Voltammetry in the spleen assesses real-time anti-inflammatory norepinephrine release elicited by autonomic neurostimulation

Abstract

Bioelectronic medicine uses neurostimulation devices to modulate the activity of autonomic nerves and restore function in visceral organs. The autonomic, noradrenergic, innervation of the spleen is implicated in the neural control of inflammation; for that reason, the spleen is the target of autonomic stimulation therapies tested in rheumatoid arthritis and other inflammatory diseases. However, there are no real time markers for successful engagement of the spleen by autonomic stimulation. Here, we use fast-scan cyclic voltammetry (FSCV) in the spleen to assess, in real time, the release of norepinephrine (NE) in response to autonomic stimulation in mice. We show that spleen voltammograms demonstrate oxidative current peaks at a voltage of ~0.8 V that is proportional up to a NE blood concentration of 30 to 300nM. The oxidative current increases within seconds in response to electrical splenic nerve stimulation and is blocked by interventions that deplete NE or inhibit NE release. Oxidative current increases in response to electrical vagus nerve stimulation (VNS) and is elicited by efferent, but not afferent, fiber-selective optogenetic VNS. Spleen cyclic voltammetry can potentially provide a real-time physiological marker for dose calibration and monitoring of the anti-inflammatory effectiveness of autonomic stimulation therapies targeting the spleen.