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

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 daylight in-cage 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 for the discovery of autonomic markers of disease and closed-loop VNS stimulation strategies.