Cardiopulmonary effects of vagus nerve stimulation in mice

Vagus Nerve Stimulation (VNS) is an FDA-approved treatment for epilepsy, depression, and chronic stroke. While the effects of VNS are widely studied in rats and large animal models, few studies have characterized VNS in mice due to the practical challenges associated with their small size. However, mouse genetic tools provide a powerful opportunity to elucidate the diverse mechanisms underlying the many effects of VNS. Therefore, to inform the expanding use of mouse models in VNS research, we characterized the cardiopulmonary effects of left versus right VNS in anesthetized C57BL/6 mice. VNS robustly drove decreases in heart rate (HR) and breathing rate (BR) in the majority of mice. VNS-driven changes in BR were not correlated with changes in HR. We found no differences between male and female mice, nor in the effects of left vs. right VNS. VNS-induced bradycardia was abolished by transection of efferent vagal fibers, consistent with direct descending vagal control of cardiac rhythmicity. By contrast, VNS-driven changes in BR were abolished by both afferent and efferent vagotomies, consistent with the involvement of central feedback circuits in bilaterally coordinated vagal modulation of respiration. These results further our understanding of VNS effects in mice and help inform experimental design and cuff validation protocols for vagal modulation of peripheral vs. central circuits in this species. Significance Statement Vagus nerve stimulation (VNS) is under investigation for the treatment of numerous inflammatory and neurological diseases. To optimize VNS therapies, additional research is needed to better understand how VNS exerts its many effects. Mice are an attractive model for mechanistic studies of VNS because of their extensive genetic toolkit, but their small size complicates electrode implantation and validation of stimulation efficacy. Here, we applied VNS in mice to demonstrate that VNS-evoked decreases in heart rate versus breathing rate reflect the independent activation of peripherally- versus centrally-directed vagal fibers, respectively. These experiments establish a straightforward approach for validating VNS cuff function in mice.