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This article deepens a reflection on why and how symmetry/asymmetry affects the motor and postural behavior from the neural source, uterine development, child maturation, and how the notion of symmetry/asymmetry has been applied to walking robot design and control. The concepts of morphology and tensegrity are also presented to illustrate how the biological structures have been used in both sciences and arts. The development of the brain and the neuro-fascia-musculoskeletal system seems to be quite symmetric from the beginning of life through to complete maturity. The neural sources of movements (i.e., central pattern generators) are able to produce both symmetric or asymmetric responses to accommodate to environmental constraints and task requirements. Despite the fact that the human development is mainly symmetric, asymmetries already regulate neurological and physiological development. Laterality and sports training could affect natural musculoskeletal symmetry. The plasticity and flexibility of the nervous system allows the abilities to adapt and compensate for environmental constraints and musculoskeletal asymmetries in order to optimize the postural and movement control. For designing humanoid walking robots, symmetry approaches have been mainly used to reduce the complexity of the online calculation. Applications in neurological retraining and rehabilitation should also be considered.

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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 activity. We will discuss the view that the muscle activity produced during assisted passive treadmill stepping is resulting from the entrainment of spinal reflex circuits by the cyclically generated proprioceptive feedback. We suggest that the activation of CPG circuits depends rather on the presence of a sustained tonic excitatory drive, as can be provided by electrical spinal cord stimulation, or by specific combinations of dopaminergic agonists, adrenergic/ dopaminergic precursors and/or 5-HT receptor agonists. Novel rehabilitation strategies using spinal cord stimulation and rhythmic-activity producing drugs during locomotor therapy will pave the way for clinically relevant advances in restoration of motor function in people with severe spinal cord injury.

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, electrical, and sensory stimulation approaches largely used to further understand CPG function may also soon become therapeutic tools for potent CPG reactivation and locomotor movement induction in persons with SCI or developmental neuromuscular disorder.

Background: 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. Methods: Single administration of buspirone/levodopa/carbidopa (SpinalonTM), 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. Results: SpinalonTM (10-35 mg buspirone/100-350 mg levodopa/25-85 mg carbidopa) displayed no sign of safety concerns - only mild nausea was found in 3 cases. At higher doses, 50 mg/500 mg/125 mg SpinalonTM was considered to have reached maximum tolerated dose (MTD) since 3 out of 4 subjects experienced related adverse events including vomiting. PK analyses showed comparable data between groups suggesting no significant drugdrug interaction with SpinalonTM. Only the SpinalonTM–treated groups displayed significant EMG activity accompanied by locomotor-like characteristics - that is with rhythmic and bilaterally alternating bursts. Conclusion: Therefore, this study provides evidence of safety and preliminary efficacy following a single administration of SpinalonTM in subjects with SCI.

Homo sapiens constitute the only currently obligate bipedal mammals and, as it stands, upright bipedal locomotion is a defining characteristic of humans. Indeed, while the evolution to bipedalism has allowed for the upper limbs to be liberated from ground contact during ambulation, their role in locomotion is far from obsolete. Rather, there is reason to believe that arm swing offers important mechanical and neurological advantages to bipedal locomotion. In this short review, we present some compelling findings on the neural connections between the arms and legs during human locomotion. We begin with a description of the importance of arm swing during walking from a mechanical perspective. Then, we examine evidence for the existence of interappendicular connections that converge along with peripheral afferents, descending inputs, and propriospinal projections, onto the neural circuits innervating the muscles of the arms and legs. The varied effects of interappendicular coupling on the neural control of locomotion are also examined in cases of neurological injury. We use the insight gained from these collected works as well as those from our own studies on locomotor training to discuss strategies to use interappendicular connections to rehabilitate walking in individuals experiencing loss of function after debilitating spinal cord injury.

Relatively soon after their accident, patients suffering a spinal cord injury (SCI) begin generally experiencing the development of significant, often life-threatening secondary complications. Many of which are associated with chronic physical inactivity-related immune function problems and increasing susceptibility to infection that repeatedly requires intensive care treatment. Therapies capable of repairing the spinal cord or restoring ambulation would normally prevent many of these problems but, as of now, there is no cure for SCI. Thus, management strategies and antibiotics remain the standard of care although antimicrobial resistance constitutes a significant challenge for patients with chronic SCI facing recurrent infections of the urinary tract and respiratory systems. Identifying alternative therapies capable of safe and potent actions upon these serious health concerns should therefore be considered a priority. This editorial presents some of the novel approaches currently in development for the prevention of specific infections after SCI. Among them, brain-permeable small molecule therapeutics acting centrally on spinal cord circuits that can augment respiratory capabilities or bladder functions. If eventually approved by regulatory authorities, some of these new avenues may potentially become clinically-relevant therapies capable of indirectly preventing the occurrence and/or severity of these life-threatening complications in people with paraplegic or tetraplegic injuries.

Central pattern generators (CPGs) are generally defined as networks of neurons capable of enabling the production of central commands, specifically controlling stereotyped, rhythmic motor behaviors. Several CPGs localized in brainstem and spinal cord areas have been shown to underlie the expression of complex behaviors such as deglutition, mastication, respiration, defecation, micturition, ejaculation, and locomotion. Their pivotal roles have clearly been demonstrated although their organization and cellular properties remain incompletely characterized. In recent years, insightful findings about CPGs have been made mainly because (1) several complementary animal models were developed; (2) these models enabled a wide variety of techniques to be used and, hence, a plethora of characteristics to be discovered; and (3) organizations, functions, and cell properties across all models and species studied thus far were generally found to be well-preserved phylogenetically. This article aims at providing an overview for non-experts of the most important findings made on CPGs inin vivoanimal models,in vitropreparations from invertebrate and vertebrate species as well as in primates. Data about CPG functions, adaptation, organization, and cellular properties will be summarized with a special attention paid to the network for locomotion given its advanced level of characterization compared with some of the other CPGs. Similarities and differences between these networks will also be highlighted.

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.

For non-neuroscientists, the spinal cord is often considered simply as a relay between the brain and peripheral organs such as the skin, smooth muscles, and skeletal muscles. However, its gray matter has also been shown to play a pivotal role in the control of stereotyped motor behaviors. Neuroscientists have indeed clearly shown recently that the spinal cord contains command centers also known as central pattern generators. Those spinal centers have been found to elicit, inhibit or modulate locomotion, ejaculation, defecation and micturition. This short communication briefly outlines the main characteristics of the central pattern generator for micturition and how it could become a therapeutic target for innovative drugs against micturition-related problems.

Most animal models of contused, compressed or transected spinal cord injury (SCI) require a laminectomy to be performed. However, despite advantages and disadvantages associated with each of these models, the laminectomy itself is generally associated with significant problems including longer surgery and anaesthesia (related post-operative complications), neuropathic pain, spinal instabilities, deformities, lordosis, and biomechanical problems, etc. This review provides an overview of findings obtained mainly from our laboratory that are associated with the development and characterization of a novel murine model of spinal cord transection that does not require a laminectomy. A number of studies successfully conducted with this model provided strong evidence that it constitutes a simple, reliable and reproducible transection model of complete paraplegia which is particularly useful for studies on large cohorts of wild-type or mutant animals - e.g., drug screening studies in vivo or studies aimed at characterizing neuronal and non-neuronal adaptive changes post-trauma. It is highly suitable also for studies aimed at identifying and developing new pharmacological treatments against aging associated comorbid problems and specific SCI-related dysfunctions (e.g., stereotyped motor behaviours such as locomotion, sexual response, defecation and micturition) largely related with 'command centers' located in lumbosacral areas of the spinal cord.

γ-aminobutyric acid (GABA) plays many of its key roles in embryonic development and functioning of the central nervous system (CNS) by acting on ligand gated chloride-permeable channels known as GABA A receptors (GABA A R). Classically, GABA A Rmediated synaptic communication is tailored to allow rapid and precise transmission of information to synchronize the activity of large populations of cells to generate and maintain neuronal networks oscillations. An alternative type of inhibition mediated by GABA A receptors, initially described about 25 years ago, is characterized by a tonic activation of receptors that react to ambient extracellular GABA. The receptors that mediate this action are wide-spread throughout the nerve cells but are located distant from the sites of GABA release, and therefore they have been called extrasynaptic GABA A receptors. The molecular nature of the extrasynaptic GABA A receptors and the tonic inhibitory current they generate have been characterized in many brain structures, and due to its relevance in controlling neuron excitability they have become attractive pharmacological targets for a variety of neurological disorders such as schizophrenia, epilepsy and Parkinson disease. In the spinal cord, early studies have implicated these receptors in anesthesia, chronic pain, motor control, and locomotion. This review highlights past and present developments in the field of extrasynaptic GABA A receptors and emphasizes their subunit containing distribution and physiological role in the spinal cord.

Cardiotoxicity effects, cardiovascular diseases (CVDs), and hypertension occurring months to several years postchemotherapy and/or radiotherapy are well-recognized by experts. Anthracyclines were found in the late 1960s to be dose-dependently associated with induced-cardiotoxicity, often leading to cardiomyopathy and cardiac failure. Since then, epidemiologic research has led to some advances, although pivotal questions about global incidence, populations at risk, cellular mechanisms, and preventive treatments remain either incompletely understood or unaddressed. For instance, the incidence of cancer-surviving patients who die of cardiac failure after chemotherapy and/or radiotherapy is still a subject of debate - for reasons that are unclear, available statistics vary significantly from one epidemiology study to another. Moreover, no safe cardioprotective agents have yet been fully endorsed and approved by regulatory agencies for prevention or treatment of this specific medical problem. A drug called dexrazoxane was initially approved by the US Food and Drug Administration and the European Medicines Agency, but a restricted use notice was released in 2011 since several cases of secondary acute myeloid leukemia and myelodysplactic syndrome had been reported. As of today, hematologists and cardiologists remain generally reluctant to recommend dexrazoxane or other cardioprotective drugs (off-label prescription), probably because of unclear risks and lack of evidence-based medicine. Questions about unexpected adverse events or drug-drug interaction issues reducing the efficacy of specific chemotherapies also need to be addressed.

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 involving deficits in gait.

Background Individuals with spinal cord injury (SCI) have increased rates of glucose intolerance, insulin insensitivity, and type II diabetes caused mainly by the deconditioning of paralyzed muscle. The purpose of this systematic review was to determine the effectiveness of locomotor training in individuals with SCI on blood glucose control. Methods We searched studies on locomotor training for individuals with SCI with outcomes of glucose, insulin, or outcomes that could change glucose handling (i.e. increases in muscle mass, shifts in muscle fiber type composition, changes in transport proteins, or enzymes involved in glucose metabolism) in PubMed and EMBASE. Results Eleven studies (10 with incomplete SCI; 1 with complete SCI) were included in our review. Locomotor training included body weight supported treadmill training (BWSTT) with manual or robotic assistance, with and without functional electrical stimulation (FES), or involved FES-assisted over ground training. Six months of locomotor training in individuals with SCI resulted in significant decreases in glucose (15%) and insulin (33%) areas under the curve during oral glucose tolerance tests. Two to twelve months of locomotor training reversed some of the muscle atrophy - with muscle being the site of most glucose consumption, this is important for glucose control. Training also increased capacity for glucose storage, enzymes involved in glucose phosphorylation (hexokinase) and oxidation (citrate synthase), and glucose transport proteins (GLUT-4). Fiber type composition shifted to a slower fiber type, which favors glucose handling. There were no effects on fat mass. Conclusion Locomotor training in individuals with SCI (generally an incomplete injury) increases capacity to handle glucose and results in muscular changes that should reduce the risk of type II diabetes.

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 subjects was designed to compare the effects of repeated administration in different conditions (arms). Tests with a motorized treadmill, a harness for body weight support, a transdermal spinal cord stimulator and/or an exoskeleton were proposed because: 1) these devices are unlikely to alter safety but, 2) they are reasonably expected to increase spinal locomotor neuron activation, reflex walking induction, and musculoskeletal/cardiovascular benefits. This approach would normally allow the phase III study to demonstrate clearly, with fewer subjects and at lower costs, long-term benefits on health of SpinalonTM used in optimized conditions and settings. This innovative strategy in drug development may contribute to further describe the mechanisms of action as well as optimized conditions of use for patients. Adapted to the development of other products, such an approach may enable greater safety, efficacy, clinical utility and compliance to be sought for next-generation CNS drugs.

Locomotion is a complex motor behavior that may be expressed in different ways using a variety of strategies depending upon species and pathological or environmental conditions. Quadrupedal or bipedal walking, running, swimming, flying and gliding constitute some of the locomotor modes enabling the body, in all cases, to move from one place to another. Despite these apparent differences in modes of locomotion, both vertebrate and invertebrate species share, at least in part, comparable neural control mechanisms for locomotor rhythm and pattern generation and modulation. Significant advances have been made in recent years in studies of the genetic aspects of these control systems. Findings made specifically using Drosophila (fruit fly) models and preparations have contributed to further understanding of the key role of genes in locomotion. This review focuses on some of the main findings made in larval fruit flies while briefly summarizing the basic advantages of using this powerful animal model for studying the neural locomotor system.

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. Methods: This is a community-based, cross-sectional study of medical records from a cohort of one hundred and seventy- five (175) chronic spinal cord-injured patients (94 TSCI and 81 NTSCI individuals) who were treated at the Interval Rehabilitation Center located in Trois-Rivieres, Province of Quebec, Canada. Results: Clear differences in age, gender, extent and level of injury or associated conditions (also called secondary complications) were found between TSCI and NTSCI patients. Only one (1/81) completely injured patients was identified among the NTSCI group whereas completely injured patients constituted 37.8% of all TSCI patients. The percentage of patients with associated conditions including neurogenic bladder, neurogenic bowel, urinary tract infection, and pressure ulcer problems was significantly greater in TSCI than NTSCI patients. In contrast, a comparable proportion of TSCI and NTSCI patients was experiencing neuropathic pain. Conclusions: Given these differences between groups as well as regional-specific differences reported in studies from some other countries, it may be suggested that therapeutic approaches developed to treat these health problems and so- called associated conditions could be targeted for specific groups and subgroups of spinal cord-injured patients.

Spinal cord injury (SCI) is generally associated with a rapid and significant decrease in muscle mass and corresponding changes in skeletal muscle properties. Although beta(2)-adrenergic and androgen receptor agonists are anabolic substances clearly shown to prevent or reverse muscle wasting in some pathological conditions, their effects in SCI patients remain largely unknown. Here we studied the effects of clenbuterol and testosterone propionate administered separately or in combination on skeletal muscle properties and adipose tissue in adult CD1 mice spinal-cord-transected (Tx) at the low-thoracic level (i.e., induced complete paraplegia). Administered shortly post-Tx, these substances were found to differentially reduce loss in body weight, muscle mass, and muscle fiber cross-sectional area (CSA) values. Although all three treatments induced significant effects, testosterone-treated animals were generally less protected against Tx-related changes. However, none of the treatments prevented fat tissue loss or muscle fiber type conversion and functional loss generally found in Tx animals. These results provide evidence suggesting that clenbuterol alone or combined with testosterone may constitute better clinically-relevant treatments than testosterone alone to decrease muscle atrophy (mass and fiber CSA) in SCI subjects.

Experiments in a mouse model of complete paraplegia. To evaluate the effect of non-assisted treadmill training on motor recovery and body composition in completely spinal cord-transected mice. Laval University Medical Center, Neuroscience Unit, Quebec City, Quebec, Canada. Following a complete low-thoracic (Th9/10) spinal transection (Tx), mice were divided into two groups that were either untrained or trained with no assistance. Training consisted of placing the mice during 15 min with no further intervention (that is no tail pinching or body weight support) on a motorized treadmill (8–10 cm s−1) five times per week for 5 weeks. Locomotor performances were assessed weekly in both groups using two complementary locomotor rating scales. After 5 weeks, all mice were killed and adipose tissue, soleus, and extensor digitorum longus muscles were dissected for analyses. No significant difference in locomotor performances or in muscle fibre type conversion was found between trained and untrained mice. In contrast, body weight, adipose tissue, whole muscle, and individual fibre cross-sectional area (CSA) values were significantly lower in trained compared with untrained animals. Non-assisted treadmill training in these conditions did not improve motor performances and contributed to further accentuate body composition changes post-Tx, suggesting that assistance provided manually, robotically, or pharmacologically may be key to spinal learning and recovery of locomotor function and body composition.

Spinal cord injury (SCI) is a devastating condition generally leading to a permanent and irreversible loss of sensory and motor functions. We have identified recently a number of serotonergic, adrenergic and dopaminergic receptor agonists or precursors that can acutely elicit some motor and locomotor-like movements in completely spinal cord-transected (thoracic level) animals. However, only partial central network-activating effects were found with single molecules since none administered separately could elicit weight-bearing and functional stepping movements in Tx animals. In turn, a recent breakthrough revealed that full spinal locomotor network-activating effects may be induced with synergistic drug combinations. Indeed, specific cocktails comprising some of these agonists and precursors were found, indeed, to powerfully generate weight-bearing stepping with plantar foot placement in untrained, non-assisted and non-sensory-stimulated Tx mice. This significant finding provides clear evidence suggesting that combinatorial approaches based on drug-drug synergistic interactions may constitute innovative solutions for the design and development of novel pharmacological therapies in the field of SCI and related neurological disorders.

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.

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.

Experiments in completely spinal cord transected (Tx) cats have provided compelling evidence that clonidine combined with tail stimulation can promote locomotor function recovery. However, clonidine has generally failed to induce locomotor activity in other comparable animal models suggesting the existence of species- or condition-specific effects. This study aimed at investigating the effects of clonidine administered (0.25 or 5.0 mg/kg, i.p.) in mice during tail pinching in early (6-7 days post-Tx) or late (41-42 days post-Tx) paraplegic animals (Th9/10 level). Comparisons were made with the effects induced by 8-OH-DPAT (1.0 mg/kg, i.p.), a 5-HT1A/7 receptor agonist known to display prolocomotor effects. Clonidine with or without tail pinching failed to induce hind limb movements and even suppressed the frequency of spontaneously occurring nonlocomotor (NLM) and locomotor-like movements (LM) whereas tail pinching alone (prior to clonidine administration) increased the frequency of spontaneous movements specifically in late chronic animals. In turn, 8-OH-DPAT clearly induced hind limb movements that remained relatively unchanged during tail pinching. Altogether, the results suggest that the prolocomotor effects of clonidine reported elsewhere must depend upon stimuli or factors that remain to be identified.

Background: The basic motor patterns driving rhythmic limb movements during walking are generated by networks of neurons called central pattern generators (CPGs). Within motor control systems, neuromodulators are necessary for proper and efficient CPG function because they induce or regulate essential components of spinal network activity, including firing parameters of CPG neurons and network synaptic strength, allowing the network to change/adapt and sometimes to even become functional. Methods: The goal of this work is to focus on classical and recent findings addressing the role of neuromodulators such as glutamate, dopamine, acetylcholine and adenosine in eliciting, changing and sometimes terminating spinal CPG network function in rodents. Results: Neuromodulatory inputs onto CPG locomotor networks have been additionally related to inducing state changes such as locomotor timing, phasing and speed, and to the induction/maintenance of actual network function. These inputs originate from supraspinal centers such as the brainstem and from intraspinal neurotransmission. The isolated in vitro rodent spinal cord preparation is a powerful model for studies on locomotor network organization because of its physiological and anatomical accessibility, as well as the incorporation of various transgenic approaches to identify specific neuronal populations. Both roles are accomplished through the action of neuromodulators on ionotropic and metabotropic receptors mediating synaptic neurotransmission, which can be used by neurons that are intrinsic or extrinsic components of a CPG network itself. Conclusion: This article has hopefully provided a comprehensive overview of some of the main spinal mechanisms involved in the modulatory control of locomotor activity.

Neuronal plasticity has been traditionally associated with learning and memory processes in the hippocampal regions of the brain. It is now generally accepted that plasticity phenomena are also associated with other kinds of cellular changes and modifications occurring in all areas of the CNS after injury or intense neuronal activity. For instance, spinal cord injuries have been associated with a series of cellular modifications and adaptations taking place distally in sublesional areas. Some of these modifications include changes in the expression of immediate early genes (e.g., c-fos and nor-1), TNF-alpha, preprodynorphin, neurotrophic factors (e.g., BDNF and NT-3), and several subtypes of transmembranal receptors (e.g., 5-HT1A and 5-HT2A). This review constitutes an update of the current knowledge regarding this broadly defined plasticity phenomenon that occurs spontaneously or can be modulated by training in sublesional segments of the spinal cord. Spinal cord plasticity is an increasingly popular field of research, believed by many as being a complex phenomenon that may contribute to the development of innovative therapeutics and rehabilitative approaches for spinal cord injured patients.

Spinal cord injury (SCI) is associated with the development of deep venous thrombosis (DVT) in the lower limbs and, hence, with rapidly increasing risks of cardiovascular and pulmonary complications soon after trauma. However, specific mechanisms underlying DVT formation following SCI are poorly understood. Here, we studied in mice, employing in vivo confocal microscopy, changes in deep vein size over 4 weeks after spinal cord transection (Tx). Changing levels of biochemical markers that may be associated with DVT formation were also examined. The results showed decreased concentrations of cholesterols, triglycerides, and low-density lipoprotein (LDL), but not of high-density lipoproteins (HDL) and platelets. Concentrations of creatinine, bilirubin, glucose, albumin, total protein and uric acid did not significantly change. In turn, the femoral and saphenous veins underwent a large increase (1.5-fold) in diameter throughout the entire period studied. Overall, this study reveals that a profound change in deep vein size and, an unsuspected decrease in triglyceride and LDL levels, occur as early as at one week post-Tx in mice. This indicates, given the well-documented risk of DVT formation soon after SCI, that deep vein enlargement, but not lipoprotein level changes, may constitute an early event contributing to venous stasis and thrombi formation in paralyzed individuals.

Spinal cord injury (SCI) is associated with immune deficiencies and life-threatening infections. However, the specific mechanisms underlying this pathological condition remain unclear. In recent years, increasing evidence has suggested that anabolic hormones may be involved in immunological complications. Here, we monitored candidate hormone concentrations and immune cell counts, in CD1 mice, for 4 weeks after low-thoracic transection of the spinal cord (Tx). Serum dihydroepiandrosterone (DHEA), insulin, and parathyroid hormone (PTH) levels decreased throughout the time period studied compared with control, non-Tx mice. In turn, testosterone and growth hormone (GH) levels were only transiently changed, with a decrease of testosterone during the first 2 weeks and an increase of GH at 1 week post-Tx. A complete blood count revealed either unchanged or moderately decreased erythrocyte, platelet, hemoglobin and hematocrit levels. Total leukocyte, lymphocyte, and eosinophil counts also decreased, whereas neutrophils and monocytes did not change significantly. In the bone marrow, lymphocyte numbers decreased and neutrophils increased, whereas monocytes, eosinophils, and megakariocytes did not change significantly. These results revealed significant changes occurring rapidly (1-2 weeks) after Tx in both hormonal and immunological systems, providing compelling evidence of a role for anabolic hormones in SCI-related immune deficiencies.

Growing evidence from in vitro studies suggests that spinal serotonin (5-HT) receptor subtypes 5-HTR(1A) and 5-HTR(7) are associated with an induction of central pattern generator activity. However, the possibility of a specific role for these receptor subtypes in locomotor rhythmogenesis in vivo remains unclear. Here, we studied the effects of a single dose (1 mg/kg, i.p.) of 8-hydroxy-2-(di-N-propylamino)-tetralin (8-OH-DPAT), a potent and selective 5-HTR(1A/7) agonist, in mice spinal cord transected at the low-thoracic level (Th9/10). The results show that 8-OH-DPAT acutely induced, within 15 min, hindlimb movements that share some characteristics with normal locomotion. Paraplegic mice pretreated with the selective 5-HTR(1A) antagonists, WAY100,135 or WAY100,635, displayed significantly less 8-OH-DPAT-induced movement. A similar reduction of 8-OH-DPAT-induced movements was found in animals pretreated with SB269970, a selective 5-HTR(7) antagonist. Moreover, a near complete blockade of 8-OH-DPAT-induced movement was obtained in wild-type mice pretreated with 5-HTR(1A) and 5-HTR(7) antagonists, and in 5-HTR(7)-/- mice pretreated with 5-HTR(1A) antagonists. Overall, these results clearly demonstrate that 8-OH-DPAT potently induces locomotor-like movement in the previously paralysed hindlimbs of low-thoracic-transected mice. The results, with selective antagonists and knockout animals, provide compelling evidence of a specific contribution of both receptor subtypes to spinal locomotor rhythmogenesis in vivo.

Although intrinsic neuronal properties in invertebrates are well known to undergo specific adaptive changes in culture, long-term adaptation of similar properties in mature vertebrate neurons remain poorly understood. To investigate this, we used an organotypic slice preparation from the spinal cord of adult turtles maintainable for several weeks in culture conditions. N-methyl-d-aspartate (NMDA)-induced-tetrodotoxin (TTX)-resistant voltage oscillations in motoneurons were ∼10 times faster in culture than in acute preparations. Oscillations in culture were abolished by NMDA receptor antagonists or by high extracellular Mg2+ concentrations. However, in contrast with results from motoneurons in the acute slice, NMDA-induced oscillations in culture did not depend on CaV1.3 channel activation as they still remained after nifedipine application. Other CaV1.3 channel-mediated properties such as metabotropic receptor-induced oscillations and plateau potentials failed to be induced in culture. This study shows that changes specifically affecting CaV1.3 channel contribution to intrinsic oscillatory property expression may occur in culture. The results contribute also to understanding further the potential for plasticity of mature vertebrate neurons.

Centrally expressed 5-HT3 receptors (5-HTR3) are well known for their role in wakefulness, cognition, and nociception. However, clear evidence of their participation in motor control is still lacking despite specific 5-HTR3 expression in hindlimb motor areas of the spinal cord (i.e., lumbar laminae VII-IX). Here, we studied the acute effects of 4-amino-(6-chloro-2-pyridyl)-1-piperidine hydrochloride (SR 57227A), a potent and selective 5-HTR3 agonist, on hindlimb movement generation in complete paraplegic mice. The induced movements were assessed in open-field, air-stepping, and treadmill conditions using a combination of qualitative and quantitative methods. The results revealed that SR 57227A (1–4 mg/kg ip) produced hindlimb movements corresponding to scores ranging from 1 to 5 on the motor scales of Basso, Beattie, and Bresnahan and of Antri, Orsal, and Barthe. Additional analyses revealed that one-third of the movements displayed on a treadmill were “locomotor-like” (i.e., bilateral alternation), whereas only nonlocomotor movements were observed in the other testing conditions suggesting a task-dependent contribution of peripheral afferent inputs to these effects. Locomotor-like movements could also be induced in open field and air stepping if SR 57227A was combined with subthreshold doses of 5-carboxytryptamine (5-HT1A/7 receptor agonist), suggesting synergistic actions of these drugs on central neurons. These results demonstrate that 5-HTR3 activation can induce motor activity and, under some conditions, rhythmic locomotor-like movements in the hindlimbs of paraplegic mice providing evidence of an unsuspected role for this receptor subtype in hindlimb motor control.

The effects induced by serotonergic (5-HT) agonists of the 5-HT1 and 5-HT2 subclasses were examined on hindlimb movement generation in adult mice completely spinal cord transected at the low thoracic level. One week postspinalization, intraperitoneal injection (0.5-10 mg/kg) of meta-chlorophenylpiperazine (m-CPP; 5-HT(2B/2C) agonist) or trifluoromethylpiperazine (TFMPP; 5-HT(1B) agonist) failed to induce locomotor-like movements. However, dose-dependent nonlocomotor movements were induced in air-stepping condition or on a motor-driven treadmill. In contrast, hindlimb locomotor-like movements were found after the injection of quipazine (5-HT(2A/2C) agonist; 1-2 mg/kg). Combined with L-DOPA (50 mg/kg, i.p.), low doses of quipazine but not of m-CPP and TFMPP produced locomotor-like and nonlocomotor movements in air-stepping condition or on the treadmill. Subsequent administration of m-CPP or TFMPP significantly reduced and often completely abolished the hindlimb movements induced by quipazine and L-DOPA. Altogether, these results demonstrate that 5-HT(2A/2C) receptor agonists promote locomotion while 5-HT(1B) and 5-HT(2B/2C) receptor agonists interfere with locomotor genesis in the hindlimbs of complete paraplegic mice. These results suggest that only subsets of spinal 5-HT receptors are specific to locomotor rhythmogenesis and should be activated to successfully induce stepping movements after spinal cord injury.