Abstract
Spinal motor control networks are regulated by neuromodulatory systems to allow adaptability of movements. The present study aimed to elucidate the role of nitric oxide (NO) in the modulation of mammalian spinal locomotor networks. This was investigated with isolated spinal cord preparations from neonatal mice in which rhythmic locomotor-related activity was induced pharmacologically. Bath application of the NO donor diethylamine NONOate (DEA/NO) decreased the frequency and modulated the amplitude of locomotor-related activity recorded from ventral roots. Removal of endogenous NO with coapplication of a NO scavenger (PTIO) and a nitric oxide synthase (NOS) blocker [nitro-l-arginine methyl ester (l-NAME)] increased the frequency and decreased the amplitude of locomotor-related activity. This demonstrates that endogenously derived NO can modulate both the timing and intensity of locomotor-related activity. The effects of DEA/NO were mimicked by the cGMP analog 8-bromo-cGMP. In addition, the soluble guanylyl cyclase (sGC) inhibitor ODQ blocked the effects of DEA/NO on burst amplitude and frequency, although the frequency effect was only blocked at low concentrations of DEA/NO. This suggests that NO-mediated modulation involves cGMP-dependent pathways. Sources of NO were studied within the lumbar spinal cord during postnatal development (postnatal days 1–12) with NADPH-diaphorase staining. NOS-positive cells in the ventral horn exhibited a rostrocaudal gradient, with more cells in rostral segments. The number of NOS-positive cells was also found to increase during postnatal development. In summary, we have shown that NO, derived from sources within the mammalian spinal cord, modulates the output of spinal motor networks and is therefore likely to contribute to the fine-tuning of locomotor behavior.
Highlights
AT ITS CORE vertebrate locomotion involves rhythmic, stereotyped contractions of muscles, locomotor behavior must be flexible so that it can be adjusted to suit changing environmental and developmental demands
DEA/nitric oxide (NO) caused a reversible decrease in the frequency of bursts of locomotor-related ventral root activity (13.9 Ϯ 6.1% decrease with 50 M, 21.1 Ϯ 7.5% decrease with 100 M, 28.4 Ϯ 6.0% decrease with 200 M, and 57.6 Ϯ 7.3% decrease with 400 M; Fig. 1, Ai, Aii, C: locomotor burst amplitude (Ci), Cii, and Dii)
Given the variability in control frequencies of different preparations, we investigated whether there was a relationship between the starting frequency and the magnitude of the effect induced by DEA/ NO; no significant relationship was identified
Summary
AT ITS CORE vertebrate locomotion involves rhythmic, stereotyped contractions of muscles, locomotor behavior must be flexible so that it can be adjusted to suit changing environmental and developmental demands. During later developmental stages in Xenopus, when limbs and presumably their spinal control circuitry develop, NOS-expressing cells are present in the spinal cord (Ramanathan et al 2006) At these later stages NO may act as an intrinsic modulator of locomotion that, in contrast to early stages, increases the frequency of locomotor activity (Sillar et al 2008). NO donors appear to reduce the frequency and amplitude of spontaneous respiratory motor output while NOS inhibitors produce the opposite effect, indicating neuromodulation by endogenous NO (Mironov and Langohr 2007; Pierrefiche et al 2007) These findings demonstrate that NO can modulate rhythmic motor activity produced by a mammalian CPG network. We identify potential sources of this intrinsic, neuromodulatory NO and describe their postnatal development
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