Peripheral nerve stimulation for control of the mesolimbic dopamine system

项目摘要/摘要 迷走神经是来自肠道和其他内脏的食欲和营养信息的重要载体 器官转移到中枢神经系统(CNS)。新的研究揭示了令人惊讶和显著的差异 中枢神经系统内左右迷走神经的连接。特别是，最近有研究表明，激活 向上的肠脑投射通过右侧，而不是左侧，迷走神经可能激活经典 中枢神经系统内的多巴胺能“奖赏”回路。这些最近的发现提出了一个耐人寻味的问题 迷走神经电刺激(VNS)传递到右侧颈神经的可能性，而不是 传统上以左颈神经为靶点的神经可以用来调节这些奖赏网络中的活动， 为神经疾病的治疗提供新的策略。然而，左侧和右侧迷走神经纤维 广泛分布在外周的分支，携带来自肠道以及肝脏、胰腺和其他器官的信息 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 需要充分了解偏侧迷走神经信号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是至关重要的 这项治疗技术的进一步临床开发。左颈VNS(L-VNS)目前是FDA 被批准用于治疗癫痫和严重的抑郁症，并正在迅速成为一种治疗方法 促进减肥、戒毒和神经损伤后的运动康复。重要的是， VNS对这一扩大的治疗适应症的有效性取决于最佳的激活 已知的多巴胺能通路支持与奖励相关的行为强化。因此，定向调制 这些途径中的一种可能为诱导治疗性神经可塑性提供额外的机制。VNS的交付 因此，与传统的L颈内翻术相比，右侧颈神经切断可能会提供额外的好处 例如，肥胖、成瘾、情绪或运动障碍。 在目前的建议中，我们的目标是确定差异的功能相关性和治疗潜力 左与右VNS对中脑多巴胺能网络的募集。拟议的研究对我们的 假设右VNS和左VNS不同地参与中脑DA网络，导致偏侧化的VNS 对运动和食欲行为的影响。这些研究将提供对神经生物学的基本见解。 偏侧化迷走神经信号的机制，并关键地提供了发展和优化的信息 新的VNS策略用于DA系统的治疗调节。

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.