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      Cholinergic mechanisms in spinal locomotion—potential target for rehabilitation approaches

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          Abstract

          Previous experiments implicate cholinergic brainstem and spinal systems in the control of locomotion. Our results demonstrate that the endogenous cholinergic propriospinal system, acting via M 2 and M 3 muscarinic receptors, is capable of consistently producing well-coordinated locomotor activity in the in vitro neonatal preparation, placing it in a position to contribute to normal locomotion and to provide a basis for recovery of locomotor capability in the absence of descending pathways. Tests of these suggestions, however, reveal that the spinal cholinergic system plays little if any role in the induction of locomotion, because MLR-evoked locomotion in decerebrate cats is not prevented by cholinergic antagonists. Furthermore, it is not required for the development of stepping movements after spinal cord injury, because cholinergic agonists do not facilitate the appearance of locomotion after spinal cord injury, unlike the dramatic locomotion-promoting effects of clonidine, a noradrenergic α-2 agonist. Furthermore, cholinergic antagonists actually improve locomotor activity after spinal cord injury, suggesting that plastic changes in the spinal cholinergic system interfere with locomotion rather than facilitating it. Changes that have been observed in the cholinergic innervation of motoneurons after spinal cord injury do not decrease motoneuron excitability, as expected. Instead, the development of a “hyper-cholinergic” state after spinal cord injury appears to enhance motoneuron output and suppress locomotion. A cholinergic suppression of afferent input from the limb after spinal cord injury is also evident from our data, and this may contribute to the ability of cholinergic antagonists to improve locomotion. Not only is a role for the spinal cholinergic system in suppressing locomotion after SCI suggested by our results, but an obligatory contribution of a brainstem cholinergic relay to reticulospinal locomotor command systems is not confirmed by our experiments.

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          Most cited references 104

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          A cluster of cholinergic premotor interneurons modulates mouse locomotor activity.

          Mammalian motor programs are controlled by networks of spinal interneurons that set the rhythm and intensity of motor neuron firing. Motor neurons have long been known to receive prominent "C bouton" cholinergic inputs from spinal interneurons, but the source and function of these synaptic inputs have remained obscure. We show here that the transcription factor Pitx2 marks a small cluster of spinal cholinergic interneurons, V0(C) neurons, that represents the sole source of C bouton inputs to motor neurons. The activity of these cholinergic interneurons is tightly phase locked with motor neuron bursting during fictive locomotor activity, suggesting a role in the modulation of motor neuron firing frequency. Genetic inactivation of the output of these neurons impairs a locomotor task-dependent increase in motor neuron firing and muscle activation. Thus, V0(C) interneurons represent a defined class of spinal cholinergic interneurons with an intrinsic neuromodulatory role in the control of locomotor behavior.
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            Distribution of networks generating and coordinating locomotor activity in the neonatal rat spinal cord in vitro: a lesion study.

            The isolated spinal cord of the newborn rat contains networks that are able to create a patterned motor output resembling normal locomotor movements. In this study, we sought to localize the regions of primary importance for rhythm and pattern generation using specific mechanical lesions. We used ventral root recordings to monitor neuronal activity and tested the ability of various isolated parts of the caudal thoraciclumbar cord to generate rhythmic bursting in a combination of 5-HT and NMDA. In addition, pathways mediating left/right and rostrocaudal burst alternation were localized. We found that the isolated ventral third of the spinal cord can generate normally coordinated rhythmic activity, whereas lateral fragments resulting from sagittal sections showed little or no rhythmogenic capability compared with intact control preparations. The ability to generate fast and regular rhythmic activity decreased in the caudal direction, but the rhythm-generating network was found to be distributed over the entire lumbar region and to extend into the caudal thoracic region. The pathways mediating left/ right alternation exist primarily in the ventral commissure. As with the rhythmogenic ability, these pathways were distributed along the lumbar enlargement. Both lateral and ventral funiculi were sufficient to coordinate activity in the rostral and caudal regions. We conclude that the networks organizing locomotor-related activity in the spinal cord of the newborn rat are distributed.
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              Spinal cholinergic interneurons regulate the excitability of motoneurons during locomotion.

              To effect movement, motoneurons must respond appropriately to motor commands. Their responsiveness to these inputs, or excitability, is regulated by neuromodulators. Possible sources of modulation include the abundant cholinergic "C boutons" that surround motoneuron somata. In the present study, recordings from motoneurons in spinal cord slices demonstrated that cholinergic activation of m2-type muscarinic receptors increases excitability by reducing the action potential afterhyperpolarization. Analyses of isolated spinal cord preparations in which fictive locomotion was elicited demonstrated that endogenous cholinergic inputs increase motoneuron excitability during locomotion. Anatomical data indicate that C boutons originate from a discrete group of interneurons lateral to the central canal, the medial partition neurons. These results highlight a unique component of spinal motor networks that is critical in ensuring that sufficient output is generated by motoneurons to drive motor behavior.
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                Author and article information

                Contributors
                Journal
                Front Neural Circuits
                Front Neural Circuits
                Front. Neural Circuits
                Frontiers in Neural Circuits
                Frontiers Media S.A.
                1662-5110
                06 November 2014
                2014
                : 8
                Affiliations
                1Department of Physiology and Pathophysiology, Spinal Cord Research Centre, University of Manitoba Winnipeg, MB, Canada
                2Department of Neurological Surgery, The Miami Project to Cure Paralysis, University of Miami Miami, FL, USA
                3Department of Neurophysiology, Nencki Institute of Experimental Biology PAS Warsaw, Poland
                4Department of Nerve-Muscle Engineering, Institute of Biocybernetics and Biomedical Engineering PAS Warsaw, Poland
                5Groupe de Recherche sur le Système Nerveux Central and Department of Neuroscience, Faculty of Medicine, Université de Montréal Montreal, QC, Canada
                Author notes

                Edited by: Shawn Hochman, Emory University, USA

                Reviewed by: Sandrine S. Bertrand, Université Bordeaux 2, France; Andrea Nistri, Scuola Internazionale Superiore di Studi Avanzati, Italy; David Magnuson, University of Louisville, USA

                *Correspondence: Larry M. Jordan, Department of Physiology, Spinal Cord Research Centre, The University of Manitoba, 745 Bannatyne ave., BMSB 425, Winnipeg, MB R3E 0W3, Canada e-mail: larry@ 123456scrc.umanitoba.ca ;
                Serge Rossignol, Department of Neuroscience, Faculty of Medicine, Université de Montréal, Desmarais Pavillion, 2960 Chemin de la Tour, Montreal, QC H3T 1J4, Canada e-mail: serge.rossignol@ 123456umontreal.ca

                This article was submitted to the journal Frontiers in Neural Circuits.

                Article
                10.3389/fncir.2014.00132
                4222238
                Copyright © 2014 Jordan, McVagh, Noga, Cabaj, Majczyński, Sławińska, Provencher, Leblond and Rossignol.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                Page count
                Figures: 14, Tables: 1, Equations: 0, References: 107, Pages: 26, Words: 18765
                Categories
                Neuroscience
                Original Research Article

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