Department of Biomedical Sciences, Quillen College of Medicine, East Tennessee State University, Johnson City, TN, USA.
Oregon Health & Science University, Portland, OR, USA.
J Physiol. 2021 Dec;599(23):5261-5279. doi: 10.1113/JP282064. Epub 2021 Nov 17.
Vagus nerve stimulation (VNS) treats patients with drug-resistant epilepsy, depression and heart failure, but the mechanisms responsible are uncertain. The mild stimulus intensities used in chronic VNS suggest activation of myelinated primary visceral afferents projecting to the nucleus of the solitary tract (NTS). Here, we monitored the activity of second and higher order NTS neurons in response to peripheral vagal activation using therapeutic VNS criteria. A bipolar stimulating electrode activated the left cervical vagus nerve, and stereotaxically placed single tungsten electrodes recorded unit activity from the left caudomedial NTS of chloralose-anaesthetized rats. High-intensity single electrical stimuli established vagal afferent conduction velocity (myelinated A-type or unmyelinated C-type) as well as synaptic order (second vs. higher order using paired electrical stimuli) for inputs to single NTS neurons. Then, VNS treatment was applied. A mid-collicular knife cut (KC) divided the brainstem from all supramedullary regions to determine their contribution to NTS activity. Our chief findings indicate that the KC reduced basal spontaneous activity of second-order NTS neurons receiving myelinated vagal input by 85%. In these neurons, acute VNS increased activity similarly in Control and KC animals. Interestingly, the KC interrupted VNS activation of higher order NTS neurons and second-order NTS neurons receiving unmyelinated vagal input, indicating that supramedullary descending projections to NTS are needed to amplify the peripheral neuronal signal from VNS. The present study begins to define the pathways activated during VNS and will help to better identify the central nervous system contributions to the therapeutic benefits of VNS therapy. KEY POINTS: Vagus nerve stimulation is routinely used in the clinic to treat epilepsy and depression, despite our uncertainty about how this treatment works. For this study, the connections between the nucleus of the solitary tract (NTS) and the higher brain regions were severed to learn more about their contribution to activity of these neurons during stimulation. Severing these brain connections reduced baseline activity as well as reducing stimulation-induced activation for NTS neurons receiving myelinated vagal input. Higher brain regions play a significant role in maintaining both normal activity in NTS and indirect mechanisms of enhancing NTS neuronal activity during vagus nerve stimulation.
迷走神经刺激（VNS）可治疗耐药性癫痫、抑郁症和心力衰竭患者，但具体机制尚不清楚。慢性 VNS 采用的轻度刺激强度提示激活投射到孤束核（NTS）的有髓初级内脏传入。在这里，我们使用治疗性 VNS 标准监测外周迷走神经激活时第二级和更高级 NTS 神经元的活动。双极刺激电极激活左侧颈迷走神经，立体定向放置的单个钨电极记录氯醛麻醉大鼠左侧尾内侧 NTS 的单位活动。高强度单电刺激确定了传入神经传导速度（有髓 A 型或无髓 C 型）以及传入单个 NTS 神经元的突触顺序（使用成对电刺激的第二级与更高级）。然后，应用 VNS 治疗。中脑横切（KC）将脑干与所有延髓以上区域分开，以确定它们对 NTS 活动的贡献。我们的主要发现表明，KC 将接受有髓迷走神经输入的第二级 NTS 神经元的基础自发性活动减少了 85%。在这些神经元中，急性 VNS 使对照和 KC 动物的活性相似增加。有趣的是，KC 中断了 VNS 对高级 NTS 神经元和接受无髓鞘迷走神经输入的第二级 NTS 神经元的激活，表明需要延髓下行投射到 NTS 来放大 VNS 产生的外周神经元信号。本研究开始定义 VNS 期间激活的途径，并将有助于更好地确定中枢神经系统对 VNS 治疗的治疗益处的贡献。关键点：尽管我们对这种治疗方法的工作原理仍不确定，但迷走神经刺激已在临床上常规用于治疗癫痫和抑郁症。在这项研究中，切断了孤束核（NTS）与更高脑区之间的连接，以更多地了解它们对刺激期间这些神经元活动的贡献。切断这些脑连接降低了基线活动，并减少了接受有髓鞘迷走神经输入的 NTS 神经元的刺激诱导激活。高级脑区在维持 NTS 的正常活动以及增强迷走神经刺激期间 NTS 神经元活动的间接机制方面发挥着重要作用。
