Cholinergic mechanisms in spinal locomotion—potential target for rehabilitation approaches

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.

Spinalization and locomotor training differentially affect muscarinic acetylcholine receptor type 2 abutting on α‐motoneurons innervating the ankle extensor and flexor muscles

“…Development of the hyper‐cholinergic state in paraplegic animals (Jordan et al . ) suggests that presynaptic deficits are accompanied by up‐regulation of postsynaptic components of cholinergic signaling. If postsynaptic adaptation of M2 receptors to these deficits develops (Bernard et al .…”

“…Manifestations of the hyper‐cholinergic state described after SCT (Jordan et al . ) prompted us to search for its molecular underpinnings.…”

“…Jordan and collaborators have shown that reduced inputs to MNs after spinalization convert into a hyper‐cholinergic state, described at 1–2 weeks in cats, and at 10 post‐lesion weeks in rats (Jordan et al . ). Moreover, whereas carbachol administered to spinal rats causes immediate cessation of treadmill locomotion induced by tail pinching, a subsequent application of atropine reverses this effect (Jordan et al .…”

“…Moreover, whereas carbachol administered to spinal rats causes immediate cessation of treadmill locomotion induced by tail pinching, a subsequent application of atropine reverses this effect (Jordan et al . ). These observations raise a functionally important question regarding the molecular basis of maladaptive changes, which develop postsynaptically in the MN pools after spinalization.…”

Spinal neuronal activation during locomotor‐like activity enabled by epidural stimulation and 5‐hydroxytryptamine agonists in spinal rats

“…A decrease in the activation of these cholinergic interneurons in step‐trained rats also could be due to an increase in upstream inhibitory influences indirectly through the control of presynaptic inhibition of primary afferents. Electrophysiological studies have demonstrated that cholinergic interneurons surrounding the central canal do not receive primary afferent input (Zagoraiou et al, ), but they may receive oligosynaptic sensory input (Witts et al, ) as well as rhythmic input from locomotor central pattern generators (Jordan et al, ; Witts et al, ). Fink and colleagues () have demonstrated that a subset of γ‐aminobutyric acid (GABA)‐ergic (GAD 65 ) interneurons provides presynaptic inhibitory control over sensory input involved in performing skilled limb movements.…”