Highly Selective Brain-to-Gut Communication via Genetically-Defined Vagus Neurons

The vagus nerve innervates many organs, and most if not all of its motor fibers are cholinergic. However, no one knows its organizing principles; whether or not there are dedicated neurons with restricted targets that act as "labeled lines" to perform certain functions – including two opposing ones (gastric contraction versus relaxation). By performing unbiased transcriptional profiling of DMV cholinergic neurons, we discovered seven molecularly-distinct subtypes of motor neurons. Then, by using subtype-specific Cre driver mice, we go on to show that two of these subtypes exclusively innervate the glandular domain of the stomach where, remarkably, they contact different enteric neurons releasing functionally opposing neurotransmitters (acetylcholine versus nitric oxide). Thus, the vagus motor nerve communicates via genetically-defined labeled lines to control functionally unique enteric neurons within discrete subregions of the gastrointestinal tract. This discovery provides a conceptual breakthrough on the division of labor used by the vagus motor nerve to control function. Single-nuclei RNA-Seq (sNuc-Seq) analysis of 384 samples isolated from the dorsal motor nucleus of the vagus of 12 week old Chat-IRES-cre male mice (C57Bl6/j background)