The aim of this review is to describe the rationale and main underlying reasons for undertaking, ... more The aim of this review is to describe the rationale and main underlying reasons for undertaking, during clinical development, the study of drug candidates used separately and/or in combination with other technologies. To ease comprehension, reference will be made to the case of SpinalonTM, a new fixed-dose combination (FDC) product composed of levodopa/carbidopa/buspirone. This drug is capable of triggering, within minutes after a single administration orally, 45 minute- episodes of basic involuntary 'reflex' walking in paraplegic animals. Daily administration during one month was shown to lead to increased performance over time, with health benefits onto musculoskeletal and cardiovascular systems. A double-blind, dose-escalation, randomized phase I/IIa study with 45 spinal cord-injured subjects successfully provided the maximal tolerated dose (MTD) and preliminary evidence of efficacy. As an attempt to explore how efficacy may be optimized, a phase IIb study with 150 subjec...
Locomotion is one of the most complex motor behaviors. Locomotor patterns change during early lif... more Locomotion is one of the most complex motor behaviors. Locomotor patterns change during early life, reflecting development of numerous peripheral and hierarchically organized central structures. Among them, the spinal cord is of particular interest since it houses the central pattern generator (CPG) for locomotion. This main command center is capable of eliciting and coordinating complex series of rhythmic neural signals sent to motoneurons and to corresponding target-muscles for basic locomotor activity. For a long-time, the CPG has been considered a black box. In recent years, complementary insights from in vitro and in vivo animal models have contributed significantly to a better understanding of its constituents, properties and ways to recover locomotion after a spinal cord injury (SCI). This review discusses key findings made by comparing the results of in vitro isolated spinal cord preparations and spinal-transected in vivo models from neonatal animals. Pharmacological, electr...
The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry, 2017
The ability of dedicated spinal circuits, referred to as central pattern generators (CPGs), to pr... more The ability of dedicated spinal circuits, referred to as central pattern generators (CPGs), to produce the basic rhythm and neural activation patterns underlying locomotion can be demonstrated under specific experimental conditions in reduced animal preparations. The existence of CPGs in humans is a matter of debate. Equally elusive is the contribution of CPGs to normal bipedal locomotion. To address these points, we focus on human studies that utilized spinal cord stimulation or pharmacological neuromodulation to generate rhythmic activity in individuals with spinal cord injury, and on neuromechanical modeling of human locomotion. In the absence of volitional motor control and step-specific sensory feedback, the human lumbar spinal cord can produce rhythmic muscle activation patterns that closely resemble CPG-induced neural activity of the isolated animal spinal cord. In this sense, CPGs in humans can be defined by the activity they produce. During normal locomotion, CPGs could con...
The mammalian lumbar spinal cord experimentally isolated from supraspinal and afferent feedback i... more The mammalian lumbar spinal cord experimentally isolated from supraspinal and afferent feedback input remains capable of expressing some basic locomotor function when appropriately stimulated. This ability has been attributed to spinal neural circuits referred to as central pattern generators (CPGs). In individuals with a severe spinal cord injury, rhythmic activity in paralyzed leg muscles can be generated by phasic proprioceptive feedback during therapist- or robotic-assisted stepping on a motorized treadmill. Here, we critically review to what extent the resulting motor output represents locomotor-like activity, and whether these motor patterns are the result of activation of CPGs, as commonly suggested in the literature. Attempts will be made to further delineate the pivotal roles played by mechanisms such as spinal proprioceptive reflexes and their alterations after spinal cord injury, the central excitability level, and by neurotransmitters critical for spinal locomotor activi...
Locomotion is a semi-automatic daily task. Several studies show that muscle activity is fairly st... more Locomotion is a semi-automatic daily task. Several studies show that muscle activity is fairly stereotyped during normal walking. Nevertheless, each human leg contains over 50 muscles and locomotion requires flexibility in order to adapt to different conditions as, for instance, different speeds, gaits, turning, obstacle avoidance, altered gravity levels, etc. Therefore, locomotor control has to deal with a certain level of flexibility and non-linearity. In this review, we describe and discuss different findings dealing with both simplicity and variability of the muscular control, as well as with its maturation during development. Despite complexity and redundancy, muscle activity patterns and spatiotemporal maps of spinal motoneuron output during human locomotion show both stereotypical features as well as functional re-organization. Flexibility and different solutions to adjust motor patterns should be considered when considering new rehabilitation strategies to treat disorders in...
In recent years, many researches put significant efforts into understanding and assessing the fun... more In recent years, many researches put significant efforts into understanding and assessing the functional state of the spinal locomotor circuits in humans. Various techniques have been developed to stimulate the spinal cord circuitries, which may include both diffuse and quite specific tuning effects. Overall, the findings indicate that tonic and rhythmic spinal activity control are not separate phenomena but are closely integrated to properly initiate and sustain stepping. The spinal cord does not simply transmit information to and from the brain. Its physiologic state determines reflex, postural and locomotor control and, therefore, may affect the recovery of the locomotor function in individuals with spinal cord and brain injuries. This review summarizes studies that examine the rhythmogenesis capacity of cervical and lumbosacral neuronal circuitries in humans and its importance in developing central pattern generator-modulating therapies.
No drug treatment capable of restoring locomotor capabilities in patients suffering a motor-compl... more No drug treatment capable of restoring locomotor capabilities in patients suffering a motor-complete spinal cord injury (SCI) has ever been developed. We assessed the safety and efficacy of an activator of spinal locomotor neurons in humans, which were shown in paraplegic animals to elicit temporary episodes of involuntary walking. Single administration of buspirone/levodopa/carbidopa (Spinalon TM), levodopa/carbidopa (ratio 4: 1), and buspirone or placebo was performed using a dose-escalation design in 45 subjects placed in supine position who had had an SCI classified as complete (AIS A) or motor-complete/sensory incomplete (AIS B) for at least 3 months. Blood samples before and at regular intervals (15, 30, 60, 120, 240 min) after treatment were collected for hematological and pharmacokinetic (PK) analyses. Electromyographic (EMG) activity of eight muscles (four per leg) was monitored prior to and at several time points after drug administration. SpinalonTM (10-35 mg buspirone/10...
Non-volatile general anaesthetics are thought to reduce brain activity by potentiating inhibitory... more Non-volatile general anaesthetics are thought to reduce brain activity by potentiating inhibitory GABA A receptor channels but also cause adverse effects by suppressing L-type calcium channels in the heart. In sections of the spinal cord, the non-volatile anaesthetics pentobarbital, thiopental and propofol reduced excitability of sensorimotor neurons by suppressing plateau potentials mediated by L-type calcium channels. This effect was independent of GABA A receptor potentiation but occurred in an overlapping concentration range. Therefore, the suppressive effect of non-volatile anaesthetics on L-type calcium channels can contribute to the reduction of spinal sensorimotor activity during anaesthesia. The results support the idea that general anaesthesia is achieved through several mechanisms and suggest that procedures for anaesthesia may be improved by combining selective agents for each mechanism in optimal concentrations. 1998 IBRO. Published by Elsevier Science Ltd.
Objective: Differences between traumatic (TSCI) and non-traumatic (NTSCI) spinal cord-injured pat... more Objective: Differences between traumatic (TSCI) and non-traumatic (NTSCI) spinal cord-injured patients with comparable geographical and socio-economical background have rarely been studied. The objective was to examine and compare a set of epidemiological, clinical, and functional characteristics in TSCI and NTSCI patients.
Study design: Case report. Objectives: To report a case where a monoplegic patient received L-DOP... more Study design: Case report. Objectives: To report a case where a monoplegic patient received L-DOPA and/or buspirone. These compounds, normally used in the treatment of Parkinson's disease and anxiety respectively, were recently shown to induce spinal locomotor network activity and reflex stepping-like movements in animal models of spinal cord injury (SCI). However, the safety of these drugs as potential treatments for Central Pattern Generator (CPG) activation in paralyzed individuals remain unclear. Setting: St-Jean-Chrysostome, Quebec, Canada. Method: The acute effects induced by these compounds were qualitatively assessed by the patient, a 38-year-old man who underwent surgery 17 years ago to remove an intracavernous angioma located at the mid-thoracic level (T5-T6) of the spinal cord. Results: Self-administration every 2 days of L-DOPA (200, 400 and 600 mg, p.o.) and buspirone (5, 10 and 15 mg, p.o.) either separately or combined led to no atypical side effects (that is, occasional sleepiness, nervousness, insomnia or mild headaches). No movement was induced ipsilaterally although some sensations referred to by the patient as an increased blood flow in the lower back and upper leg regions were reported shortly after administration of the combined treatment.
YH. Suppression by intrathecal BmK IT2 on rat spontaneous pain behaviors and spinal c-Fos express... more YH. Suppression by intrathecal BmK IT2 on rat spontaneous pain behaviors and spinal c-Fos expression induced by formalin. Brain Res Bull 73: 248 -253, 2007. Ballermann M, Fouad K. Spontaneous locomotor recovery in spinal cord injured rats is accompanied by anatomical plasticity of reticulospinal fibers. S. Noradrenergic agonists and locomotor training affect locomotor recovery after cord transection in adult cats. Brain Res Bull 30: 387-393, 1993. Barbeau H, Rossignol S. Recovery of locomotion after chronic spinalization in the adult cat. Brain Res 412: 84 -95, 1987. Bareyre FM, Kerschensteiner M, Raineteau O, Mettenleiter TC, Weinmann O, Schwab ME. The injured spinal cord spontaneously forms a new intraspinal circuit in adult rats. Behrman AL, Harkema SJ. Locomotor training after human spinal cord injury: a series of case studies. Phys Ther 80: 688 -700, 2000. Belanger M, Drew T, Provencher J, Rossignol S. A comparison of treadmill locomotion in adult cats before and after spinal transaction. J Neurophysiol 76: 471-491, 1996. Brown TG. The intrinsic factors in the act of progression in the mammals. Proc R Soc Lond B Biol Sci 84: 308 -319, 1911. Brown TG. On the nature of the fundamental activity of the nervous centres;
Reorganization and plasticity after spinal cord injury have been recently shown to take place in ... more Reorganization and plasticity after spinal cord injury have been recently shown to take place in sublesional neuronal networks, but the possibility of strain-dependent changes at that level has never been explored. The authors studied the spontaneous return of hindlimb movement in low-thoracic spinal cord transected (Tx) mice from 3 commonly used strains. Without intervention, most CD1, C57BL/6, and BALB/c mice displayed some hindlimb movement recovery after Tx. Although all assessment methods unanimously reported that CD1 displayed higher recovery levels than did the C57BL/6 and BALB/c, higher scores were generally found with the Antri-Orsal-Barthe (M. Antri, D. Orsal, & J. Y. Barthe, 2002) and the Average Combined Score (P. A. Guertin, 2005a) methods. Such spontaneous recovery in low-thoracic Tx mice is likely the result of neuronal plasticity at the lumbosacral spinal cord level, suggesting that these sublesional changes are strain dependent.
L-beta-3,4-Dihydroxyphenylalanine (L-DOPA) and quipazine, respectively dopamine/noradrenaline pre... more L-beta-3,4-Dihydroxyphenylalanine (L-DOPA) and quipazine, respectively dopamine/noradrenaline precursor and serotonergic (5-HT 2 ) receptor agonist, were injected intraperitoneally in low-thoracic spinal mice at 7 days post-spinalization. In mice pre-treated with decarboxylase and monoamine oxydase inhibitors, L-DOPA (30-100 mg/kg) was found not to induce air-stepping. On the other hand, L-DOPA (40 mg/kg) consistently triggered locomotor-like movements if combined with low doses of quipazine (0.4-0.7 mg/kg) or if mice were placed on a motor-driven treadmill running at low speed. However, twitches, spasms, and other non-locomotor movements were also induced, especially on the treadmill. These results suggest that (1) spinal catecholaminergic and serotonergic receptors interact synergistically to generate locomotor-like movements in chronic spinal mice, and that (2) hindlimb afferent inputs associated with the treadmill conditions contribute to the genesis of locomotor-like and non-locomotor movements induced by these drugs. q
A role of serotonin receptors (5-HTRs) in spinal rhythmogenesis has been proposed several years a... more A role of serotonin receptors (5-HTRs) in spinal rhythmogenesis has been proposed several years ago based mainly upon data showing that bath-applied 5-HT could elicit locomotor-like rhythms in in vitro isolated spinal cord preparations. Such a role was partially confirmed in vivo after revealing that systemically administered 5-HTR(2) agonists, such as quipazine, could induce some locomotor-like movements (LM) in completely spinal cord-transected (Tx) rodents. However, given the limited binding selectivity of currently available 5-HTR(2) agonists, it has remained difficult to determine clearly if one receptor subtype is specifically associated with LM induction. In situ hybridization, data using tissues from L1-L2 spinal cord segments, where critical locomotor network elements have been identified in mice, revealed greater 5-HTR(2A) mRNA levels in low-thoracic Tx than non-Tx animals. This expression level remained elevated for several days, specifically in the lateral intermediate zone, where peak values were detected at 1 week post-Tx and returned to normal at 3 weeks post-Tx. Behavioral and kinematic analyses revealed quipazine-induced LM in 1-week Tx mice either non-pretreated or pretreated with selective 5-HTR(2B) and/or 5-HTR(2C) antagonists. In contrast, LM completely failed to be induced by quipazine in animals pretreated with selective 5-HTR(2A) antagonists. Altogether, these results provide strong evidence suggesting that 5-HTR(2A) are specifically associated with spinal locomotor network activation and LM generation induced by quipazine in Tx animals. These findings may contribute to design drug treatments aimed at promoting locomotor function recovery in chronic spinal cord-injured patients.
Study design: Experimental laboratory investigations with paraplegic mouse models. Objectives: To... more Study design: Experimental laboratory investigations with paraplegic mouse models. Objectives: To review the most recent advances in the field of spinal cord injury research; immune system response, regeneration, and functional recovery. Settings: Methods: Assessment of regenerative processes and locomotor function recovery induced by a variety of treatments and approaches in wild-type and genetically engineered mice with complete or incomplete lesions of the spinal cord.
Dopamine (DA) is well-recognized for its determinant role in the modulation of various brain func... more Dopamine (DA) is well-recognized for its determinant role in the modulation of various brain functions. DA was also found in in vitro isolated invertebrate preparations to activate per se the central pattern generator for locomotion. However, it is less clear whether such a role as an activator of central neural circuitries exists in vertebrate species. Here, we studied in vivo the effects induced by selective DA receptor agonists and antagonists on hindlimb movement generation in mice completely spinal cord-transected (Tx) at the low-thoracic level (Th9/10). Administration of D1/D5 receptor agonists (0.5-2.5 mg kg −1 , i.p.) was found to acutely elicit rhythmic locomotor-like movements (LMs) and non-locomotor movements (NLMs) in untrained and non-sensory stimulated animals. Comparable effects were found in mice lacking the D5 receptor (D5KO) whereas D1/D5 receptor antagonist-pretreated animals (wild-type or D5KO) failed to display D1/D5 agonist-induced LMs. In contrast, administration of broad spectrum or selective D2, D3 or D4 agonists consistently failed to elicit significant hindlimb movements. Overall, the results clearly show in mice the existence of a role for D1 receptors in spinal network activation and corresponding rhythmic movement generation.
The aim of this review is to describe the rationale and main underlying reasons for undertaking, ... more The aim of this review is to describe the rationale and main underlying reasons for undertaking, during clinical development, the study of drug candidates used separately and/or in combination with other technologies. To ease comprehension, reference will be made to the case of SpinalonTM, a new fixed-dose combination (FDC) product composed of levodopa/carbidopa/buspirone. This drug is capable of triggering, within minutes after a single administration orally, 45 minute- episodes of basic involuntary 'reflex' walking in paraplegic animals. Daily administration during one month was shown to lead to increased performance over time, with health benefits onto musculoskeletal and cardiovascular systems. A double-blind, dose-escalation, randomized phase I/IIa study with 45 spinal cord-injured subjects successfully provided the maximal tolerated dose (MTD) and preliminary evidence of efficacy. As an attempt to explore how efficacy may be optimized, a phase IIb study with 150 subjec...
Locomotion is one of the most complex motor behaviors. Locomotor patterns change during early lif... more Locomotion is one of the most complex motor behaviors. Locomotor patterns change during early life, reflecting development of numerous peripheral and hierarchically organized central structures. Among them, the spinal cord is of particular interest since it houses the central pattern generator (CPG) for locomotion. This main command center is capable of eliciting and coordinating complex series of rhythmic neural signals sent to motoneurons and to corresponding target-muscles for basic locomotor activity. For a long-time, the CPG has been considered a black box. In recent years, complementary insights from in vitro and in vivo animal models have contributed significantly to a better understanding of its constituents, properties and ways to recover locomotion after a spinal cord injury (SCI). This review discusses key findings made by comparing the results of in vitro isolated spinal cord preparations and spinal-transected in vivo models from neonatal animals. Pharmacological, electr...
The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry, 2017
The ability of dedicated spinal circuits, referred to as central pattern generators (CPGs), to pr... more The ability of dedicated spinal circuits, referred to as central pattern generators (CPGs), to produce the basic rhythm and neural activation patterns underlying locomotion can be demonstrated under specific experimental conditions in reduced animal preparations. The existence of CPGs in humans is a matter of debate. Equally elusive is the contribution of CPGs to normal bipedal locomotion. To address these points, we focus on human studies that utilized spinal cord stimulation or pharmacological neuromodulation to generate rhythmic activity in individuals with spinal cord injury, and on neuromechanical modeling of human locomotion. In the absence of volitional motor control and step-specific sensory feedback, the human lumbar spinal cord can produce rhythmic muscle activation patterns that closely resemble CPG-induced neural activity of the isolated animal spinal cord. In this sense, CPGs in humans can be defined by the activity they produce. During normal locomotion, CPGs could con...
The mammalian lumbar spinal cord experimentally isolated from supraspinal and afferent feedback i... more The mammalian lumbar spinal cord experimentally isolated from supraspinal and afferent feedback input remains capable of expressing some basic locomotor function when appropriately stimulated. This ability has been attributed to spinal neural circuits referred to as central pattern generators (CPGs). In individuals with a severe spinal cord injury, rhythmic activity in paralyzed leg muscles can be generated by phasic proprioceptive feedback during therapist- or robotic-assisted stepping on a motorized treadmill. Here, we critically review to what extent the resulting motor output represents locomotor-like activity, and whether these motor patterns are the result of activation of CPGs, as commonly suggested in the literature. Attempts will be made to further delineate the pivotal roles played by mechanisms such as spinal proprioceptive reflexes and their alterations after spinal cord injury, the central excitability level, and by neurotransmitters critical for spinal locomotor activi...
Locomotion is a semi-automatic daily task. Several studies show that muscle activity is fairly st... more Locomotion is a semi-automatic daily task. Several studies show that muscle activity is fairly stereotyped during normal walking. Nevertheless, each human leg contains over 50 muscles and locomotion requires flexibility in order to adapt to different conditions as, for instance, different speeds, gaits, turning, obstacle avoidance, altered gravity levels, etc. Therefore, locomotor control has to deal with a certain level of flexibility and non-linearity. In this review, we describe and discuss different findings dealing with both simplicity and variability of the muscular control, as well as with its maturation during development. Despite complexity and redundancy, muscle activity patterns and spatiotemporal maps of spinal motoneuron output during human locomotion show both stereotypical features as well as functional re-organization. Flexibility and different solutions to adjust motor patterns should be considered when considering new rehabilitation strategies to treat disorders in...
In recent years, many researches put significant efforts into understanding and assessing the fun... more In recent years, many researches put significant efforts into understanding and assessing the functional state of the spinal locomotor circuits in humans. Various techniques have been developed to stimulate the spinal cord circuitries, which may include both diffuse and quite specific tuning effects. Overall, the findings indicate that tonic and rhythmic spinal activity control are not separate phenomena but are closely integrated to properly initiate and sustain stepping. The spinal cord does not simply transmit information to and from the brain. Its physiologic state determines reflex, postural and locomotor control and, therefore, may affect the recovery of the locomotor function in individuals with spinal cord and brain injuries. This review summarizes studies that examine the rhythmogenesis capacity of cervical and lumbosacral neuronal circuitries in humans and its importance in developing central pattern generator-modulating therapies.
No drug treatment capable of restoring locomotor capabilities in patients suffering a motor-compl... more No drug treatment capable of restoring locomotor capabilities in patients suffering a motor-complete spinal cord injury (SCI) has ever been developed. We assessed the safety and efficacy of an activator of spinal locomotor neurons in humans, which were shown in paraplegic animals to elicit temporary episodes of involuntary walking. Single administration of buspirone/levodopa/carbidopa (Spinalon TM), levodopa/carbidopa (ratio 4: 1), and buspirone or placebo was performed using a dose-escalation design in 45 subjects placed in supine position who had had an SCI classified as complete (AIS A) or motor-complete/sensory incomplete (AIS B) for at least 3 months. Blood samples before and at regular intervals (15, 30, 60, 120, 240 min) after treatment were collected for hematological and pharmacokinetic (PK) analyses. Electromyographic (EMG) activity of eight muscles (four per leg) was monitored prior to and at several time points after drug administration. SpinalonTM (10-35 mg buspirone/10...
Non-volatile general anaesthetics are thought to reduce brain activity by potentiating inhibitory... more Non-volatile general anaesthetics are thought to reduce brain activity by potentiating inhibitory GABA A receptor channels but also cause adverse effects by suppressing L-type calcium channels in the heart. In sections of the spinal cord, the non-volatile anaesthetics pentobarbital, thiopental and propofol reduced excitability of sensorimotor neurons by suppressing plateau potentials mediated by L-type calcium channels. This effect was independent of GABA A receptor potentiation but occurred in an overlapping concentration range. Therefore, the suppressive effect of non-volatile anaesthetics on L-type calcium channels can contribute to the reduction of spinal sensorimotor activity during anaesthesia. The results support the idea that general anaesthesia is achieved through several mechanisms and suggest that procedures for anaesthesia may be improved by combining selective agents for each mechanism in optimal concentrations. 1998 IBRO. Published by Elsevier Science Ltd.
Objective: Differences between traumatic (TSCI) and non-traumatic (NTSCI) spinal cord-injured pat... more Objective: Differences between traumatic (TSCI) and non-traumatic (NTSCI) spinal cord-injured patients with comparable geographical and socio-economical background have rarely been studied. The objective was to examine and compare a set of epidemiological, clinical, and functional characteristics in TSCI and NTSCI patients.
Study design: Case report. Objectives: To report a case where a monoplegic patient received L-DOP... more Study design: Case report. Objectives: To report a case where a monoplegic patient received L-DOPA and/or buspirone. These compounds, normally used in the treatment of Parkinson's disease and anxiety respectively, were recently shown to induce spinal locomotor network activity and reflex stepping-like movements in animal models of spinal cord injury (SCI). However, the safety of these drugs as potential treatments for Central Pattern Generator (CPG) activation in paralyzed individuals remain unclear. Setting: St-Jean-Chrysostome, Quebec, Canada. Method: The acute effects induced by these compounds were qualitatively assessed by the patient, a 38-year-old man who underwent surgery 17 years ago to remove an intracavernous angioma located at the mid-thoracic level (T5-T6) of the spinal cord. Results: Self-administration every 2 days of L-DOPA (200, 400 and 600 mg, p.o.) and buspirone (5, 10 and 15 mg, p.o.) either separately or combined led to no atypical side effects (that is, occasional sleepiness, nervousness, insomnia or mild headaches). No movement was induced ipsilaterally although some sensations referred to by the patient as an increased blood flow in the lower back and upper leg regions were reported shortly after administration of the combined treatment.
YH. Suppression by intrathecal BmK IT2 on rat spontaneous pain behaviors and spinal c-Fos express... more YH. Suppression by intrathecal BmK IT2 on rat spontaneous pain behaviors and spinal c-Fos expression induced by formalin. Brain Res Bull 73: 248 -253, 2007. Ballermann M, Fouad K. Spontaneous locomotor recovery in spinal cord injured rats is accompanied by anatomical plasticity of reticulospinal fibers. S. Noradrenergic agonists and locomotor training affect locomotor recovery after cord transection in adult cats. Brain Res Bull 30: 387-393, 1993. Barbeau H, Rossignol S. Recovery of locomotion after chronic spinalization in the adult cat. Brain Res 412: 84 -95, 1987. Bareyre FM, Kerschensteiner M, Raineteau O, Mettenleiter TC, Weinmann O, Schwab ME. The injured spinal cord spontaneously forms a new intraspinal circuit in adult rats. Behrman AL, Harkema SJ. Locomotor training after human spinal cord injury: a series of case studies. Phys Ther 80: 688 -700, 2000. Belanger M, Drew T, Provencher J, Rossignol S. A comparison of treadmill locomotion in adult cats before and after spinal transaction. J Neurophysiol 76: 471-491, 1996. Brown TG. The intrinsic factors in the act of progression in the mammals. Proc R Soc Lond B Biol Sci 84: 308 -319, 1911. Brown TG. On the nature of the fundamental activity of the nervous centres;
Reorganization and plasticity after spinal cord injury have been recently shown to take place in ... more Reorganization and plasticity after spinal cord injury have been recently shown to take place in sublesional neuronal networks, but the possibility of strain-dependent changes at that level has never been explored. The authors studied the spontaneous return of hindlimb movement in low-thoracic spinal cord transected (Tx) mice from 3 commonly used strains. Without intervention, most CD1, C57BL/6, and BALB/c mice displayed some hindlimb movement recovery after Tx. Although all assessment methods unanimously reported that CD1 displayed higher recovery levels than did the C57BL/6 and BALB/c, higher scores were generally found with the Antri-Orsal-Barthe (M. Antri, D. Orsal, & J. Y. Barthe, 2002) and the Average Combined Score (P. A. Guertin, 2005a) methods. Such spontaneous recovery in low-thoracic Tx mice is likely the result of neuronal plasticity at the lumbosacral spinal cord level, suggesting that these sublesional changes are strain dependent.
L-beta-3,4-Dihydroxyphenylalanine (L-DOPA) and quipazine, respectively dopamine/noradrenaline pre... more L-beta-3,4-Dihydroxyphenylalanine (L-DOPA) and quipazine, respectively dopamine/noradrenaline precursor and serotonergic (5-HT 2 ) receptor agonist, were injected intraperitoneally in low-thoracic spinal mice at 7 days post-spinalization. In mice pre-treated with decarboxylase and monoamine oxydase inhibitors, L-DOPA (30-100 mg/kg) was found not to induce air-stepping. On the other hand, L-DOPA (40 mg/kg) consistently triggered locomotor-like movements if combined with low doses of quipazine (0.4-0.7 mg/kg) or if mice were placed on a motor-driven treadmill running at low speed. However, twitches, spasms, and other non-locomotor movements were also induced, especially on the treadmill. These results suggest that (1) spinal catecholaminergic and serotonergic receptors interact synergistically to generate locomotor-like movements in chronic spinal mice, and that (2) hindlimb afferent inputs associated with the treadmill conditions contribute to the genesis of locomotor-like and non-locomotor movements induced by these drugs. q
A role of serotonin receptors (5-HTRs) in spinal rhythmogenesis has been proposed several years a... more A role of serotonin receptors (5-HTRs) in spinal rhythmogenesis has been proposed several years ago based mainly upon data showing that bath-applied 5-HT could elicit locomotor-like rhythms in in vitro isolated spinal cord preparations. Such a role was partially confirmed in vivo after revealing that systemically administered 5-HTR(2) agonists, such as quipazine, could induce some locomotor-like movements (LM) in completely spinal cord-transected (Tx) rodents. However, given the limited binding selectivity of currently available 5-HTR(2) agonists, it has remained difficult to determine clearly if one receptor subtype is specifically associated with LM induction. In situ hybridization, data using tissues from L1-L2 spinal cord segments, where critical locomotor network elements have been identified in mice, revealed greater 5-HTR(2A) mRNA levels in low-thoracic Tx than non-Tx animals. This expression level remained elevated for several days, specifically in the lateral intermediate zone, where peak values were detected at 1 week post-Tx and returned to normal at 3 weeks post-Tx. Behavioral and kinematic analyses revealed quipazine-induced LM in 1-week Tx mice either non-pretreated or pretreated with selective 5-HTR(2B) and/or 5-HTR(2C) antagonists. In contrast, LM completely failed to be induced by quipazine in animals pretreated with selective 5-HTR(2A) antagonists. Altogether, these results provide strong evidence suggesting that 5-HTR(2A) are specifically associated with spinal locomotor network activation and LM generation induced by quipazine in Tx animals. These findings may contribute to design drug treatments aimed at promoting locomotor function recovery in chronic spinal cord-injured patients.
Study design: Experimental laboratory investigations with paraplegic mouse models. Objectives: To... more Study design: Experimental laboratory investigations with paraplegic mouse models. Objectives: To review the most recent advances in the field of spinal cord injury research; immune system response, regeneration, and functional recovery. Settings: Methods: Assessment of regenerative processes and locomotor function recovery induced by a variety of treatments and approaches in wild-type and genetically engineered mice with complete or incomplete lesions of the spinal cord.
Dopamine (DA) is well-recognized for its determinant role in the modulation of various brain func... more Dopamine (DA) is well-recognized for its determinant role in the modulation of various brain functions. DA was also found in in vitro isolated invertebrate preparations to activate per se the central pattern generator for locomotion. However, it is less clear whether such a role as an activator of central neural circuitries exists in vertebrate species. Here, we studied in vivo the effects induced by selective DA receptor agonists and antagonists on hindlimb movement generation in mice completely spinal cord-transected (Tx) at the low-thoracic level (Th9/10). Administration of D1/D5 receptor agonists (0.5-2.5 mg kg −1 , i.p.) was found to acutely elicit rhythmic locomotor-like movements (LMs) and non-locomotor movements (NLMs) in untrained and non-sensory stimulated animals. Comparable effects were found in mice lacking the D5 receptor (D5KO) whereas D1/D5 receptor antagonist-pretreated animals (wild-type or D5KO) failed to display D1/D5 agonist-induced LMs. In contrast, administration of broad spectrum or selective D2, D3 or D4 agonists consistently failed to elicit significant hindlimb movements. Overall, the results clearly show in mice the existence of a role for D1 receptors in spinal network activation and corresponding rhythmic movement generation.
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Papers by Pierre Guertin