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

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

Jackson Brougher¹, Camilo A. Sanchez², Umaymah S. Aziz¹, Kiree F. Gove¹ and Catherine A. Thorn^1*

• ¹Department of Neuroscience, University of Texas at Dallas, Richardson, TX, United States
• ²Department of Bioengineering, University of Texas at Dallas, Richardson, TX, United States

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.

Introduction

Preclinical studies suggest that vagus nerve stimulation (VNS) paired with rehabilitation training is a promising approach for enhancing motor recovery after neural injury (Khodaparast et al., 2013; Pruitt et al., 2016; Ganzer et al., 2018; Meyers et al., 2018). Training-paired VNS induces significant neuroplasticity within the motor cortex (Porter et al., 2012; Hulsey et al., 2016, 2019; Morrison et al., 2019; Tseng et al., 2020), which is thought to be critical for successful motor rehabilitation (Di Lazzaro et al., 2010; Pruitt et al., 2016; Bundy and Nudo, 2019; Meyers et al., 2019). While the precise mechanisms underlying VNS efficacy remain unclear, VNS-driven cortical plasticity is known to depend on the coordinated signaling of multiple neuromodulatory systems (Hays, 2016). Cortical depletion of noradrenergic, serotonergic, or cholinergic fibers blocks VNS-driven cortical reorganization (Hulsey et al., 2016, 2019), consistent with the known contributions of each of these neuromodulators to synaptic plasticity (Rasmusson, 2000; Gu, 2002; Lesch and Waider, 2012; Vitrac and Benoit-Marand, 2017). Dopamine (DA) is similarly recognized as a plasticity promoting neuromodulator within neocortical circuits (Hosp and Luft, 2013; Guo et al., 2015), but the necessity of dopaminergic signaling in VNS efficacy has not been previously tested (Guo et al., 2015).

Several lines of evidence suggest that DA could play a key role in VNS-driven cortical plasticity. VNS increases the firing rates of noradrenergic neurons in the locus coeruleus (LC) (Hulsey et al., 2017), which are known to activate dopaminergic neurons in the ventral tegmental area (VTA) (Mejias-Aponte, 2016; Park et al., 2017). VTA then sends dopaminergic projections throughout the forebrain, including to M1 (Lindvall et al., 1974; Hosp et al., 2011). Vagal signaling has recently been shown to enhance the activation of midbrain dopaminergic neurons and to increase the expression of behaviors known to depend on dopaminergic signaling (Han et al., 2018; Fernandes et al., 2020).

Cortical dopaminergic signaling plays a critical role in motor learning and M1 synaptic plasticity. Behaviorally, early skill acquisition is associated with increased VTA activation (Leemburg et al., 2018), and disruptions in cortical dopaminergic signaling have been shown to impair motor learning (Molina-Luna et al., 2009; Hosp et al., 2011; Rioult-Pedotti et al., 2015). Synaptically, DA receptor antagonism inhibits long-term potentiation in M1 (Molina-Luna et al., 2009; Rioult-Pedotti et al., 2015), and dendritic spine growth and pruning are differentially controlled by D1 and D2 receptor subtypes, respectively (Guo et al., 2015). Interestingly, after a task becomes well-learned, movement-related VTA activation is reduced (Leemburg et al., 2018), and cortical DA depletion no longer impacts motor performance (Molina-Luna et al., 2009; Hosp et al., 2011). Combined, these studies suggest that cortical DA is necessary for promoting the M1 plasticity that underlies new skill acquisition.

We hypothesized that DA may also be a key mediator of VNS-driven cortical plasticity, as it is during initial motor learning. To test this hypothesis, we trained rats on a skilled reaching lever press task prior to implantation of VNS electrodes and 6-OHDA mediated M1 DA depletion. Our findings indicate that while VNS treatment may increase cortical catecholaminergic innervation in intact M1, DA itself is not required for VNS-driven cortical plasticity to occur. These results raise the possibility that VNS efficacy during stroke rehabilitation may depend on a set of neuroplasticity-promoting mechanisms that are distinct from those that underlie initial motor skill acquisition.