Vagus Nerve Stimulation Induced Motor Map Plasticity Does Not Require Cortical Dopamine

Abstract

Background: Vagus nerve stimulation (VNS) paired with motor rehabilitation is an emerging therapeutic strategy to enhance functional recovery after neural injuries such as stroke. Training-paired VNS drives significant neuroplasticity within the motor cortex (M1), which is thought to underlie the therapeutic effects of VNS. Though the mechanisms are not fully understood, VNS-induced cortical plasticity is known to depend on intact signaling from multiple neuromodulatory nuclei that innervate M1. Cortical dopamine (DA) plays a key role in mediating M1 synaptic plasticity and is critical for motor skill acquisition, but whether cortical DA contributes to VNS efficacy has not been tested.Objective: To determine the impact of cortical DA depletion on VNS-induced cortical plasticity.Methods: Rats were trained on a skilled reaching lever press task prior to implantation of VNS electrodes and 6-hydroxydopamine (6-OHDA) mediated DA depletion in M1. Rats then underwent training-paired VNS treatment, followed by cortical motor mapping and lesion validation.Results: In both intact and DA-depleted rats, VNS significantly increased the motor map representation of task-relevant proximal forelimb musculature and reduced task-irrelevant distal forelimb representations. VNS also significantly increased tyrosine hydroxylase (TH+) fiber density in intact M1, but this effect was not observed in lesioned hemispheres.Conclusion: Our results reveal that though VNS likely upregulates catecholaminergic signaling in intact motor cortices, DA itself is not required for VNS-induced plasticity to occur. As DA is known to critically support M1 plasticity during skill acquisition, our findings suggest that VNS may engage a unique set of neuromodulatory signaling pathways to promote neocortical plasticity.

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

“…These effects of l-VNS are thought to depend on the coordinated activation of multiple neuromodulatory systems, including broadly projecting cholinergic, noradrenergic, and serotonergic systems ( 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 ; Hays, 2016 ; Hulsey et al, 2016 , 2019 ; Meyers et al, 2019 ; Collins et al, 2021 ). Consistent with the results of the current study, we recently demonstrated that cortical dopamine is not required for l-VNS induced neuroplasticity to occur ( Brougher et al, 2021 ), nor is l-VNS typically found to be inherently rewarding ( Noble et al, 2019 ; Hickman et al, 2021 ; Müller et al, 2021 ). Taken together with this prior literature, the results of the current study thus suggest that, unlike l-VNS, r-VNS strongly engages the midbrain dopaminergic system.…”

“…Following Acclimation, rats underwent five 2-h VNS-SA sessions (1/day) in which food pellets were removed and pressing behavior was instead paired with VNS delivery and the onset of a visual cue ( Figure 1A ). VNS stimulation parameters were identical to those shown in our previous studies of l-VNS to induce neuroplasticity within the motor cortex ( Tseng et al, 2020 ; Brougher et al, 2021 ). Immediately upon detection of a lever press, a single 0.5 s train of 16 pulses (amplitude = 0.8 mA, pulse frequency = 30 Hz, pulse width = 100 μs biphasic) was delivered through the implanted cuff electrode.…”

“…During daily 2-h VNS-SA sessions, each lever press was paired with simultaneous onset of a visual stimulus and delivery of a brief train of VNS ( Figure 1A ). VNS stimulation parameters were matched in r-VNS and l-VNS treatment groups, and identical to those used in prior studies ( Tseng et al, 2020 ; Brougher et al, 2021 ).…”

Frequency Specific Optogenetic Stimulation of the Locus Coeruleus Induces Task-Relevant Plasticity in the Motor Cortex

“…Behavioral training. Prior to the start of behavioral training, rats were acclimated to handling during 10 min acclimation sessions for 5-7 d. Rats were then trained to perform a previously published automated skilled reaching lever-press task (Tseng et al, 2020(Tseng et al, , 2021Brougher et al, 2021). The task required subjects to fully depress (to >9.5°below horizontal) and release (to <4.75°below horizontal) a lever positioned 2 cm outside a MotoTrak behavioral training booth (Vulintus) within a 2 s time window to receive a 45 mg food pellet reward (Bio-Serv #F0021).…”

“…ICMS motor mapping. Within 24 h of the final training-paired stimulation session, ICMS was performed as previously described (Tseng et al, 2020(Tseng et al, , 2021Brougher et al, 2021). Rats were anesthetized with ketamine hydrochloride (70 mg/kg) and xylazine (5 mg/kg) injected intraperitoneally and placed in a stereotaxic frame.…”