Abstract

Background: Left cervical vagus nerve stimulation (l-VNS) is an FDA-approved treatment for neurological disorders including epilepsy, major depressive disorder, and stroke, and l-VNS is increasingly under investigation for a range of other neurological indications. Traditional l-VNS is thought to induce therapeutic neuroplasticity in part through the coordinated activation of multiple broadly projecting neuromodulatory systems in the brain. Recently, it has been reported that striking lateralization exists in the anatomical and functional connectivity between the vagus nerves and the dopaminergic midbrain. These emerging findings suggest that VNS-driven activation of this important plasticity-promoting neuromodulatory system may be preferentially driven by targeting the right, rather than the left, cervical nerve.Objective: To compare the effects of right cervical VNS (r-VNS) vs. traditional l-VNS on self-administration behavior and midbrain dopaminergic activation in rats.Methods: Rats were implanted with a stimulating cuff electrode targeting either the right or left cervical vagus nerve. After surgical recovery, rats underwent a VNS self-administration assay in which lever pressing was paired with r-VNS or l-VNS delivery. Self-administration was followed by extinction, cue-only reinstatement, and stimulation reinstatement sessions. Rats were sacrificed 90 min after completion of behavioral training, and brains were removed for immunohistochemical analysis of c-Fos expression in the dopaminergic ventral tegmental area (VTA) and substantia nigra pars compacta (SNc), as well as in the noradrenergic locus coeruleus (LC).Results: Rats in the r-VNS cohort performed significantly more lever presses throughout self-administration and reinstatement sessions than did rats in the l-VNS cohort. Moreover, this appetitive behavioral responding was associated with significantly greater c-Fos expression among neuronal populations within the VTA, SNc, and LC. Differential c-Fos expression following r-VNS vs. l-VNS was particularly prominent within dopaminergic midbrain neurons.Conclusion: Our results support the existence of strong lateralization within vagal-mesencephalic signaling pathways, and suggest that VNS targeted to the right, rather than left, cervical nerve preferentially activates the midbrain dopaminergic system. These findings raise the possibility that r-VNS could provide a promising strategy for enhancing dopamine-dependent neuroplasticity, opening broad avenues for future research into the efficacy and safety of r-VNS in the treatment of neurological disease.

Highlights

  • Stimulation of the left cervical vagus nerve (l-VNS) is an FDAapproved therapeutic approach for a wide range of neurological diseases, including epilepsy, major depressive disorder, migraine, and stroke

  • Han et al (2018) reported a remarkable lateralization in the anatomical and functional connectivity between the vagus nerves and midbrain dopaminergic nuclei. These authors demonstrated that optogenetic stimulation of selectively targeted, gut-innervating vagal neurons located in the right, but not left, nodose ganglion (NG) resulted in strong activation of the ventral tegmental area (VTA) and substantia nigra pars compacta (SNc)

  • Rats in r-VNS and Left cervical vagus nerve stimulation (l-VNS) groups performed during habituation (Lever r-VNS Activates Midbrain Dopaminergic Nuclei presses during final habituation session: r-VNS: 144 ± 15.66, l-VNS = 137 ± 13.63; p = 0.742, unpaired t-test)

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Summary

Introduction

Stimulation of the left cervical vagus nerve (l-VNS) is an FDAapproved therapeutic approach for a wide range of neurological diseases, including epilepsy, major depressive disorder, migraine, and stroke. Though the mechanisms of l-VNS efficacy are incompletely understood, it has been shown that VNS exerts wide-ranging neurological effects in part through activation of the broadly projecting nucleus of the solitary tract and several downstream neuromodulatory nuclei, which include the noradrenergic locus coeruleus (LC), the serotonergic raphe nuclei, and the cholinergic medial forebrain (Detari et al, 1983; Krahl et al, 1998; Dorr and Debonnel, 2006; Osharina et al, 2006; Cunningham et al, 2008; Manta et al, 2009; Ruffoli et al, 2011; Collins et al, 2021) Coordinated activation of these neuromodulatory systems is thought to promote therapeutic neuroplasticity, resulting in improved clinical outcomes (Hays et al, 2013; Conway and Xiong, 2018; Wang et al, 2021). These emerging findings suggest that VNS-driven activation of this important plasticity-promoting neuromodulatory system may be preferentially driven by targeting the right, rather than the left, cervical nerve

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