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.
Highlights
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)
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)
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
Summary
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). 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
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