Longitudinal Characterization of Compound Action Potentials in Chronic Vagus Nerve Recordings in Mice

Abstract

The vagus nerve (VN) mediates bidirectional communication between the body and brain to maintain physiological homeostasis; likewise, alterations in ongoing vagal signaling may be indicators of disease and/or contribute to disease pathogenesis. Even though extensively documented in acute experiments, ongoing vagal activity has not been characterized longitudinally, over days or weeks, in mice, a preferred preclinical model. In addition, even though many VN recordings in mice occur during anesthesia, the effects of anesthesia on vagal signaling are unknown. This study uses a chronic implant mouse model to record vagal activity in anesthetized and awake, behaving animals for an average of 10 weeks and up to 6 months. Individual compound action potentials (CAPs) are tracked across multiple days by quantifying comparisons in features, including firing rates, waveform shape, inter-CAP interval histograms, and phase-locking to cardiac and respiratory signals while demonstrating long-term electrode-nerve interface viability and stable signal-to-noise ratios. Additionally, cytokine challenge experiments produced detectable CAP responses up to 3 months after electrode implantation. Lastly, awake recordings incorporated video analysis to identify and remove motion artifacts to preserve and extract neural and cardiac recordings during behavior. Results reveal diverse CAP populations with diverse physiological coupling and firing rates modulated by anesthesia. This work highlights the potential of chronic VN recordings to assess long-term changes in vagal activity in health and disease, with implications in discovery of autonomic markers of disease and closed-loop VNS stimulation strategies.