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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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Induction of locomotion in vitro by 50 μM EDRO. (A) ENG recordings showing sustained alternating flexor/extensor and left/right activity. (B) Rectified and filtered waveforms of the traces in (A). (C) Polar plots derived from pooled data from 19 experiments showing the circular distribution of mean phase values and mean angles of the right flexor ventral root ENG (r L2) vs. the right extensor ventral root ENG (r L5), and right (r L2) vs. left (l L2) flexor ENGs (green vectors). The superimposed r vectors show the concentration of phase values around the mean angle. Mean rhythm frequency (Hz) of all filtered and rectified r L2 waveforms: 0.213 ± 0.052 Hz (0.13–0.33 Hz). Mean step duration of all rectified and filtered r L2 waveforms: 4.908 ± 1.312 s (4.85–7.87 s). The phase value for ipsilateral flexor/extensor activity (θ = 205°) as well as the bilateral flexor (r L2 vs. l L2) phase value (θ = 201°) for the example shown in (A,B,D) is shown in (C) with the red vector. (D) Overlay of step cycles (triggered on the onset of l L2 activity) of each rectified and filtered waveform shown in (B).
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Figure 2: Induction of locomotion in vitro by 50 μM EDRO. (A) ENG recordings showing sustained alternating flexor/extensor and left/right activity. (B) Rectified and filtered waveforms of the traces in (A). (C) Polar plots derived from pooled data from 19 experiments showing the circular distribution of mean phase values and mean angles of the right flexor ventral root ENG (r L2) vs. the right extensor ventral root ENG (r L5), and right (r L2) vs. left (l L2) flexor ENGs (green vectors). The superimposed r vectors show the concentration of phase values around the mean angle. Mean rhythm frequency (Hz) of all filtered and rectified r L2 waveforms: 0.213 ± 0.052 Hz (0.13–0.33 Hz). Mean step duration of all rectified and filtered r L2 waveforms: 4.908 ± 1.312 s (4.85–7.87 s). The phase value for ipsilateral flexor/extensor activity (θ = 205°) as well as the bilateral flexor (r L2 vs. l L2) phase value (θ = 201°) for the example shown in (A,B,D) is shown in (C) with the red vector. (D) Overlay of step cycles (triggered on the onset of l L2 activity) of each rectified and filtered waveform shown in (B).

Mentions: After baseline recordings of 30 s duration, EDRO (25–100 μM) was applied to the bath. Episodes of rhythmic activity (Figures 1A,B), with superimposed slower rhythms, were produced in 88% (64/73) of experiments after a period of 5–370 s (mean ± SD; 69.9 ± 75.5 s). In the remaining nine experiments, the activity was either tonic or was observed in one or two ventral roots only. In 44 of the 64 experiments in which EDRO produced rhythmic activity (69%), the activity consisted of sustained patterns of ventral root activity characterized by right/left and ipsilateral flexor/extensor alternation typical of locomotion (Figures 1C, 2). The mean number of episodes of locomotion was 6.5 per 30 min recording period. The mean duration of each episode of activity was 110.4 ± 56.1 s (range 50–184 s). The mean rhythm frequency was 0.21 ± 0.05 Hz (0.13–0.33 Hz), and the mean step duration was 4.90 ± 1.31 s (range 1.8–7.8 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)

Induction of locomotion in vitro by 50 μM EDRO. (A) ENG recordings showing sustained alternating flexor/extensor and left/right activity. (B) Rectified and filtered waveforms of the traces in (A). (C) Polar plots derived from pooled data from 19 experiments showing the circular distribution of mean phase values and mean angles of the right flexor ventral root ENG (r L2) vs. the right extensor ventral root ENG (r L5), and right (r L2) vs. left (l L2) flexor ENGs (green vectors). The superimposed r vectors show the concentration of phase values around the mean angle. Mean rhythm frequency (Hz) of all filtered and rectified r L2 waveforms: 0.213 ± 0.052 Hz (0.13–0.33 Hz). Mean step duration of all rectified and filtered r L2 waveforms: 4.908 ± 1.312 s (4.85–7.87 s). The phase value for ipsilateral flexor/extensor activity (θ = 205°) as well as the bilateral flexor (r L2 vs. l L2) phase value (θ = 201°) for the example shown in (A,B,D) is shown in (C) with the red vector. (D) Overlay of step cycles (triggered on the onset of l L2 activity) of each rectified and filtered waveform shown in (B).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 2: Induction of locomotion in vitro by 50 μM EDRO. (A) ENG recordings showing sustained alternating flexor/extensor and left/right activity. (B) Rectified and filtered waveforms of the traces in (A). (C) Polar plots derived from pooled data from 19 experiments showing the circular distribution of mean phase values and mean angles of the right flexor ventral root ENG (r L2) vs. the right extensor ventral root ENG (r L5), and right (r L2) vs. left (l L2) flexor ENGs (green vectors). The superimposed r vectors show the concentration of phase values around the mean angle. Mean rhythm frequency (Hz) of all filtered and rectified r L2 waveforms: 0.213 ± 0.052 Hz (0.13–0.33 Hz). Mean step duration of all rectified and filtered r L2 waveforms: 4.908 ± 1.312 s (4.85–7.87 s). The phase value for ipsilateral flexor/extensor activity (θ = 205°) as well as the bilateral flexor (r L2 vs. l L2) phase value (θ = 201°) for the example shown in (A,B,D) is shown in (C) with the red vector. (D) Overlay of step cycles (triggered on the onset of l L2 activity) of each rectified and filtered waveform shown in (B).
Mentions: After baseline recordings of 30 s duration, EDRO (25–100 μM) was applied to the bath. Episodes of rhythmic activity (Figures 1A,B), with superimposed slower rhythms, were produced in 88% (64/73) of experiments after a period of 5–370 s (mean ± SD; 69.9 ± 75.5 s). In the remaining nine experiments, the activity was either tonic or was observed in one or two ventral roots only. In 44 of the 64 experiments in which EDRO produced rhythmic activity (69%), the activity consisted of sustained patterns of ventral root activity characterized by right/left and ipsilateral flexor/extensor alternation typical of locomotion (Figures 1C, 2). The mean number of episodes of locomotion was 6.5 per 30 min recording period. The mean duration of each episode of activity was 110.4 ± 56.1 s (range 50–184 s). The mean rhythm frequency was 0.21 ± 0.05 Hz (0.13–0.33 Hz), and the mean step duration was 4.90 ± 1.31 s (range 1.8–7.8 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