[R01] Unraveling Cardiovagal Circuits for Heart Rate with Molecular Connectomics

Ente: National Heart Lung and Blood Institute

Scadenza: 2030-05-31

Importo max: 721.977 EUR

Paese: US

Descrizione

PROJECT SUMMARY. Parasympathetic neurons in the brainstem innervate the heart through the vagus nerve to maintain normal heart rhythm and protect against arrhythmias and heart failure. Despite their importance, little is known about whether functionally distinct subtypes of cardiovagal neurons (CVNs) exist, how they are organized, or whether they are engaged during different reflexes or by different physiological stimuli. This knowledge gap has limited development of therapies that would selectively enhance cardiovagal tone to treat heart disease and failure. This project will uncover fundamental principles for how CVNs are organized at the molecular, circuit, and functional levels. Preliminary studies from our laboratory have identified two distinct CVN subtypes: Npy2r- expressing neurons of the nucleus ambiguus (Npy2rnAmb neurons), which is in the ventral medulla, and Vip- expressing neurons of the dorsal motor nucleus of the vagus (VipDMV neurons). These neurons each innervate cardiac ganglia and, when activated, robustly decrease heart rate. In addition, the Npy2rnAmb neurons are activated during voluntary underwater diving in mice, implicating them in the heart rate decrease that occurs during the diving reflex, one of the most conserved autonomic reflexes known. On the other hand, DMV neurons are known to integrate signaling from higher order brain regions related to stress and feeding. We therefore hypothesize that ventral CVNs in the nAmb provide reflexive, bottom-up control of heart rate, while dorsal CVNs in the DMV mediating top-down control, including the effects of stress and feeding on heart rate. Aim 1 studies will map the synaptic inputs, outputs, and functional sufficiency of each CVN subtype using anterograde tracing, intersectional chemogenetics, and rabies-based molecular connectomics. Our results will define and compare the synaptic inputs as well as the anatomical and functional outputs of each CVN subtype. In Aim 2, we will use fiber photometry, chemogenetic inhibition, and in vivo physiology to determine the activity and necessity of each CVN subtype during both top-down and bottom-up challenges to heart rate, including the diving reflex, baroreceptor reflex, acute stress, and feeding. We expect to find that ventral and dorsal CVNs mediate bottom-up cardiac reflexes and top-down state-dependent control of heart rate, respectively. This work is innovative in its integration of single-cell transcriptomics, viral connectomics, and circuit-level manipulations to build the first molecular and functional atlas of cardiovagal neurons. By identifying the cell types and signaling mechanisms for parasympathetic heart control, these studies will provide critical new insight into the autonomic regulation of heart function and lay the groundwork for cardiovagal-based therapies. Istituzione: UNIVERSITY OF VIRGINIA PI: John Nelson Campbell Progetto: 1R01HL188399-01

Settori: National Heart Lung and Blood Institute

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