Abstract
Synergizing the effect of afferent fibre stimulation with pharmacological interventions is a desirable goal to trigger spinal locomotor activity, especially after injury. Thus, to better understand the mechanisms to optimize this process, we studied the role of the neuropeptide oxytocin (previously shown to stimulate locomotor networks) on network and motoneuron properties using the isolated neonatal rat spinal cord. On motoneurons oxytocin (1 nM–1 μM) generated sporadic bursts with superimposed firing and dose-dependent depolarization. No desensitization was observed despite repeated applications. Tetrodotoxin completely blocked the effects of oxytocin, demonstrating the network origin of the responses. Recording motoneuron pool activity from lumbar ventral roots showed oxytocin mediated depolarization with synchronous bursts, and depression of reflex responses in a stimulus and peptide-concentration dependent fashion. Disinhibited bursting caused by strychnine and bicuculline was accelerated by oxytocin whose action was blocked by the oxytocin antagonist atosiban. Fictive locomotion appeared when subthreshold concentrations of NMDA plus 5HT were coapplied with oxytocin, an effect prevented after 24 h incubation with the inhibitor of 5HT synthesis, PCPA. When fictive locomotion was fully manifested, oxytocin did not change periodicity, although cycle amplitude became smaller. A novel protocol of electrical stimulation based on noisy waveforms and applied to one dorsal root evoked stereotypic fictive locomotion. Whenever the stimulus intensity was subthreshold, low doses of oxytocin triggered fictive locomotion although oxytocin per se did not affect primary afferent depolarization evoked by dorsal root pulses. Among the several functional targets for the action of oxytocin at lumbar spinal cord level, the present results highlight how small concentrations of this peptide could bring spinal networks to threshold for fictive locomotion in combination with other protocols, and delineate the use of oxytocin to strengthen the efficiency of electrical stimulation to activate locomotor circuits.
Highlights
It is well known that the thoraco-lumbar spinal cord of mammals contains the neuronal hardware, indicated as central pattern generator (CPG), required to express the basic program that drives the alternated activation of flexor and extensor limb muscles during gait [1,2]
The most likely explanation is that the depolarization mediated by oxytocin was not evoked by the direct action on motoneuron membrane, but it arose from the activation of a premotoneuron network
Synergy between oxytocin and NMDA plus 5HT in eliciting fictive locomotion (FL) oxytocin receptors (OTRs) did not physiologically control chemicallyinduced FL, we explored whether the accelerating property shown by this neuropeptide could be exploited to facilitate the activation of locomotor circuits
Summary
It is well known that the thoraco-lumbar spinal cord of mammals contains the neuronal hardware, indicated as central pattern generator (CPG), required to express the basic program that drives the alternated activation of flexor and extensor limb muscles during gait [1,2]. Among the wide family of neuromodulators, certain agents can trigger locomotion, while others can speed it up or facilitate it in concomitance with suitable stimuli [4]. Drugs in the latter category are the most interesting, as they might be used to synergize rehabilitation techniques that exploit the proprioceptive physiological feedback [5,6] to restore post-lesion locomotor patterns [7,8,9,10,11,12]. In vitro studies have shown that neuromodulators can differently affect the chemically and electrically evoked fictive locomotion (FL) [14,15,16], indicating the complexity of network targets
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