Peripheral nerve stimulation for activation of dopaminergic nuclei

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PROJECT SUMMARY/ABSTRACT The vagus nerves are important carriers of appetitive and nutritive information from the viscera to the central nervous system (CNS). New studies are revealing surprising and striking differences between left and right vagal-CNS connectivity. In particular, it was recently shown that activation of ascending gut projections through the right, but not left, vagus nerve may activate classical dopaminergic “reward” circuits in the CNS. These recent findings raise the intriguing possibility that electrical vagus nerve stimulation (VNS) delivered to the right cervical nerve, rather than the traditionally-targeted left cervical nerve, could be used to modulate activity within these reward networks, providing novel strategies for the treatment of movement disorders. However, both left and right vagal fibers branch extensively in the periphery and carry information from the gut as well as liver, pancreas, and other organs that may convey potentially rewarding nutritive or metabolic information. Additional research is thus needed to fully understand the functional and translational relevance of lateralized vagal signaling. Understanding whether and how lateralized vagal stimulation differentially activates reward networks is crucial for further clinical development of this therapeutic technology. Left cervical VNS is currently FDA approved for the treatment of epilepsy and major depressive disorders, and is rapidly emerging as a treatment to promote weight loss, extinction of drug seeking, and motor rehabilitation after neural injuries. Importantly, the effectiveness of VNS over this expanded set of therapeutic indications depends on optimal activation of the dopaminergic pathways known to support reward-related reinforcement of learned behaviors. Thus, targeted modulation of these pathways could provide additional mechanisms to induce therapeutic neuroplasticity within the motor system. Delivery of VNS to the right cervical nerve may therefore offer additional benefits compared to traditional left VNS for the treatment of motor dysfunction arising from, e.g., Parkinson's disease or stroke. While evidence of strong laterality in vagal-midbrain connectivity is emerging, the extent to which right versus left VNS evokes differential activation of central reward networks has not been systematically tested. Here, we propose to comprehensively compare the dose-dependence of right vs. left VNS-driven midbrain activity, and to test the functional relevance of lateralized VNS-driven dopaminergic signaling for the induction of neuroplasticity within the motor system. We additionally examine the extent to which VNS-evoked midbrain activity and behavioral reinforcement are impacted by known modulators of vagal signaling, including prior exposure to food and food rewards. To elucidate the mechanisms of VNS-mediated reinforcement, we propose to record neural activity and optogenetically manipulate dopaminergic signaling in the midbrain during VNS-reinforced behavior. These studies will provide fundamental insights into the neurobiological mechanisms underlying lateralized vagal signaling, informing the development of novel VNS strategies for therapeutic modulation of the dopamine system.