New Findings What is the topic of this review? The vagus nerve is a crucial regulator of cardiovascular homeostasis, and its activity is linked to heart health. Vagal activity originates from two brainstem nuclei: the nucleus ambiguus (fast lane) and the dorsal motor nucleus of the vagus (slow lane), nicknamed for the time scales that they require to transmit signals. What advances does it highlight? Computational models are powerful tools for organizing multi‐scale, multimodal data on the fast and slow lanes in a physiologically meaningful way. A strategy is laid out for how these models can guide experiments aimed at harnessing the cardiovascular health benefits of differential activation of the fast and slow lanes. AbstractThe vagus nerve is a key mediator of brain–heart signaling, and its activity is necessary for cardiovascular health. Vagal outflow stems from the nucleus ambiguus, responsible primarily for fast, beat‐to‐beat regulation of heart rate and rhythm, and the dorsal motor nucleus of the vagus, responsible primarily for slow regulation of ventricular contractility. Due to the high‐dimensional and multimodal nature of the anatomical, molecular and physiological data on neural regulation of cardiac function, data‐derived mechanistic insights have proven elusive. Elucidating insights has been complicated further by the broad distribution of the data across heart, brain and peripheral nervous system circuits. Here we lay out an integrative framework based on computational modelling for combining these disparate and multi‐scale data on the two vagal control lanes of the cardiovascular system. Newly available molecular‐scale data, particularly single‐cell transcriptomic analyses, have augmented our understanding of the heterogeneous neuronal states underlying vagally mediated fast and slow regulation of cardiac physiology. Cellular‐scale computational models built from these data sets represent building blocks that can be combined using anatomical and neural circuit connectivity, neuronal electrophysiology, and organ/organismal‐scale physiology data to create multi‐system, multi‐scale models that enable in silico exploration of the fast versus slow lane vagal stimulation. The insights from the computational modelling and analyses will guide new experimental questions on the mechanisms regulating the fast and slow lanes of the cardiac vagus toward exploiting targeted vagal neuromodulatory activity to promote cardiovascular health.

The baroreceptor reflex is a multi‐input, multi‐output physiological control system that regulates short‐term blood pressure by modulating parasympathetic and sympathetic nerve activity between the brainstem and the heart. The opposing effects of parasympathetic and sympathetic nerve activity work in conjunction to maintain cardiovascular homeostasis, with imbalances in activity associated with cardiovascular disease. Recently, attention has focused on the role of the intrinsic cardiac nervous system (ICN) in local control of nervous regulation of the heart and its role in balancing parasympathetic and sympathetic nerve activity. However, it is unknown how the ICN network structure contributes to integrative control of the heart. We formulated multiple alternative network options based on the anatomical, molecular and physiological evidence. We extended a quantitative closed‐loop computational model of the baroreceptor reflex by incorporating a high‐fidelity representation of the ICN to evaluate the impact of altered ICN network structures on overall cardiovascular control. The present computational model consists of (1) a system of ordinary differential equations to represent blood flow in the cardiovascular system, and (2) transfer function representations of sensory neurons, central nervous system neuronal groups, and ICN neuronal groups, connected in a closed‐loop control circuit. We use this model to investigate, via simulation, the role of the intrinsic cardiac nervous system in integrating and modulating parasympathetic and sympathetic nerve activity in healthy and diseased states. Our results show that the local circuit neurons may modulate the ICN network response to distinct vagal inputs towards the integrative control of local cardiac function.

Hypertension is a multifactorial disease involving the dysregulation of several organs. The organ‐organ interactions and time course dynamics are yet to be well delineated. We analyzed pathway‐scale gene expression across five organs during the development of hypertension in female Spontaneously Hypertensive rats (SHR), at five time points from early onset (8,10,12 weeks of age) to established hypertension (16 and 24 weeks), and age‐matched normotensive Wistar Kyoto (WKY) rats. We studied the interactions within and across organs by integrating the gene expression analysis with a Hartley Modulating Function based system identification approach to reverse engineer data‐driven dynamic network models of multi‐organ gene regulatory influences. Our results indicate a dynamic dysregulation of gene expression spanning multiple organs over time in female SHR. Adrenal gland showed the most robust gene expression changes across multiple pathways, including the renin angiotensin system and catecholaminergic processes. These changes in the adrenal gland preceded the differential regulation of inflammation‐relevant processes in the kidney. The inferred multi‐organ network model suggests a diminished influence of the differential gene regulation in the central nervous system on the gene expression changes in spleen and lung. This was paralleled by an increased influence of adrenal gene regulation over the gene expression changes in multiple other organs. We compared the results to the available male SHR multi‐organ gene expression analysis and modeling. We found that the gene dysregulation patterns, temporal sequencing and putative organ‐organ influences are distinct to female SHR, highlighting the sex‐specific multi‐organ regulatory processes driving hypertension.

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.