Peripheral nerve stimulation for control of the mesolimbic dopamine system - PROJECT SUMMARY/ABSTRACT The vagus nerve is an important carrier of appetitive and nutritive information from the gut and other visceral organs to the central nervous system (CNS). New studies are revealing surprising and striking differences between left and right vagal connectivity within the CNS. In particular, it was recently shown that activation of ascending gut-brain projections through the right, but not the left, vagus nerve may activate classical dopaminergic “reward” circuits within the central nervous system. 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 neurological 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 capable of conveying potentially rewarding nutritive or metabolic information. Additional research is thus needed to fully understand the functional and clinical 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 (l-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 behavior. Thus, targeted modulation of these pathways could provide additional mechanisms to induce therapeutic neuroplasticity. Delivery of VNS to the right cervical nerve may therefore offer additional benefits compared to traditional l-VNS for the treatment of e.g., obesity, addiction, mood, or motor disorders. In the current proposal, we aim to determine the functional relevance and therapeutic potential of the differential recruitment of midbrain dopaminergic networks by left versus right VNS. The proposed studies critically test our hypothesis that right-VNS and left-VNS differentially engage midbrain DA networks, resulting in lateralized VNS effects on motor and appetitive behaviors. These studies will provide fundamental insights into neurobiological mechanisms underlying lateralized vagal signaling, and critically inform the development and optimization of novel VNS strategies for therapeutic modulation of the DA system.
