Mapping the linkage between auricular vagus nerve receptors and cardiovagal modulation

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ABSTRACT The vagus nerve is regarded as the main parasympathetic conduit of the autonomic nervous system and is involved in the regulation of heart rate, cardiac contractility, ventricular electrical stability and baroreflex sensitivity. Vagus nerve stimulation (VNS) has been suggested and/or used as a neuromodulatory therapy for multiple cardiovascular disorders, including hypertension, coronary artery disease, and heart failure. However, given that VNS is an invasive procedure and has been associated with significant adverse events, the mapping of alternative non-invasive pathways for vagal modulation is of critical relevance. Interestingly, the auricular branch of the vagus (ABVN) is the only peripheral branch of this nerve that distributes to the skin. Previous animal studies have demonstrated that ABVN sensory fibers terminate in the nucleus tractus solitarius (NTS), and, similar to invasive VNS, ABVN stimulation has also been shown to modulate cardiac electrophysiology resulting in atrial fibrillation suppression, and regulation of left ventricular remodeling. While the anatomy of this nerve has been studied in detail, the functional mapping of the circuitry connecting ABVN stimulation with cardiovascular outcomes remains poorly understood. Moreover, as NTS activity and the dorsal medullary vagal system operates in tune with respiration, our group has previously suggested that the neuromodulatory effects of ABVN afference can be optimized by gating stimulation to the respiratory cycle. Hence, our overall goal is to functionally map the ABVN-brainstem-cardiovagal outflow pathway in both humans and rodents and assess its sensitivity to the modulatory effects of respiration. In humans, state-of-the-art ultrahigh-field functional MRI (7T fMRI) will afford enhanced spatiotemporal resolution to evaluate the response of the dorsal medullary vagal system and hypothalamus to ABVN stimulation. Neuroimaging will incorporate simultaneous cardiophysiological assessment and dynamic high frequency heart rate variability (HF-HRV) assessment of cardiovagal modulation, using advanced point-process adaptive filtering algorithms developed by our group. More invasive experiments in a rat model will evaluate the effects of ABVN afference on cervical vagus nerve activity (CVNA), while electrocardiography will be recorded to calculate HF-HRV response to ABVN stimulation, thereby directly linking unique rat and human outcomes via a metric common to both. Rat studies will also assess activation in brainstem and hypothalamic homologue nuclei by c-Fos immunohistochemistry in the absence and presence of neuronal activity blocker, and excitatory and inhibitory neurotransmitter antagonists injected stereotactically into the target nuclei. In summary, the functional mapping of the ABVN pathway in humans is of pivotal importance given its accessibility and its potential neuromodulatory effects on cardiovascular physiology, and our proposal will significantly improve our understanding of the mapping from auricular vagus nerve receptors to the heart.