Dorsal motor vagal neurons can suppress heart rate in mice

Abstract

The dorsal motor nucleus of the vagus (DMV) is a functionally heterogeneous vagal motor region which controls a variety of digestive and metabolic functions but also innervates the heart, where its role in controlling heart rate is less clear. We therefore chemogenetically activated DMV neurons in awake behaving mice while monitoring heart rate. To selectively activate DMV neurons, we injected an adeno-associated virus (AAV) which expresses the excitatory chemogenetic receptor, hM3Dq (8 injections, 40nl each), only after recombination by both Cre and Flp recombinases, into the DMV of Chat-Cre::Phox2b-Flp mice. Several months later, we injected the hM3Dq ligand clozapine N-oxide (CNO; 1mg/kg) via intraperitoneal injection (n=2 females, 3 males; mean age ± S.D., 32 ± 2 weeks) to activate hM3Dq+ DMV neurons while measuring heart rate via a non-invasive ECG system (ECGenie). We measured heart rate 20 minutes prior to CNO and 0, 20, 40 minutes and 1, 2, 6, 8, 24 hours later. CNO administration significantly but reversibly decreased heart rate (mean ± standard deviation, S.D.: 20min before CNO, 705 ± 15 bpm; 40min after CNO, 536 ± 86 bpm, p=0.0271; 24hr after CNO, 727 ± 25 bpm, p=0.7347; one-way ANOVA, all timepoints, F 1.660, 6.638 =10.31; Dunnet's post-hoc test, p=0.0107). In order to identify the specific neurons responsible, we repeated these studies in Calb2-Cre::Chat-Flp mice (n=2 females, 3 males; mean age ± S.D., 29 ± 2 weeks) to target Calb2+ DMV neurons, a recently identified DMV molecular subtype. However, in striking contrast to what we observed when activating DMV neurons generally, administering CNO to activate Calb2+ DMV neurons specifically did not significantly affect heart rate (mean ± S.D.: 20min before CNO, 691 ± 69 bpm; 40min after CNO, 718 ± 31 bpm, p=0.6787; 24hr after CNO, 710 ± 54 bpm, p=0.4701; one-way ANOVA, all timepoints, F 2.911, 11.65 =0.6277; Dunnet’s, p=0.6069). A higher dose of CNO (3.5mg/kg) also had no effect on heart rate in Calb2-Cre::Chat-Flp mice (data not shown). Together, our studies indicate that DMV neurons are capable of suppressing heart rate and that the underlying neurons likely do not express Calb2. Uncovering the DMV’s role in heart rate will expand our understanding of how this clinically relevant metric, associated with a host of cardiovascular disorders, is controlled. Ingrassia Family Echols Scholars Research Grant and Schwager Summer Research Scholarship to L.S.K.; ADA Pathway to Stop Diabetes Award 1-18-INI-14 and NIH grant HL153916 to J.N.C. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.