Neuroanatomical basis for cholinergic modulation of locomotor networks by sacral relay neurons with ascending lumbar projections

Abstract

Synaptic excitation by sacrocaudal afferent (SCA) input of sacral relay neurons projecting rostrally through the ventral white matter funiculi (VF neurons) is a potent activator of the hindlimb central pattern generators (CPGs) in rodent spinal cords lacking descending supraspinal control. Using electrophysiological recordings from the sacral and lumbar spinal segments, we show that the motor output of the lumbar segments produced by SCA stimulation is enhanced by exposing the sacral segments of the neonatal rat spinal cord to the acetylcholinesterase inhibitor edrophonium (EDR). Histochemical and immunostaining of the sacral cord reveals expression of acetylcholinesterase activity, ability to synthesize acetylcholine, and/or innervation by cholinergic synaptic inputs in significant proportions of fluorescently back-labeled sacral VF neurons. Moreover, the majority of the VF neurons express M2 muscarinic receptors, raising the possibility that the elevated acetylcholine levels resulting from inhibition of acetylcholinesterase act on such receptors. Indeed, sacral application of atropine or the M2 -type receptor antagonist methoctramine was found to reverse the effects of EDR. We suggest that variations in the sacral level of acetylcholine modulate the SCA-induced locomotor rhythm via muscarinic receptor-dependent mechanisms and that the modified activity of sacral VF neurons in the presence of an acetylcholinesterase inhibitor can be partially ascribed to the cholinergic components associated with them. Thus, pharmacological manipulations of the sacral cholinergic system may be used to modulate the locomotor-related motor output in the absence of descending supraspinal control.

Cholinergic mechanisms in spinal locomotion—potential target for rehabilitation approaches

“…Similar results with another inhibitor of acetylcholine esterase (NEO) confirm this conclusion. Sacral application of EDRO has been shown to elicit locomotor activity in the lumbar cord (Finkel et al, 2014), and this component of a sacrocaudal afferent system capable of eliciting locomotor activity may have contributed to the results reported here. Our results suggest that using cholinesterase inhibitors allows the expression of cholinergic-induced rhythms triggered by release from the intrinsic cholinergic neurons, rather than by application of an exogenous agonist, to give rise to coordinated locomotion.…”

“…Some commissural cells with excitatory actions on contralateral motoneurons are cholinergic (Bertrand and Cazalets, 2011), and sacral cholinergic neurons modulate locomotor activity recorded from the lumbar segments in vitro (Finkel et al, 2014). A portion of these cholinergic neurons are commissural.…”

Vertical Finger Displacement Is Reduced in Index Finger Tapping During Repeated Bout Rate Enhancement

“…Such an increase might be due to a net excitation of supraspinal centres (De Luca & Erim, 1994). However, it is perhaps also possible that the increased frequency output is caused by net excitation of the spinal CPG itself (Finkel et al, 2014) or by a combination of spinal and supraspinal mechanisms.…”

Ascending pathways that mediate cholinergic modulation of lumbar motor activity

“…; Finkel et al . ). These latter studies revealed that EDR, applied to sacral segments, increased the locomotor‐related output of lumbar motoneurons, and decreased the frequency of the rhythm, in response to SCA stimulation.…”