Nicotine induces abnormal motor coupling through sensitization of a mechanosensory circuit in Caenorhabditis elegans

Nicotine exposure elicits diverse behavioral changes, yet the underlying neural pathways and molecular mechanisms remain incompletely understood. Here, we demonstrate that chronic nicotine exposure markedly increases both the initiation and duration of reversals in Caenorhabditis elegans. Strikingly, these reversals were tightly coupled with the rhythmic body contractions of the defecation motor program (DMP). Through pharmacological, genetic, in situ electrophysiological, and calcium imaging analyses, we show that nicotine enhances the activity of the AVA interneuron via selective upregulation of ACR-16, a nicotinic ACh receptor critical for nicotine-induced motor coupling. Ablation of touch receptor neurons (TRNs) or inhibition of TRNs-mediated mechanosensation completely abolished this coupling. Furthermore, optogenetic activation of TRNs in nicotine-treated animals evoked stronger AVA depolarization, and nicotine amplified gentle touch-evoked reversals. Together, these findings reveal a potential interoceptive effect of nicotine mediated by sensitization of the TRNs-AVA mechanosensory pathway, providing new insight into the neural and molecular basis of nicotine’s modulation of sensory-motor coupling.Nicotine exposure elicits diverse behavioral changes, yet the underlying neural pathways and molecular mechanisms remain incompletely understood. This study shows that in C. elegans, chronic nicotine exposure couples reversal behaviors to rhythmic body contractions by modulating the sensitivity of a mechanosensory-motor circuit.