1530-P: Mind over Metabolism—Dorsal Vagal Neurons Can Improve Glucose Tolerance, Reduce Heart Rate, and Suppress Anxiety-Like Behavior

Parasympathetic neurons of the dorsal motor nucleus of the vagus (DMV) play a crucial role in regulating glucose metabolism via the vagus nerve, making them potential targets for diabetes treatment. We sought to identify and investigate these neurons by chemogenetically activating them in awake, behaving mice during glucose tolerance tests. We virally targeted hM3Dq receptors to DMV neurons by the co-expression of Chat- and Phox2b- driven recombinases in our transgenic mouse model (Chat-Cre;Phox2b-Flp;dsHTB mice). The experimental protocol involved recording baseline glucose levels (after fast), followed by the injection of the hM3Dq ligand, Clozapine-n-oxide (CNO), or vehicle. After a 30min wait, we administered glucose (i.p) and conducted tail blood glucometry at 5min intervals from -30min to 120min. Average blood glucose readings were compared between CNO and vehicle. Our findings indicate that activating DMV neurons significantly improves glucose tolerance 5min after glucose injection: Vehicle-5min: 276.8 ± 12.8, CNO-5min: 218.8 ± 12.0, p=0.0459, n=8 (RM two-way ANOVA with Šídák’s). To identify specific DMV neurons involved in glucose regulation, we selectively activated a molecular subtype characterized by co-expression of Calb2 and Chat. Activating Calb2+ DMV neurons with CNO also substantially improved glucose tolerance compared to vehicle at both 5- and 15-minute time points: Vehicle-5min: 281.4 ± 12.7, CNO-5min: 242.3± 8.6, p=0.0459; Vehicle-15min: 411.0 ± 14.0, CNO-15min: 335.5 ± 9.2, p=0.0016, n=16 (RM two-way ANOVA with Šídák’s). Together our data indicates that activating DMV neurons generally or Calb2+ DMV neurons specifically improves glucose tolerance. These findings identify a specific vagal motor neuron population which can control glucose tolerance and so may lead to novel therapeutics for diabetes and other metabolic disorders.