A 3D Anatomical and Molecular Map of Cardiac Vagal Motor Neurons

Hornung E, Robbins S, Srivastava A, Achanta S, Schwaber J, and Vadigepalli R

Vagus nerve stimulation is an effective therapeutic option for some but not all cardiovascular disease patients, as shown in human clinical trials. The Dorsal Motor Nucleus of the Vagus (DMV) contains the cell bodies of cardiac vagal motoneurons forming the vagus nerve and innervating the intrinsic cardiac nervous system (ICN). The DMV is required for cardioprotection against heart failure pathology from physiological interventions such as remote ischemic pre-conditioning (RIPC). However, the anatomical and molecular underpinnings of cardioprotective DMV neurons are yet to be resolved. Herein, we discover transcriptomic phenotypes of DMV neurons, by combining neural tracing, transcriptomics, and 3D mapping in male and female Sprague Dawley rats. We find that DMV neurons are not solely cholinergic, but instead express many different neurotransmitter synthesis enzymes, and highlight the functional significance of several transcripts and proteins detected in cardiac-projecting DMV neurons. A phenotype with strong cardioprotective potential is present at the rostro-caudal position of left DMV previously shown to affect ventricular contractility, suggesting this subdivision of DMV may be involved in cardioprotection. While there is consistent detection of this phenotype across transcriptomic techniques and sexes, we also highlight anatomical and sex differences. Overall, our results suggest DMV neurons may participate in neuromodulatory co-transmission as well as phenotype switching and highlight their anatomically and molecularly distinct cardioprotective potential across sexes. Based on these results, we present a 3D anatomical and molecular map of cardiac vagal motoneurons which may be used as a resource to identify DMV phenotypes from whole brain sc-RNA-seq or bulk RNA-seq datasets.