Local activation of α2 adrenergic receptors is required for vagus nerve stimulation induced motor cortical plasticity.

Vagus nerve stimulation (VNS) paired with rehabilitation training is emerging as a potential treatment for improving recovery of motor function following stroke. In rats, VNS paired with skilled forelimb training results in significant reorganization of the somatotopic cortical motor map; however, the mechanisms underlying this form of VNS-dependent plasticity remain unclear. Recent studies have shown that VNS-driven cortical plasticity is dependent on noradrenergic innervation of the neocortex. In the central nervous system, noradrenergic α2 receptors (α2-ARs) are widely expressed in the motor cortex and have been critically implicated in synaptic communication and plasticity. In current study, we examined whether activation of cortical α2-ARs is necessary for VNS-driven motor cortical reorganization to occur. Consistent with previous studies, we found that VNS paired with motor training enlarges the map representation of task-relevant musculature in the motor cortex. Infusion of α2-AR antagonists into M1 blocked VNS-driven motor map reorganization from occurring. Our results suggest that local α2-AR activation is required for VNS-induced cortical reorganization to occur, providing insight into the mechanisms that may underlie the neuroplastic effects of VNS therapy.

Vagus nerve stimulation promotes cortical reorganization and reduces task-dependent calorie intake in male and female rats.

Numerous preclinical studies demonstrate that vagus nerve stimulation (VNS) paired with motor rehabilitation improves functional recovery after neural injuries such as stroke, traumatic brain injury, and spinal cord injury, in part by driving neural plasticity within the motor cortex. To date, these studies have been performed almost exclusively in female rats, however, the risk for neural injuries of all types is significantly higher among males than females. We therefore sought to determine whether VNS was equally effective at driving motor cortical plasticity in both sexes. Male and female rats were trained on a skilled lever press task prior to VNS electrode implantation. After recovery, rats received ten training sessions in which VNS, or sham stimulation, was paired with correct motor performance. At the completion of these treatment sessions, somatotopic mapping of motor cortex was performed. We found that performance on the lever task was similar between male and female rats, though on average, males performed more trials per training session, consistent with their larger size and higher caloric need. Training-paired VNS effectively induced cortical motor map reorganization in both male and female rats. Notably, we also found that VNS reduced lever-press associated caloric intake during treatment in both sexes. These VNS-driven effects were robust to behavioral and biological differences between male and female subjects. Taken together, our results suggest that, in both male and female rats, VNS simultaneously engages both pro-plasticity neuromodulation within the neocortex and satiety or reward-related networks that reduce task-associated caloric intake.