Peripheral nerve stimulation for control of the mesolimbic dopamine system

项目概要/摘要 迷走神经是从肠道和其他内脏器官传递食欲和营养信息的重要载体 中枢神经系统（CNS）。新的研究揭示了令人惊讶和惊人的差异 中枢神经系统内左右迷走神经连接之间的联系。特别是，最近显示， 通过右侧而不是左侧的上行肠脑投射，迷走神经可能激活经典的 中枢神经系统内的多巴胺能“奖赏”回路。这些最新的发现提出了有趣的 迷走神经电刺激（VNS）可能传递到右颈神经，而不是 传统上针对的左颈神经，可以用来调节这些奖励网络内的活动， 为治疗神经系统疾病提供了新的策略。然而，左右迷走神经纤维 分支广泛分布在外周，并携带来自肠道以及肝脏、胰腺和其他组织的信息。 能够传递潜在有益的营养或代谢信息的器官。因此，更多的研究 需要充分理解偏侧迷走神经信号传导的功能和临床相关性。 了解偏侧迷走神经刺激是否以及如何不同地激活奖赏网络至关重要 用于进一步临床开发这种治疗技术。左颈VNS（l-VNS）目前是FDA 被批准用于治疗癫痫和重度抑郁症，并迅速成为一种治疗方法， 促进体重减轻，消除药物寻求和神经损伤后的运动康复。重要的是 VNS在这组扩展的治疗适应症上的有效性取决于 已知支持奖励相关行为强化的多巴胺能通路。因此，有针对性的调制 这些途径的结合可以提供额外的机制来诱导治疗性神经可塑性。提供VNS 因此，与传统的L-VNS治疗相比， 例如，肥胖成瘾情绪或运动障碍 在目前的建议中，我们的目标是确定功能的相关性和治疗潜力的差异， 左VNS与右VNS对中脑多巴胺能网络的募集。拟议中的研究对我们的 假设右VNS和左VNS不同地参与中脑DA网络，导致VNS偏侧化 对运动和食欲行为的影响。这些研究将为神经生物学提供基本的见解 偏侧迷走神经信号传导的潜在机制，并为发展和优化提供重要信息。 用于DA系统的治疗性调节的新颖VNS策略。

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.