Peripheral nerve stimulation for activation of dopaminergic nuclei

周围神经刺激激活多巴胺能核

• 批准号: 10587440
• 负责人: CATHERINE A THORN
• 金额: $ 33.86万
• 依托单位: UNIVERSITY OF TEXAS DALLAS
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-15 至 2027-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10587440
• 关键词: Behavior; Behavioral; Behavioral Paradigm; Biological Assay; Body Weight decreased; Cell Nucleus; Central Nervous System; Cervical; Cervical nerves; Corpus striatum structure; Data; Dependence; Desire for food; Development; Dopamine; Dose; Effectiveness; Epilepsy; Exposure to; Extinction; FDA approved; Fiber; Food; Future; Goals; Handedness; Hunger; Learning; Left; Literature; Liver; Major Depressive Disorder; Maps; Mediating; Metabolic; Midbrain structure; Motivation; Motor; Motor Cortex; Movement Disorders; Neuronal Plasticity; Neurons; Nodose Ganglion; Nucleus Accumbens; Organ; Pancreas; Parkinson Disease; Pathway interactions; Peripheral Nerve Stimulation; Pharmaceutical Preparations; Play; Prefrontal Cortex; Property; Psychological reinforcement; Publishing; Rattus; Research; Rewards; Role; Satiation; Self Administration; Signal Induction; Signal Transduction; Specificity; Stroke; Substantia nigra structure; System; Technology; Testing; Therapeutic; Treatment Efficacy; Vagus nerve structure; Variant; Ventral Tegmental Area; Viscera; Visceral; Work; behavioral response; clinical development; dopamine system; dopaminergic neuron; experience; experimental study; insight; learned behavior; motor disorder; motor rehabilitation; nerve injury; neural; neural network; neurobiological mechanism; neuromechanism; novel; novel strategies; optogenetics; reinforced behavior; response; stroke rehabilitation; therapeutic development; translational potential; treatment strategy; vagus nerve stimulation

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.

项目摘要/摘要 迷走神经是从内脏到中央的开胃菜和营养信息的重要载体 神经系统（CNS）。新研究揭示了左右之间的惊喜和惊人的差异 迷走神经连通性。特别是，最近表明，通过 右而不是左，迷走神经可能会激活中枢神经系统中的经典多巴胺能“奖励”电路。这些最近 调查结果提出了一个有趣的可能性，即传递到右子宫颈的电气迷走神经刺激（VN） 神经，而不是传统的左子宫颈神经，可用于调节这些活动 奖励网络，为治疗运动障碍提供新颖的策略。但是，都离开了 右阴道纤维在周围广泛分支，并携带肠道和肝脏，胰腺的信息 以及可能传达潜在奖励营养或代谢信息的其他器官。其他研究是 因此，需要充分理解侧向迷走神经信号的功能和翻译相关性。 了解侧向迷走神经刺激是否不同地激活奖励网络至关重要 为了进一步发展这种治疗技术。左子宫颈VNS目前已获得FDA的批准 治疗癫痫和主要抑郁症，正在迅速出现作为促进的治疗方法 体重减轻，寻求药物的扩展以及神经损伤后的运动康复。重要的是， VNS对这一扩展的理论指示的有效性取决于最佳激活 已知的多巴胺能途径支持与奖励相关的行为加强。那是针对性的 这些途径的调节可以提供其他机制，以诱导热神经可塑性 电机系统。因此，将VN的VN交付到正确的颈椎紧张可能会带来其他好处 传统的左VN，以治疗由帕金森氏病或中风引起的运动功能障碍。 虽然出现了迷走神经中脑连通性中横向性强的证据，但正确与 左VNS引起了中央奖励网络的差异激活，尚未系统地测试。在这里，我们 提议全面比较右VNS驱动的中脑活动的剂量依赖性，以及 测试横向VNS驱动的多巴胺能信号传导的功能相关性，以诱导神经可塑性 在电机系统中。我们还研究了VNS引起的中脑活动的程度和 行为加强受到迷走神经信号的已知调节剂的影响，包括事先接触食物 和食物奖励。为了阐明VNS介导的增强的机制，我们建议记录中性 在VNS增强行为期间，活动和光遗传学操纵中脑的多巴胺能信号传导。 这些研究将为侧向迷走神经的神经生物学机制提供基本见解 信号传导，告知多巴胺系统热调制的新型VNS策略的发展。