Evidence for differential control of muscle sympathetic fibres in humans

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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.