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、心肌收缩力、心室电稳定性和压力感受器反射的调节 灵敏度迷走神经刺激（VNS）已经被建议和/或用作神经调节疗法，用于治疗 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，在这方面， 鉴于VNS是一种侵入性手术，并且与严重的不良事件相关， 迷走神经调节的替代性非侵入性途径具有重要意义。有趣的是， 迷走神经的分支（ABVN）是该神经分布到皮肤的唯一外周分支。先前 动物研究已经证明ABVN感觉纤维终止于孤束核（NTS）， 并且，与侵入性VNS类似，ABVN刺激也显示出调节心脏电生理学 导致心房纤维性颤动抑制和左心室重构的调节。虽然这件事的结构 已经详细研究了神经，连接ABVN刺激与 心血管结局仍然知之甚少。此外，由于NTS活动和背侧延髓迷走神经 系统的运作与呼吸协调，我们的研究小组以前曾提出，神经调节作用， 通过对呼吸周期进行门控刺激可以优化ABVN传入。因此，我们的总体目标是 在人类和啮齿类动物中功能性绘制ABVN-脑干-心迷走神经流出通路，并评估其 对呼吸调节作用的敏感性。在人类中，最先进的超高场功能性MRI（7 T fMRI）将提供增强的时空分辨率，以评估背侧延髓迷走神经的反应 系统和下丘脑对ABVN刺激的反应。神经影像学检查将同时 心脏生理学评估和动态高频心率变异性（HF-HRV）评估 心迷走神经调制，使用先进的点过程自适应滤波算法由我们的小组开发。 在大鼠模型中进行更多的侵入性实验将评估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HF-HRV对ABVN的反应 刺激，从而通过两者共同的度量直接将独特的大鼠和人类结果联系起来。大鼠研究 还将通过c-Fos免疫组化评估脑干和下丘脑同源核的激活， 神经元活动阻滞剂以及兴奋性和抑制性神经递质存在和不存在 立体定向注射到靶核中的拮抗剂。总之，ABVN的功能映射 由于其可及性及其对神经系统的潜在神经调节作用， 心血管生理学，我们的建议将显着提高我们对映射的理解， 耳迷走神经受体到心脏。

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.