Abstract
BackgroundGlucose is a crucial energy source. In humans, it is the primary sugar for high energy demanding cells in brain, muscle and peripheral neurons. Deviations of blood glucose levels from normal levels for an extended period of time is dangerous or even fatal, so regulation of blood glucose levels is a biological imperative. The vagus nerve, comprised of sensory and motor fibres, provides a major anatomical substrate for regulating metabolism. While prior studies have implicated the vagus nerve in the neurometabolic interface, its specific role in either the afferent or efferent arc of this reflex remains elusive.MethodsHere we use recently developed methods to isolate and decode specific neural signals acquired from the surface of the vagus nerve in BALB/c wild type mice to identify those that respond robustly to hypoglycemia. We also attempted to decode neural signals related to hyperglycemia. In addition to wild type mice, we analyzed the responses to acute hypo- and hyperglycemia in transient receptor potential cation channel subfamily V member 1 (TRPV1) cell depleted mice. The decoding algorithm uses neural signals as input and reconstructs blood glucose levels.ResultsOur algorithm was able to reconstruct the blood glucose levels with high accuracy (median error 18.6 mg/dl). Hyperglycemia did not induce robust vagus nerve responses, and deletion of TRPV1 nociceptors attenuated the hypoglycemia-dependent vagus nerve signals.ConclusionThese results provide insight to the sensory vagal signaling that encodes hypoglycemic states and suggest a method to measure blood glucose levels by decoding nerve signals.Trial registrationNot applicable.
Highlights
Surface vagus nerve recordings respond to insulininduced hypoglycemia We recorded from the surface of the vagus nerve in anesthetized mice (N = 19) using a Cortec Micro Cuff Sling electrode during acute hypoglycemia induced by insulin injections (Fig. 1a and b)
Vagus responses to hypoglycemia correlate with blood glucose levels While these results show that the vagus nerve responds to acute hypoglycemia, it is not clear whether information about the actual blood glucose levels is relayed through the same conduit
Vagus nerve recordings from TPRV1-Diphtheria toxin fragment A (DTA) mice contain a subset of neural responses to insulin injections We have shown previously that TRPV1 fibers are necessary for cytokine-specific sensory signaling through the vagus nerve (Zanos et al 2018)
Summary
Glucose sensing neurons are present in pancreatic beta cells, the intestine, the hepatic portal vein, the carotid body (McCrimmon 2008) or the gut (Fournel et al 2016). Signaling from these sensors is carried to various brain regions through peripheral nerves, mainly the vagus nerve and its major brainstem nuclei (Fournel et al 2016; Berthoud 2008; Jordan et al 2010; Niijima 1989). It has been suggested that this afferent nerve signalling may be part of a metabolic reflex to hypoglycemia (Lee and Miller 1985), until now, no studies have examined neural responses in the vagus nerve to insulin-triggered hypoglycemia
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