal cord injury site promotes anatomical but not functional plasticity. J. Neurotrauma 26, 2323–2333. Tom, V.J., Sandrow-Feinberg, H.R., Miller, K., Santi, L., Connors, T., Lemay, M.A., Houle, J.D., 2009b. Combining peripheral nerve grafts and chondroitinase promotes functional axonal regeneration in the chronically injured spinal cord. J. Neurosci. 29, 14881–14890. Tom, V.J., Sandrow-Feinberg, H.R., Miller, K., Domitrovich, C., Bouyer, J., Zhukareva, V., Klaw, M.C., Lemay, M.A., Houle, J.D., 2013. Exogenous BDNF enhances the integration of chronically injured axons that regenerate through a peripheral nerve grafted into a chondroitinase-treated spinal cord injury site. Exp. Neurol. 239, 91–100. Totoiu, M.O., Keirstead, H.S., 2005. Spinal cord injury is accompanied by chronic progressive demyelination. J. Comp. Neurol. 486, 373–383. Tropea, D., Caleo, M., Maffel, L., 2003. Synergistic effects of brain derived neurotropic factor and chondroitinase ABC on superior colliculus in adult rats. J. Neurosci. 23, 7034–7044. Trumbower, R.D., Jayaraman, A., Mitchell, G.S., Rymer, W.Z., 2012. Exposure to acute intermittent hypoxia augments somatic motor function in humans with incomplete spinal cord injury. Neurorehabil. Neural Repair 26, 163–172. Vahidi, B., Park, J.W., Kim, H.J., Leon, N.L., 2008. Micro-fluidic-based strip assay for testing the effects of various surface-bound inhibitors in spinal cord injury. J. Neurosci. Methods 170, 188–196. Vavrek, R., Pearse, D.D., Fouad, K., 2007. Neuronal populations capable of regeneration following a combined treatment in rats with spinal cord transection. J. Neurotrauma 24, 1667–1673.

References

Vinit, S., Gauthier, P., Stamegna, J.C., Kastner, A., 2006. High cervical lateral spinal cord injury results in long-term ipsilateral hemidiaphragm paralysis. J. Neurotrauma 23, 1137–1146. Vinit, S., Stamegna, J.C., Boulenguez, P., Gauthier, P., Kastner, A., 2007. Restorative respiratory pathways after partial cervical spinal cord injury: role of ipsilateral phrenic afferents. Eur. J. Neurosci. 25, 3551–3560. Vinit, S., Darlot, F., Stamegna, J.C., Sanchez, P., Gauthier, P., Kastner, A., 2008. Longterm respiratory pathways reorganization after partial cervical spinal cord injury. Eur. J. Neurosci. 27, 897–908. Vinit, S., Windelborn, J.A., Mitchell, G.S., 2011. Lipopolysaccharide attenuates phrenic longterm facilitation following acute intermittent hypoxia. Respir. Physiol. Neurobiol. 176, 130–135. Vorobyov, V., Kwok, J.C., Fawcett, J.W., Sengpiel, F., 2013. Effects of digesting chondroitin sulphate proteoglycans on plasticity in cat primary visual cortex. J. Neurosci. 33, 234–243. Wang, D., Ichiyama, R.M., Zhao, R., Andrews, M.R., Fawcett, J.W., 2011. Chondroitinase combined with rehabilitation promotes recovery of forelimb function in rats with chronic spinal cord injury. J. Neurosci. 31, 9332–9344. Webb, A.A., Gowribai, K., Muir, G.D., 2003. Fischer (F-344) rats have different morphology, sensorimotor and locomotor abilities compared to Lewis, Long-Evans, Sprague-Dawley and Wistar rats. Behav. Brain Res. 144, 143–156. Weishaupt, N., Li, S., DiPardo, A., Sipione, S., Fouad, K., 2013. Synergistic effects of BDNF and rehabilitive training on recovery after cervical spinal cord injury. Behav. Brain Res. 239, 31–42. White, T.E., Lane, M.A., Sandu, M.S., O’Steen, B.E., Fuller, D.D., Reier, P.J., 2010. Neuronal progenitor transplantation and respiratory outcomes following upper cervical spinal cord injury in adult rats. Exp. Neurol. 225, 231–236. Wilkerson, J.E., Mitchell, G.S., 2009. Daily intermittent hypoxia augments spinal BDNF levels. ERK phosphorylation and respiratory long-term facilitation. Exp. Neurol. 217, 116–123. Wilkerson, J.E., MacFarlane, P.M., Hoffman, M.S., Mitchell, G.S., 2007. Respiratory plasticity following intermittent hypoxia: roles of protein phosphatases and reactive oxygen species. Biochem. Soc. Trans. 35, 1269–1272. Wilkerson, J.E., Satriotomo, I., Baker-Herman, T.L., Watters, J.J., Mitchell, G.S., 2008. Okadaic acid-sensitive protein phosphatases constrain phrenic long-term facilitation after sustained hypoxia. J. Neurosci. 28, 2949–2958. Willson, C.A., Irizarry-Ramı´rez, M., Gaskins, H.E., Cruz-Orengo, L., Fiqueroa, J.D., Whittemore, S.R., Miranda, J.D., 2002. Upregulation of EphA receptor expression in the injured adult rat spinal cord. Cell Transplant. 11, 229–239. Willson, C.A., Miranda, J.D., Foster, R.D., Onifer, S.M., Whittemore, S.R., 2003. Transection of the adult rat spinal cord up-regulates EphB3 receptor and ligand expression. Cell Transplant. 12, 279–290. Windelborn, J.A., Mitchell, G.S., 2012. Glial activation in the spinal ventral horn caudal to cervical injury. Respir. Physiol. Neurobiol. 180, 61–68. Windle, W.F., Clemente, C.D., Chambers, W.W., 1952. Inhibition of formation of a glial barrier as a means of permitting a peripheral nerve to grow into the brain. J. Comp. Neurol. 96, 359–369. Winn, H.R., Rubio, G.R., Berne, R.M., 1981a. The role of adenosine in the regulation of cerebral blood flow. J. Cereb. Blood Flow Metab. 1, 239–244.

219

220


Winn, H.R., Rubio, R., Berne, R.M., 1981b. Brain adenosine concentration during hypoxia in rats. Am. J. Physiol. 241, H235–H242. Wong, I., Liao, H., Bai, X., Zaknic, A., Zhong, J., Guan, Y., Li, H.Y., Wang, Y.J., Zhou, X.F., 2010. ProBDNF inhibits infiltration of ED1 + macrophages after spinal cord injury. Brain Behav. Immun. 24, 585–597. Yamada, H., Ezure, K., Manabe, M., 1988. Efferent projections of inspiratory neurons of the ventral respiratory group. A dual labeling study in the rat. Brain Res. 455, 283–294. Yamagata, T., Saito, H., Habuchi, O., Suzuki, S., 1968. Purification and properties of bacterial chondroitinases and chondrosulfatases. J. Biol. Chem. 243, 1523–1535. Ying, Z., Roy, R.R., Edgerton, V.R., Gomez-Pinilla, F., 2005. Exercise restores levels of neurotrophins and synaptic plasticity following spinal cord injury. Exp. Neurol. 193, 411–419. Ying, Z., Roy, R.R., Zhong, H., Zdunowski, S., Edgerton, V.R., Gomez-Pinilla, F., 2008. BDNF-exercise interactions in the recovery of symmetrical stepping after a cervical hemisection in rats. Neuroscience 155, 1070–1078. Young, W., Koreh, I., 1986. Potassium and calcium changes in injured spinal cords. Brain Res. 365, 42–53. Young, J.K., Baker, J.H., Montes, M.I., 2000. The brain response to 2-deoxy glucose is blocked by a glial drug. Pharmacol. Biochem. Behav. 67, 233–239. Zabka, A.G., Behan, M., Mitchell, G.S., 1985. Selected contribution: time-dependent hypoxic respiratory responses in female rats are influenced by age and by the estrus cycle. J. Appl. Physiol. 91 (6), 2831–2838. Zabka, A.G., Behan, M., Mitchell, G.S., 2001. Long term facilitation of respiratory motor output decreases with age in male rats. J. Physiol. 531, 509–514. Zhang, Y., Zhang, X., Wu, D., Verhaagen, J., Richardson, P.M., Yeh, J., Bo, X., 2007. Lentiviral-mediated expression of polysialic acid in spinal cord and conditioning lesion promote regeneration of sensory axons into spinal cord. Mol. Ther. 15, 1796–1804. Zhao, R.R., Muir, E.M., Alves, J.N., Rickman, H., Allan, A.Y., Kwok, J.C., Roet, K.C., Verhaagen, J., Schneider, B.L., Bensadoun, J.C., Ahmed, S.G., Yanez-Munoz, R.J., Keynes, R.J., Fawcett, J.W., Rogers, J.H., 2011. Lentiviral vectors express chondroitinase ABC in cortical projections and promote sprouting of injured corticospinal axons. J. Neurosci. Methods 201, 228–238. Zheng, F., Wang, L., Brauner, M., Liewald, J.F., Kay, K., Watzke, N., Wood, P.G., Bamberg, E., Nagel, G., Gottschalk, A., Deisseroth, K., 2007. Multimodal fast optical interrogation of neural circuitry. Nature 446, 633–639. Zhou, S.Y., Goshgarian, H.G., 1999. Effects of serotonin on crossed phrenic nerve activity in cervical spinal cord hemisected rats. Exp. Neurol. 160, 446–453. Zhou, S.Y., Goshgarian, H.G., 2000. 5-Hydroxytryptophan-induced respiratory recovery after cervical spinal cord hemisection in rats. J. Appl. Physiol. 89, 1528–1536. Zhou, S.Y., Basura, G.J., Goshgarian, H.G., 2001. Serotonin(2) receptors mediate respiratory recovery after cervical spinal cord hemisection in adult rats. J. Appl. Physiol. 91, 2665–2673. Zimmer, M.B., Goshgarian, H.G., 2006. Spinal activation of serotonin 1A receptors enhances latent respiratory activity after spinal cord injury. J. Spinal Cord Med. 29, 147–155. Zimmer, M.B., Goshgarian, H.G., 2007. GABA, not glycine, mediates inhibition of latent respiratory motor pathways after spinal cord injury. Exp. Neurol. 203, 493–501. Zou, J., Neubauer, D., Dyess, K., Ferguson, T.A., Muir, D., 1998. Degradation of chondroitin sulphate proteoglycan enhances the neurite-promoting potential of spinal cord tissue. Exp. Neurol. 154, 654–666.

Targeted, activity-dependent spinal stimulation produces long-lasting motor recovery in chronic cervical spinal cord injury.

Acute hydrocephalus following cervical spinal cord injury.

TRIM32 affects the recovery of motor function following spinal cord injury through regulating proliferation of glia.

Forelimb motor performance following cervical spinal cord contusion injury in the rat.

Respiratory motor outputs following unilateral midcervical spinal cord injury in the adult rat.

Phrenic motor outputs in response to bronchopulmonary C-fibre activation following chronic cervical spinal cord injury.

Silencing ephrinB3 improves functional recovery following spinal cord injury.

Deep brain stimulation for locomotor recovery following spinal cord injury.

A cervical spinal cord injury following chiropractic manipulation.

Forelimb muscle plasticity following unilateral cervical spinal cord injury.

Cervical spinal cord injury without bony injury.

Editorial note on: Respiratory CO2 response in acute cervical spinal cord injury (CO2 response in spinal cord injury).

Recovery of the pulmonary chemoreflex and functional role of bronchopulmonary C-fibers following chronic cervical spinal cord injury.

Pregnancy following spinal cord injury.

Suicide following spinal cord injury.

Trigemino-cervical reflex in spinal cord injury.

Cervical ankylosis with acute spinal cord injury.

Cervical spinal cord injury in children.

Localized delivery of brain-derived neurotrophic factor-expressing mesenchymal stem cells enhances functional recovery following cervical spinal cord injury.

Mechanisms underlying the recovery of urinary bladder function following spinal cord injury.

Ryk controls remapping of motor cortex during functional recovery after spinal cord injury.

Electrophysiologic changes in lumbar spinal cord after cervical cord injury.

Neuroprotective effects of the Buyang Huanwu decoction on functional recovery in rats following spinal cord injury.

Spinal cord transplants enhance the recovery of locomotor function after spinal cord injury at birth.