Rhythmogenic networks are potently modulated by activation of muscarinic acetylcholine receptors in the rodent spinal cord

• Published in: Journal of neurochemistry 2021-09, Vol.158 (6), p.1263-1273
• Main Authors: Matzner, Henry, Zelinger, Moshe, Cherniak, Meir, Anglister, Lili, Lev‐Tov, Aharon
• Format: Article
• Language: English
• Subjects: Acetylcholine receptors (muscarinic); ascending pathways; central pattern generators; Cholinergics; Cholinesterase; Electrical stimuli; locomotor rhythm; mAChRs; Motor neurons; Muscarine; Neonates; Networks; Pain; Receptors; Rhythm; Rodents; sacrocaudal afferent stimulation; Sacrum; Spinal cord; spinal interneurons; Stimulation
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1111/jnc.15354

Electrical stimulation of the spinal cord is a potent means for activating mammalian stepping in the absence of the descending control from the brain. Previously, we have shown that stimulation of pain delivering (Aδ) sacrocaudal afferents (SCA) has a powerful capacity to activate the sacral and lumbar rhythmogenic networks in the neonatal rodent spinal cord. Relatively little is known about the neural pathways involved in activation of the locomotor networks by Aδ afferents, on their mechanism of action and on the possibility to modulate their activity. We have shown that elevation of the endogenous level of acetylcholine at the sacral cord by blocking cholinesterase could modulate the SCA‐induced locomotor rhythm in a muscarinic receptor‐dependent mechanism. Here, we review these and more recent findings and report that controlled stimulation of SCA in the presence of muscarine is a potent activator of the locomotor network. The possible mechanisms involved in the muscarinic modulation of the locomotor rhythm are discussed in terms of the differential projections of sacral relay neurons, activated by SCA stimulation, to the lumbar locomotor rhythm generators, and to their target motoneurons. Altogether, our studies show that manipulations of cholinergic networks offer a simple and powerful means to control the activity of locomotor networks in the absence of supraspinal control. Cover Image for this issue: https://doi.org/10.1111/jnc.15079. Cholinergic modulation of the locomotor rhythm produced by stimulation of sacrocaudal afferents (SCA, cyan) in the neonatal rat spinal cord is suggested to involve groups of cholinergic and cholinoceptive SCA‐activated sacral relay neurons (VFNs) with ventral funiculi (VF) projections (red arrows) to lumbar motoneurons (diamond shape, blue), pre‐motoneurons (yellow circles), and to the locomotor central pattern generators (CPG, dashed circles). These sacral VFNs (Cholinergic VFNs‐overlay panels) include cholinesterase synthetizing neurons (+AChE), cholinergic partition VFNs (+ChAT), VFNs with cholinergic innervation (+VAChT), and muscarinic receptor expressing VFNs (+M2 and M3 mAChR). The VFNs projections to the CPGs can decelerate the rhythm when the endogenous sacral ACh is elevated while those to the motoneurons and pattern formation circuitry increase the motor output. Cover Image for this issue: https://doi.org/10.1111/jnc.15079.