Peripheral nerve stimulation for activation of dopaminergic nuclei

项目摘要/摘要 迷走神经是将食欲和营养信息从内脏传递到中枢的重要载体 神经系统(CNS)。新的研究揭示了左翼和右翼之间令人惊讶和显著的差异 迷走神经-中枢神经系统的连接。特别是，最近的研究表明，通过激活上升的肠道投射 右侧而非左侧的迷走神经可能会激活中枢神经系统中经典的多巴胺能“奖赏”回路。这些最近的 研究结果提出了一种耐人寻味的可能性，即迷走神经电刺激(VNS)传递到右侧颈部 神经，而不是传统的以左颈神经为靶点，可以用来调节这些区域的活动。 奖励网络，为运动障碍的治疗提供了新的策略。然而，左翼和 右侧迷走神经纤维在外周广泛分支，携带来自肠道以及肝脏、胰腺、 以及其他可能传递潜在有益营养或新陈代谢信息的器官。更多研究是 因此，需要充分理解偏侧化迷走神经信号的功能和翻译相关性。 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目前在FDA批准用于 治疗癫痫和抑郁症，并正在迅速崛起，成为一种促进治疗的手段 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赏相关的学习行为强化。因此，有针对性的 这些通路的调节可以提供额外的机制来诱导治疗性神经可塑性 马达系统。因此，将迷走神经输送到右侧颈神经可能会提供更多的好处 用于治疗帕金森氏病或中风等引起的运动功能障碍的传统左侧迷走神经。 虽然迷走神经-中脑连接的强烈偏侧性的证据正在出现，但右脑和中脑之间的程度 左侧VNS诱发中枢奖赏网络的不同激活还没有得到系统的测试。在这里，我们 建议全面比较右侧和左侧VNS驱动的中脑活动的剂量依赖性，并 测试偏侧化VNS驱动的多巴胺能信号与神经可塑性诱导的功能相关性 在马达系统内。此外，我们还检查了VNS诱发的中脑活动和 行为强化受到已知的迷走神经信号调节器的影响，包括事先接触食物 和食物奖励。为了阐明VNS介导的强化机制，我们建议记录 在VNS增强的行为中，活动和光遗传操纵中脑中的多巴胺能信号。 这些研究将为偏侧化迷走神经的神经生物学机制提供基本的见解。 信号，通知新的VNS策略的发展，以治疗调节多巴胺系统。

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.