Background: The vagus nerve plays an important role in the regulation of organ function, including reflex pathways that regulate immunity and inflammation. Recent studies using genetically modified mice have improved our understanding of molecular mechanisms in the neural control of immunity. However, mapping neural signals transmitted in the vagus nerve in mice has been limited by technical challenges. Here, we have standardized an experimental protocol to record compound action potentials transmitted in the vagus nerve. Methods: The vagus nerve was isolated in Balb/c and B6.129S mice, and placed either on a hook or cuff electrode. The electrical signals from the vagus nerve were digitized using either a Neuralynx or Plexon data acquisition system. Changes in the vagus nerve activity in response to anesthesia, feeding and administration of bacterial endotoxin were analyzed. Results: We have developed an electrophysiological recording system to record compound action potentials from the cervical vagus nerve in mice. Cuff electrodes significantly reduce background noise and increase the signal to noise ratio as compared to hook electrodes. Baseline vagus nerve activity varies in response to anesthesia depth and food intake. Analysis of vagus neurograms in different mouse strains (Balb/c and C57BL/6) reveal no significant differences in baseline activity. Importantly, vagus neurogramactivity in wild type and TLR4 receptor knock out mice exhibits receptor dependency of endotoxin mediated signals. Conclusions: These methods for recording vagus neurogram in mice provide a useful tool to further delineate the role of vagus neural pathways in a standardized murine disease model.
Background Electrical stimulation of peripheral nerves is a widely used technique to treat a variety of conditions including chronic pain, motor impairment, headaches, and epilepsy. Nerve stimulation to achieve efficacious symptomatic relief depends on the proper selection of electrical stimulation parameters to recruit the appropriate fibers within a nerve. Recently, electrical stimulation of the vagus nerve has shown promise for controlling inflammation and clinical trials have demonstrated efficacy for the treatment of inflammatory disorders. This application of vagus nerve stimulation activates the inflammatory reflex, reducing levels of inflammatory cytokines during inflammation. Methods Here, we wanted to test whether altering the parameters of electrical vagus nerve stimulation would change circulating cytokine levels of normal healthy animals in the absence of increased inflammation. To examine this, we systematically tested a set of electrical stimulation parameters and measured serum cytokine levels in healthy mice. Results Surprisingly, we found that specific combinations of pulse width, pulse amplitude, and frequency produced significant increases of the pro-inflammatory cytokine tumor necrosis factor (TNF), while other parameters selectively lowered serum TNF levels, as compared to sham-stimulated mice. In addition, serum levels of the anti-inflammatory cytokine interleukin-10 (IL-10) were significantly increased by select parameters of electrical stimulation but remained unchanged with others. Conclusions These results indicate that electrical stimulation parameter selection is critically important for the modulation of cytokines via the cervical vagus nerve and that specific cytokines can be increased by electrical stimulation in the absence of inflammation. As the next generation of bioelectronic therapies and devices are developed to capitalize on the neural regulation of inflammation, the selection of nerve stimulation parameters will be a critically important variable for achieving cytokine-specific changes.
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