Self-Administration of Right Vagus Nerve Stimulation Activates Midbrain Dopaminergic Nuclei

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.

Right vagus nerve stimulation improves motor behavior by exerting neuroprotective effects in Parkinson’s disease rats

“…Several limitations have to be acknowledged in this study. First, current studies (13,30) have shown the association between vagus nerve and the midbrain dopaminergic neurons. Nevertheless, the correlation between vagus nerve and neuron network in other locations has not been extensively studied and validated.…”

“…The mean gray value of the images was measured to quantify the expression levels of TH, α-synuclein, and VMAT2 in the midbrain dopaminergic neurons using ImageJ software (NIH, USA). The range of dopaminergic neurons labeled by TH in the SN and VTA was used to draw the region of interest manually by raters blinded to the study, who also measured the mean gray value ( 13 ).…”

“…Previous studies have also shown that electrical stimulation of the vagus nerve affects the macromolecular structure and elemental composition in the midbrain dopaminergic regions of rats ( 11 , 12 ). Furthermore, vagus nerve stimulation can increase c-Fos expression in the dopaminergic neurons of the rat midbrain ( 13 ). A neuroimaging study conducted on the human brain showed that vagus nerve stimulation also activates the midbrain dopaminergic regions ( 14 ).…”

“…Han et al used optogenetics to activate the ganglion neurons of the vagus nerve, and their results revealed that the right vagus, not the left, induced dopamine release in the midbrain ( 6 ). Another study compared the effects of RVNS with LVNS on the midbrain dopaminergic system, and the results suggested that RNVS preferentially activated the midbrain dopaminergic system ( 13 ). These studies suggest that the right vagus nerve is more closely connected with the midbrain dopaminergic neurons than the left vagus nerve.…”

Dopamine D2-Subtype Receptors Outside the Blood-Brain Barrier Mediate Enhancement of Mesolimbic Dopamine Release and Conditioned Place Preference by Intravenous Dopamine

“…Recent research has highlighted vagally mediated signaling pathways that modify VTA DA neuron activity and related behavior (Han et al, 2018 ; Fernandes et al, 2020 ; Brougher et al, 2021 ). Dopamine 2 receptors are expressed within these pathways, and play an important role in modulating neurotransmission, particularly within the NTS (Kline et al, 2002 ).…”