Mapping the linkage between auricular vagus nerve receptors and cardiovagal modulation

摘要 迷走神经被认为是自主神经系统的主要副交感神经管道， 参与心率、心脏收缩能力、心室电稳定性和压力反射的调节 敏感度。迷走神经刺激(VNS)已被建议和/或用作一种神经调节疗法 多种心血管疾病，包括高血压、冠状动脉疾病和心力衰竭。然而， 鉴于VNS是一种侵入性手术，并与重大不良事件有关，标测 迷走神经调节的替代非侵入性通路的研究具有重要意义。有趣的是，耳穴 迷走神经分支(ABVN)是该神经唯一分布于皮肤的外周分支。上一首 动物研究表明，ABVN感觉纤维终止于孤束核(NTS)， 而且，与侵袭性VNS类似，ABVN刺激也被证明可以调节心脏电生理 从而抑制心房颤动，调节左心室重构。虽然对这个的解剖 对神经进行了详细的研究，绘制了ABVN刺激与 心血管后果仍然知之甚少。此外，由于NTS活性和延髓背侧迷走神经 系统的运行与呼吸是协调的，我们小组此前曾提出，神经调节作用 通过对呼吸周期的门控刺激，可以优化ABVN传入的频率。因此，我们的总体目标是 对人类和啮齿动物ABVN-脑干-心脏迷走神经流出通路进行功能定位，并评估其 对呼吸调节作用的敏感性。在人类身上，最先进的超高场功能磁共振(7T FMRI)将提供增强的时空分辨率来评估延髓背侧迷走神经的反应 系统和下丘脑对ABVN的刺激。神经成像将同时结合 心脏生理学评价和动态高频心率变异性(HF-HRV)评价 心脏迷走神经调制，采用本课题组开发的先进的点过程自适应滤波算法。 在大鼠模型上的更多侵入性实验将评估ABVN传入对颈迷走神经的影响 活动(CVNA)，同时记录心电图以计算对ABVN的HF-HRV反应 刺激，从而通过一种共同的指标将独特的大鼠和人类结果直接联系起来。大鼠研究 还将通过c-Fos免疫组织化学方法评估脑干和下丘脑同源核团的激活 神经活动阻滞剂、兴奋性和抑制性神经递质的存在和缺失 拮抗剂立体定向注射到靶核。总之，ABVN的功能映射 鉴于其可及性及其潜在的神经调节作用，在人类中的通路是至关重要的 心血管生理学，我们的建议将显著提高我们对来自 耳旁迷走神经感受器传至心脏。

ABSTRACT The vagus nerve is regarded as the main parasympathetic conduit of the autonomic nervous system and is involved in the regulation of heart rate, cardiac contractility, ventricular electrical stability and baroreflex sensitivity. Vagus nerve stimulation (VNS) has been suggested and/or used as a neuromodulatory therapy for multiple cardiovascular disorders, including hypertension, coronary artery disease, and heart failure. However, given that VNS is an invasive procedure and has been associated with significant adverse events, the mapping of alternative non-invasive pathways for vagal modulation is of critical relevance. Interestingly, the auricular branch of the vagus (ABVN) is the only peripheral branch of this nerve that distributes to the skin. Previous animal studies have demonstrated that ABVN sensory fibers terminate in the nucleus tractus solitarius (NTS), and, similar to invasive VNS, ABVN stimulation has also been shown to modulate cardiac electrophysiology resulting in atrial fibrillation suppression, and regulation of left ventricular remodeling. While the anatomy of this nerve has been studied in detail, the functional mapping of the circuitry connecting ABVN stimulation with cardiovascular outcomes remains poorly understood. Moreover, as NTS activity and the dorsal medullary vagal system operates in tune with respiration, our group has previously suggested that the neuromodulatory effects of ABVN afference can be optimized by gating stimulation to the respiratory cycle. Hence, our overall goal is to functionally map the ABVN-brainstem-cardiovagal outflow pathway in both humans and rodents and assess its sensitivity to the modulatory effects of respiration. In humans, state-of-the-art ultrahigh-field functional MRI (7T fMRI) will afford enhanced spatiotemporal resolution to evaluate the response of the dorsal medullary vagal system and hypothalamus to ABVN stimulation. Neuroimaging will incorporate simultaneous cardiophysiological assessment and dynamic high frequency heart rate variability (HF-HRV) assessment of cardiovagal modulation, using advanced point-process adaptive filtering algorithms developed by our group. More invasive experiments in a rat model will evaluate the effects of ABVN afference on cervical vagus nerve activity (CVNA), while electrocardiography will be recorded to calculate HF-HRV response to ABVN stimulation, thereby directly linking unique rat and human outcomes via a metric common to both. Rat studies will also assess activation in brainstem and hypothalamic homologue nuclei by c-Fos immunohistochemistry in the absence and presence of neuronal activity blocker, and excitatory and inhibitory neurotransmitter antagonists injected stereotactically into the target nuclei. In summary, the functional mapping of the ABVN pathway in humans is of pivotal importance given its accessibility and its potential neuromodulatory effects on cardiovascular physiology, and our proposal will significantly improve our understanding of the mapping from auricular vagus nerve receptors to the heart.