A 3D Anatomical and Molecular Map of Cardiac Vagal Motoneurons

Abstract

Recent efforts through the NIH SPARC program have opened new opportunities for harnessing vagal activity to promote cardioprotection. However, cardiac‐projecting vagal motoneurons of the Dorsal Motor Nucleus of the Vagus (DMV) are relatively understudied, even as recent studies show that DMV activity is required for cardioprotection induced by physiological interventions. By combining principles of neuroscience and single cell transcriptomics, we begin to explore the transcriptomic phenotypes of cardiac‐projecting DMV neurons. Neuromodulatory co‐transmission is an emerging discipline of neuroscience, and the work of the Allen Institute suggests transcriptomics of neuropeptides and corresponding receptors may characterize cell types. We find that DMV neurons are not solely cholinergic, but simultaneously catecholaminergic and GABAergic, including those that project to the heart. These findings challenge the conventional neuronal nomenclature. We propose that inputs determine phenotype, and work done on the Mouse Brain Atlas supports this premise, suggesting a transcriptomic diversification, less region‐specific, results from interaction with the environment. We present here a characterization of DMV cell types by input‐output transcriptomics. We combine high throughput transcriptomics, 3D anatomical mapping, and neural tracing in 12 week old Sprague Dawley male and female rats to interrogate the phenotypes of DMV neurons. To distinguish potential mechanisms of cardioprotection, we highlight the functional significance of several transcripts for secreted proteins in cardiac‐projecting DMV neurons. We have spatially mapped the location and molecular phenotypes of these single cells in the DMV and Nucleus Ambiguus (NA). The cardiac‐projecting neurons of the DMV extend approximately 2.5 mm rostrocaudally. The cardiac‐projecting neurons of the left DMV are particularly prominent caudally, while the cardiac‐projecting neurons of the right DMV are particularly prominent rostrally. A unique phenotype, with transcriptomic markers of strong cardioprotective potential, is present at the rostrocaudal position of left DMV previously shown to affect ventricular contractility. There is consistency between our findings from three spatial transcriptomics techniques. Based on these results, we propose a 3D anatomical and molecular map of cardiac vagal motoneurons.