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Updated: Jan 10, 2026

Spinal Cord Electrophysiology
Published on: January 18, 2010
Synergistic mechanisms of medullary cholinergic-serotonergic pathway interactions in regulating neuronal excitability
Yi Cheng1,2, Yue Dai3,4, Renkai Ge5
1Key Lab of Adolescent Health Assessment and Exercise Intervention of Ministry of Education, College of Physical Education and Health Care, East China Normal University, Shanghai, China.
Abstract:
Medullary serotonergic (5-HT) neurons play a pivotal role in locomotor initiation. While these neurons receive cholinergic innervation, the functional consequences and underlying mechanisms remain poorly understood. Using ePet-EYFP transgenic mice (P3-P6) and multidisciplinary approaches, we elucidated the mechanisms by which cholinergic signaling regulated medullary 5-HT neuronal activity and locomotor output. Key findings included: (1) acetylcholine (ACh) elicited location-dependent excitatory, inhibitory, or neutral responses in 5-HT neurons, recapitulated by muscarine and abolished by atropine, indicating muscarinic receptor (mAChR)-mediated regulation. (2) 5-HT neurons in parapyramidal region exhibited ACh-induced excitation, whereas those in midline raphe nuclei displayed inhibition. (3) ACh-enhanced excitability was mediated via M3 receptors, whereas ACh-induced suppression depended on M2/M4 receptor activation. (4) In vitro bath application of muscarine to medullary region induced triphasic modulation of fictive locomotion. Blockade of M1/M5 receptors did not affect locomotion, whereas M3 receptor antagonism reduced gait velocity and perturbated locomotor rhythm. Conversely, M2/M4 receptor antagonism increased stepping frequency without altering locomotor pattern. This study provided the first mechanistic dissection of how medullary cholinergic-serotonergic interactions regulated neuronal excitability and locomotion, uncovering distinct mAChR subtype contributions to motor control.
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