Mapping the linkage between auricular vagus nerve receptors and cardiovagal modulation

绘制耳迷走神经受体与心血管调节之间的联系

• 批准号: 9532518
• 负责人: VITALY NAPADOW
• 金额: $ 36.53万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-28 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9532518
• 关键词: Adverse event; Algorithms; Anatomy; Animal Model; Animals; Atrial Fibrillation; Autonomic nervous system; Baroreflex; Brain Stem; Cardiac; Cardiac Electrophysiologic Techniques; Cardiovascular Diseases; Cardiovascular Physiology; Cardiovascular system; Cell Nucleus; Cervical; Chromosome Mapping; Clinical; Coronary Arteriosclerosis; Coronary artery; Cutaneous; Data; Dorsal; Ear; Electrocardiogram; Etiology; Exhalation; FOS gene; Fiber; Frequencies; Functional Magnetic Resonance Imaging; Future; Glutamates; Goals; Heart; Heart Rate; Heart failure; Homologous Gene; Human; Hypertension; Hypothalamic structure; Immunohistochemistry; Injectable; Knowledge; Left; Left Ventricular Remodeling; Link; Magnetic Resonance Imaging; Maps; Measurement; Mediating; Modality; Modeling; Monitor; Nerve; Neural Pathways; Neurons; Nucleus solitarius; Operating System; Outcome; Output; Pathway interactions; Peripheral; Phase; Physiology; Procedures; Process; Rattus; Regulation; Resolution; Respiration; Rodent; Sensory; Series; Signal Transduction; Skin; Stimulus; System; Telemetry; Time; Vagus nerve structure; Ventricular; awake; experimental study; heart function; heart rate variability; improved; nerve supply; neuroimaging; neurophysiology; neuroregulation; neurotransmitter antagonist; novel; nucleus ambiguus; paraventricular nucleus; programs; receptor; respiratory; response; spatiotemporal; vagus nerve stimulation

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.

抽象的 迷走神经被认为是自主神经系统的主要副交感神经，是 参与心率，心脏收缩性，心室电稳定性和压力反射的调节 灵敏度。已经提出了迷走神经刺激（VNS）和/或用作神经调节疗法 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是一种侵入性程序，并且与重大不良事件有关 迷走神经调节的替代性非侵入性途径的相关性至关重要。有趣的是，耳是 迷走神经（ABVN）的分支是该神经分布在皮肤上的唯一外围分支。以前的 动物研究表明，ABVN感觉纤维终止于soltractus solitarius（NTS）， 并且，类似于侵入性VNS，ABVN刺激也已被证明可以调节心脏电生理学 导致房颤抑制，并调节左心室重塑。而解剖学 已经详细研究了神经，即连接ABVN刺激的电路的功能映射 心血管结局仍然知之甚少。此外，随着NTS活动和背髓迷走神经 系统与呼吸调整，我们的小组先前提出了神经调节作用 可以通过对呼吸周期的门控刺激来优化ABVN的传入。因此，我们的总体目标是 在功能上绘制人类和啮齿动物的ABVN-BRAINSTEM-Cardiovagal流出途径，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（7T fMRI）将提供增强的时空分辨率，以评估背髓迷走神经的响应 系统和下丘脑刺激。神经影像学将同时融合 心脏生理评估和动态高频心率变异性（HF-HRV）评估 心脏调制，使用我们组开发的先进的点过程自适应滤波算法。 大鼠模型中更多的侵入性实验将评估ABVN的影响对宫颈神经的影响 活性（CVNA），而心电图将记录以计算对ABVN的HF-HRV响应 刺激，从而直接通过两者共有的度量来直接连接独特的大鼠和人类的结果。大鼠研究 还将通过C-FOS免疫组织化学评估脑干和下丘脑同源核的激活 神经元活性阻滞剂的不存在和存在，以及兴奋性和抑制性神经递质 拮抗剂立体定位地注射到靶核中。总之，ABVN的功能映射 鉴于人类的途径至关重要，鉴于其可及性及其潜在的神经调节作用 心血管生理学以及我们的建议将大大提高我们对映射的理解 耳神经受体到心脏。