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Cholinergic mechanisms in spinal locomotion-potential target for rehabilitation approaches.

Jordan LM, McVagh JR, Noga BR, Cabaj AM, Majczyński H, Sławińska U, Provencher J, Leblond H, Rossignol S - Front Neural Circuits (2014)

Bottom Line: Our results demonstrate that the endogenous cholinergic propriospinal system, acting via M2 and M3 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.Changes that have been observed in the cholinergic innervation of motoneurons after spinal cord injury do not decrease motoneuron excitability, as expected.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology and Pathophysiology, Spinal Cord Research Centre, University of Manitoba Winnipeg, MB, Canada.

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 M2 and M3 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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Carbachol disruption of locomotion in spinal cats is reversed by atropine. (A–C) regular stepping movements before drug administration 14 days after the lesion represented by raw EMG traces (A), averaged (N = 12 cycles) joint angular displacements (B) and stick figures (C). (D) Raw EMG recordings after intrathecal carbachol (1 mM, 100 μl) showing deterioration of stepping as soon as 7 min post drug administration even with strong perineal stimulation. (E,F) 55 min post carbachol, the EMG is still not organized to produce a good stepping pattern (E). There is no foot placement as represented by the stick figures (F). (G–I) Five minutes after intrathecal administration of atropine (1 mM, 100 μl), a good pattern of stepping was observed without perineal stimulation as was the case before carbachol administration [compare (G–I) with (A–C) same display]. (J) Cycle duration expressed in terms of treadmill speed, showing disruption of locomotion by carbachol, and facilitation of locomotion with atropine.
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Figure 9: Carbachol disruption of locomotion in spinal cats is reversed by atropine. (A–C) regular stepping movements before drug administration 14 days after the lesion represented by raw EMG traces (A), averaged (N = 12 cycles) joint angular displacements (B) and stick figures (C). (D) Raw EMG recordings after intrathecal carbachol (1 mM, 100 μl) showing deterioration of stepping as soon as 7 min post drug administration even with strong perineal stimulation. (E,F) 55 min post carbachol, the EMG is still not organized to produce a good stepping pattern (E). There is no foot placement as represented by the stick figures (F). (G–I) Five minutes after intrathecal administration of atropine (1 mM, 100 μl), a good pattern of stepping was observed without perineal stimulation as was the case before carbachol administration [compare (G–I) with (A–C) same display]. (J) Cycle duration expressed in terms of treadmill speed, showing disruption of locomotion by carbachol, and facilitation of locomotion with atropine.

Mentions: At Day 14, the spinal cats could walk spontaneously (without drugs) up to a treadmill speed of 0.7 m/s. After carbachol (Figure 9) the steps deteriorated with less weight support and no foot placement at 0.3 m/s and perineal stimulation was required to improve stepping at speeds ranging from 0.3 to 0.7 m/s. Twenty minutes after carbachol the cats could walk from 0.3 to 0.7 m/s with perineal stimulation but could not walk without it at 0.4 m/s.


Cholinergic mechanisms in spinal locomotion-potential target for rehabilitation approaches.

Jordan LM, McVagh JR, Noga BR, Cabaj AM, Majczyński H, Sławińska U, Provencher J, Leblond H, Rossignol S - Front Neural Circuits (2014)

Carbachol disruption of locomotion in spinal cats is reversed by atropine. (A–C) regular stepping movements before drug administration 14 days after the lesion represented by raw EMG traces (A), averaged (N = 12 cycles) joint angular displacements (B) and stick figures (C). (D) Raw EMG recordings after intrathecal carbachol (1 mM, 100 μl) showing deterioration of stepping as soon as 7 min post drug administration even with strong perineal stimulation. (E,F) 55 min post carbachol, the EMG is still not organized to produce a good stepping pattern (E). There is no foot placement as represented by the stick figures (F). (G–I) Five minutes after intrathecal administration of atropine (1 mM, 100 μl), a good pattern of stepping was observed without perineal stimulation as was the case before carbachol administration [compare (G–I) with (A–C) same display]. (J) Cycle duration expressed in terms of treadmill speed, showing disruption of locomotion by carbachol, and facilitation of locomotion with atropine.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4222238&req=5

Figure 9: Carbachol disruption of locomotion in spinal cats is reversed by atropine. (A–C) regular stepping movements before drug administration 14 days after the lesion represented by raw EMG traces (A), averaged (N = 12 cycles) joint angular displacements (B) and stick figures (C). (D) Raw EMG recordings after intrathecal carbachol (1 mM, 100 μl) showing deterioration of stepping as soon as 7 min post drug administration even with strong perineal stimulation. (E,F) 55 min post carbachol, the EMG is still not organized to produce a good stepping pattern (E). There is no foot placement as represented by the stick figures (F). (G–I) Five minutes after intrathecal administration of atropine (1 mM, 100 μl), a good pattern of stepping was observed without perineal stimulation as was the case before carbachol administration [compare (G–I) with (A–C) same display]. (J) Cycle duration expressed in terms of treadmill speed, showing disruption of locomotion by carbachol, and facilitation of locomotion with atropine.
Mentions: At Day 14, the spinal cats could walk spontaneously (without drugs) up to a treadmill speed of 0.7 m/s. After carbachol (Figure 9) the steps deteriorated with less weight support and no foot placement at 0.3 m/s and perineal stimulation was required to improve stepping at speeds ranging from 0.3 to 0.7 m/s. Twenty minutes after carbachol the cats could walk from 0.3 to 0.7 m/s with perineal stimulation but could not walk without it at 0.4 m/s.

Bottom Line: Our results demonstrate that the endogenous cholinergic propriospinal system, acting via M2 and M3 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.Changes that have been observed in the cholinergic innervation of motoneurons after spinal cord injury do not decrease motoneuron excitability, as expected.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology and Pathophysiology, Spinal Cord Research Centre, University of Manitoba Winnipeg, MB, Canada.

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 M2 and M3 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.

Show MeSH
Related in: MedlinePlus