Evidence for differential control of muscle sympathetic fibres in humans

我的研究计划的长期目标是推进我们对控制人类交感神经系统（SNS）流出和循环的机制的理解。SNS的激活会导致心率加快、水和钠潴留以及血管收缩。这些动作使得SNS在控制血压方面很重要，血压是驱动血液流动和将营养物质输送到全身的必要条件。为了理解维持循环稳态的机制，我们需要知道交感神经流出是如何被调节的。我们对社交网络的看法是由可用的测量流出的方法形成的。最初，我们认为交感神经的流出以全身的普遍方式发生。这一概念被推翻了，因为人们发现，对区域交感神经活动的测量可能因个体器官（如心脏、肾脏、肌肉）而异。使用最先进的方法，我最近的工作，第一次在人类身上，表明在老年人或患病的受试者中，对交感神经流出的调节可以扩展到控制神经内单个交感神经纤维（或单个单位）。这意味着单个纤维可以单独增加或减少，从而在优化交感神经对扰动的反应方面提供更高的灵敏度。我们现在将使用这种技术要求很高的方法，在加拿大的许多实验室都没有，来测量单个交感神经纤维的行为，以便最终确定交感神经流出在单个纤维水平上受到调节。为了回答这个问题，我们需要始终证明，在正常的年轻受试者中，个体纤维可以受到不同的调节，并对各种传入刺激做出反应。该提案的短期目标是解决这些知识差距。在这个短期研究计划中，我们有三个主要目标要解决，每个目标都是研究微分控制和肌肉交感单一单位调节的概念。我们将进行研究，以测试肌肉交感神经单单位是否可以单独调节（通过两个具有相反放电特征的单单位亚群来证明），以响应选择性传入刺激或综合运动挑战（腿部循环）；单个放电模式对血流的功能影响；以及负责控制交感神经单位放电的机制。这些研究的新结果将为人类社交网络的组织和调控提供基础信息。这将广泛应用于确定在静止和运动等扰动期间负责血压稳态控制的机制。

The long-term goal of my research program is to advance our understanding of the mechanisms that control sympathetic nervous system (SNS) outflow and the circulation in humans. Activation of the SNS leads to increased heart rate, retention of water and sodium, and vasoconstriction of blood vessels. These actions make the SNS important for controlling blood pressure, a necessity to drive blood flow and deliver nutrients throughout the body. To understand the mechanisms responsible for maintaining circulatory homeostasis we need to know how sympathetic outflow is regulated. Our view of the SNS has been shaped by the methods available to measure outflow.  Initially, we thought that sympathetic outflow occurred in a general systemic fashion throughout the whole body. This concept was overturned with the discovery that measurements of regional sympathetic activity could be different to individuals organs (e.g. to the heart, kidneys, muscle). Using a state-of-the-art method, my recent work, the first in humans, suggests that in older or diseased subjects regulation of sympathetic outflow can extend to the control of individual sympathetic fibres (or single-units) within a nerve. This means that individual fibres can be increased or decreased separately, providing greater sensitivity in optimizing the sympathetic response to a perturbation. We will now use this technically demanding method, not available in many laboratories in Canada, to measure the behaviour of individual sympathetic fibres in order to establish conclusively that sympathetic outflow is regulated at the individual fibre level.  To answer this question, we need to demonstrate consistently that individual fibres can be differentially regulated in normal young subjects and in response to a variety of afferent stimuli. The short-term objectives of the proposal are to address these knowledge gaps. We have three main aims to address in this short-term research proposal, with each investigating the concepts of differential control and the regulation of muscle sympathetic single-units. We will conduct studies designed to test whether muscle sympathetic single-units can be individually regulated (evidenced by two single-unit sub-populations with opposite discharge characteristics) in response to selective afferent stimulation or an integrated exercise challenge (leg cycling); the functional impact of single-unit firing pattern on blood flow; and the mechanisms responsible for controlling the firing of sympathetic single-units. The novel results of these studies will provide fundamental information on the organization and regulation of the SNS in humans. This will have broad applications for identifying the mechanisms responsible for the homeostatic control of blood pressure at rest and during perturbations, such as exercise.