The Role of the Intracardiac Nervous System in Cardiac Autoregulation

The heart beats an incredible 3-4 billion times over a lifetime. To accomplish this amazing feat, millions of cells must work in a well-coordinated fashion, while rapidly adjusting their activity to physiological changes. This coordination and adaptation are driven largely by regulation that occurs entirely within the heart itself. The long-term objective of my research program is to explore this `intrinsic' regulation of heart function. One critical factor for the regulation of heart function is a complex network of nerves within the heart, known as the intracardiac nervous system (IcNS). Yet, little is known about the overall function of the IcNS, as it is embedded within the tissue of the heart, so difficult to study with current technologies. The goal of our current project is to understand the role of the IcNS in the maintenance of normal heart activity. It is currently thought that the IcNS is simply a `relay station' for signals from the central nervous system to the heart. Recent evidence suggests that it is in fact involved in the local processing and feedback of nerve signals, thus acting as a `little brain' in the heart. In this project, we will apply an innovative approach to determine whether the IcNS is important for local control of heart activity, independent of the central nervous system. Our approach will involve the use of: (i) Zebrafish as an animal model that enables access to the IcNS in the whole heart. (ii) Advanced 3D fluorescence imaging techniques that enable measurement of activity across the entire IcNS. (iii) Mathematical modelling to answer questions not possible with experimentation alone. Our pioneering studies will be driven by an international team of experts with backgrounds in cardiac and neuronal physiology, engineering, physics, and mathematics. The results of these studies will reveal the: (i) Function of the IcNS and its communication with heart cells across the whole heart. (ii) Role and importance of different cell types in the IcNS for its overall function. (iii) Response of the IcNS to physiological stimuli. (iv) Changes in the IcNS that occur during heart development and with ageing. Overall, our project will `push the boundaries' of experimental and mathematical investigation of the IcNS to overcome previous limitations for its integrative study. We will provide direct evidence demonstrating whether the IcNS processes neuronal inputs and feeds back information directly to the heart, independent of the central nervous system. This new information will reveal the role of the IcNS in local control of heart function in development and with age, which is critical for understanding the fundamental nature of the regulation of heart function. At the same time, the innovative experimental-mathematical modelling approach developed in this project will be highly useful for other researchers studying the importance of local nervous system control in other organs across the body.