Wiring the Vagus: Molecular and Functional Dissection of Vagal Circuits Governing Heart Rate and Immune Modulation 9 views

The vagus nerve is a critical regulator of visceral homeostasis, coordinating cardiac, respiratory, gastrointestinal, and immune functions. Yet, despite its broad clinical relevance including its use in vagus nerve stimulation (VNS) therapies, the molecular and cellular architecture of it has remained poorly understood. This dissertation provides a comprehensive functional and molecular characterization of vagal neurons, generating reference atlases for both major vagal nuclei; the dorsal motor nucleus of the vagus (DMV) and the nucleus ambiguus (nAmb). These studies reveal extensive neuronal heterogeneity within both nuclei and identify six transcriptionally distinct neuronal populations within the nucleus ambiguus (nAmb) and twelve within the dorsal motor nucleus of the vagus (DMV). Through anterograde and retrograde tracing, we confirmed that one population from each nucleus specifically innervates the cardiac ganglia. Functional experiments further established that activation of these cardiovagal neurons elicits robust bradycardia, confirming their direct role in parasympathetic regulation of heart rate. Beyond cardiac control, this work also explores the vagus nerve’s emerging role in the cholinergic anti-inflammatory pathway (CAIP). Using transcriptomic profiling across no injection, vehicle, and lipopolysaccharide (LPS) induced inflammatory conditions, coupled with the machine learning tool Augur, this work systematically identified a neuronal subtype within the DMV that exhibit the strongest transcriptional response to inflammation, potentially linking vagal neuronal activity to modulation of systemic immune responses. Collectively, these findings advance our understanding of vagal circuit organization and function in five key ways: 1) they define the molecular diversity of neurons within both the nAmb and DMV 2) provide anatomical and functional evidence for two discrete vagal populations that control heart rate 3) identify a DMV neuronal subtype that may mediate vagus-dependent immune regulation 4) establish integrative molecular and functional frameworks for investigating visceral motor circuits 5) lay the foundation for future mechanistic studies and potential therapeutic strategies targeting cardiovagal and neuroimmune pathways.

PHD (Doctor of Philosophy)

English

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2026-04-13