The Role of Noradrenergic Signaling in Vagus Nerve Stimulation Dependent Motor Cortical Plasticity


August 2023

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The combination of vagus nerve stimulation (VNS) and motor rehabilitation is being reported as a promising therapy for enhancing motor function recovery after neural injuries. Recent preclinical studies in rats have shown that VNS in conjunction with skilled forelimb training leads to substantial reorganization of the somatotopic cortical motor map, which has been shown to be important for VNS efficacy. However, most of the preclinical research have been conducted in female rats, even though the risk of neural injuries of all kinds is considerably greater in males than in females. Furthermore, the neural mechanisms underlying VNS-induced neuroplasticity remain unclear. Here, we aim to deepen our understanding of VNS through three different, but linked, projects. First, we test whether VNS generates plasticity differently between male and females. Results from our experiments indicate that VNS is equally effective in inducing plasticity in both sexes. Second, we assess the necessity of activation of alpha2-adrenergic receptors (alpha2-ARs), the key regulator in governance of noradrenaline (NA) release and synaptic plasticity in the central nervous system (CNS), in VNS effect. Our results show that infusion of alpha2-ARs antagonist blocks VNS-driven neuroplasticity. Finally, we examine the effect of phasic activation of the locus coeruleus (LC), the noradrenergic center in the CNS, on motor cortical plasticity. We found that 10 Hz, but not 3 or 30 Hz, LC stimulation paired with learned motor task promote motor cortical map reorganization. Taken together, these findings inform the generalization of VNS therapy to the general population and broaden the understanding of LC-NA mechanisms underlying VNS-driven plasticity.



Biology, Neuroscience