Clinical Vagus Nerve Stimulation Paradigms Induce Pronounced Brain and Body Hypothermia in Rats

Abstract

Vagus nerve stimulation (VNS) is a widely used neuromodulation technique that is currently used or being investigated as therapy for a wide array of human diseases such as epilepsy, depression, Alzheimer's disease, tinnitus, inflammatory diseases, pain, heart failure and many others. Here, we report a pronounced decrease in brain and core temperature during VNS in freely moving rats. Two hours of rapid cycle VNS (7s on/18s off) decreased brain temperature by around [Formula: see text]C, while standard cycle VNS (30[Formula: see text]s on/300[Formula: see text]s off) was associated with a decrease of around [Formula: see text]C. Rectal temperature similarly decreased by more than [Formula: see text]C during rapid cycle VNS. The hypothermic effect triggered by VNS was further associated with a vasodilation response in the tail, which reflects an active heat release mechanism. Despite previous evidence indicating an important role of the locus coeruleus-noradrenergic system in therapeutic effects of VNS, lesioning this system with the noradrenergic neurotoxin DSP-4 did not attenuate the hypothermic effect. Since body and brain temperature affect most physiological processes, this finding is of substantial importance for interpretation of several previously published VNS studies and for the future direction of research in the field.

Hypothermia Masks Most of the Effects of Rapid Cycling VNS on Rat Hippocampal Electrophysiology

“…VNS-induced hypothermia in rats is mediated by vasodilatation in tail and paws and release of heat to the environment via the circulation (8). In this study ambient temperature was increased using an infrared lamp to normalize body temperature during VNS.…”

“…In a recent study, we found that VNS induces hypothermia in freely moving rats (8). The VNS paradigm producing the largest hypothermia (i.e.…”

Identification of vagus nerve stimulation parameters affecting rat hippocampal electrophysiology without temperature effects

“…population spike (PS), was delayed but increased [15,16]. However, further research demonstrated that these neurophysiological effects were accompanied by a pronounced brain and body hypothermia strongly confounding the simultaneously recorded hippocampal excitability parameters [17]. This is problematic for two reasons.…”

Genetic identification of a population of noradrenergic neurons implicated in attenuation of stress-related responses

“…To test this hypothesis, we examined two additional physiological changes associated with vagal nerve stimulation: decreased core temperature and increased corticosterone levels. 38–40 Upon Hoxb1 -NE neuron activation we measured no change in either temperature or corticosterone levels compared to controls (temperature: repeated measures ANOVA, effect of treatment: F(1, 78)=0.271, P=0.604; corticosterone: two-way ANOVA, effect of treatment: F(1, 50)=0.134, P=0.716) (Figure 3b and c). These results suggest that the behavioral and physiological phenomena observed upon Hoxb1 -NE neuron activation are likely governed by the central noradrenergic system.…”