Anatomical and Molecular Phenotypes of Fast and Slow Vagal Targets in the Intrinsic Cardiac Nervous System

Abstract

The vagus nerve coordinates the communication between the brain and most of the visceral organs. Vagus nerve activity is critical to promote cardiac health and cardioprotective response in heart failure. The vagal motor outflow involves two nuclei, the nucleus ambiguous (NA) and the dorsal motor nucleus of the vagus (DMV). NA acts via nicotinic cholinergic processes to elicit fast kinetics of the intrinsic cardiac nervous system (ICN) response at the heart. By contrast, the DMV influences the ICN neurons via muscarinic cholinergic processes yielding slower kinetics of response. Interestingly, NA and DMV project to distinct neuronal populations in the ICN, providing an anatomical basis for the fast versus slow vagal action on the heart. We aim to delineate the ICN neuronal network mediating the two lanes of vagal inputs for regulating distinct cardiac functions with lane‐specific transcriptomic identities of ICN neuron targets. We performed immunohistochemistry (IHC) on the rat heart tissue sections embedded in the optimal cutting temperature (OCT) followed by confocal microscopy imaging. We found that while the ICN neurons express muscarinic and nicotinic acetylcholine receptors (AChRs) broadly across the ICN, with several neurons predominantly expressing either muscarinic or nicotinic AChRs. We used Laser Capture Microscopy (LCM) to acquire neurons that predominantly express muscarinic or nicotinic AChRs. We are profiling the transcriptomic identities of these LCM‐captured neuron classes. Our results suggest that mAChR‐only and nAChR‐only neurons differentially express neuromodulatory processes, including receptors, neurotransmitter synthesis enzymes, and neuropeptides. Further, we incorporate a systems approach combining spatial single‐cell transcriptomics, neuronal network modeling, and physiological control systems modeling to identify selective targets for novel neuromodulatory interventions that improve heart health.