Molecular Neurogenetics of the Brainstem Neuronal Source of Cardioprotective Vagal Outflow

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We aim to identify, predict and control the central brainstem neurons that integrate interoceptive inputs to produce and determine the activity of the vagus nerve in regulating the heart. The level of “vagal outflow” is strongly associated with the health of the heart. Insufficient vagal outflow contributes to many forms of heart disease, which appear preventable and, potentially, reversible by increases in cardioprotective vagal outflow. We aim to study the central neurons within the dorsal motor nucleus of the vagus (DMV) that are an important source of cardioprotective vagal outflow to the heart, as these are associated with some of the most devastating diseases of the heart. We will determine the cardioprotective molecular mechanisms in DMV neurons in order to use this information to intervene and affect those molecular mechanisms in ways that allow control of the vagal outflow. We will accomplish this through an integrated experimental and computational analysis of the responses of microRNAs and mRNAs in DMV neurons (e.g., Gorky et al. 2021). We have successfully followed this approach using microRNA regulation in a parallel project on hypertension (DeCicco et al. 2015; Gorky, DeDicco et al. in review), and seek to emulate that approach here. We have preliminary DMV data integrating interoceptive inputs in cardiac ischemia and remote ischemic preconditioning (rIPC) suggesting this approach will be applicable for vagal cardioprotection in male and female rats. We hypothesize that the vagal outflow that drives cardioprotection in rIPC derives from an altered molecular activity within the dorsal motor nucleus of the vagus (DMV), mediated by differential microRNA regulation in DMV neurons. Aim 1 will seek to renormalize the molecular state of DMV neurons following left anterior descending coronary artery (LAD) ligation by modulating the microRNA regulatory networks within the DMV. Aim 2 will identify the dynamic trajectory of rIPC-induced microRNA and gene regulatory networks in DMV to predict rIPC-induced microRNA control points in DMV that can potentially extend the molecular cardioprotective effect beyond the currently described 24-hour efficacy window post rIPC. Aim 3 will test the hypothesis that microRNAs regulated in response to rIPC, and their targets putatively contributing to cardioprotection, are co-regulated in one or more specific subsets of DMV neurons. We have assembled an interdisciplinary team for this project. Dr. Vadigepalli is a systems biologist with skills in the analysis of high-dimensional datasets to derive predictions of transcriptional network modules and of microRNA network regulators. Dr. Schwaber has extensive experience with the integrative circuit neuroanatomy and neurophysiology of the central mechanisms of vagal cardiac activity. Dr. Brailoiu is an expert on neuronal processes in the brainstem autonomic nuclei and brings technical expertise on single neuron isolation and analysis. These studies will take state-of-the-art molecular neurogenetics of systems biology and control systems approaches, to enable test of our new central neuronal cardioprotection hypothesis, revealing brainstem neuronal druggable targets for treatment of heart disease.