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Illuminating Structural and Functional Determinants of GPCR-mediated Neuron–Cardiomyocyte Crosstalk across Spatial Scales
The heart is an electrically driven pump that continuously adapts its activity to the systemic demand for oxygen and nutrients. Sympathetic and parasympathetic neurons with efferents in all chambers of the heart play an important role in controlling cardiac output. The activity of sympathetic nerves is transmitted by norepinephrine release and this has stimulatory effects on heart rate, electrical excitability and conduction, pump activity, and speed of relaxation. In contrast, the release of acetylcholine by parasympathetic nerves is associated with reduced cardiac output. It remains unclear at which levels the antagonistic signals from sympathetic and parasympathetic neurons are integrated in order to precisely modulate cardiac function. Imbalanced efferent signaling to cardiomyocytes (CM) can trigger, among other things, life-threatening arrhythmias and pathological remodeling processes. We have shown that hearts from old mice (18–24 months) have a lower density of parasympathetic efferents and acetylcholine receptors in the ventricle compared to young mice (2–4 months) and that they more frequently develop ventricular arrhythmias when stimulated with carbachol.
This project aims to investigate the structural and functional principles of neuronal control of CM activity, and how these might be affected by the aging process. The research program, which is structured into three tasks, is based on optogenetic methods for targeted neuronal activation, functional and structural imaging from nanometer to centimeter scales, electrophysiological measurements, computer models and quantitative data analysis. We will use both transgenic mouse models and human cell cultures. In the first task, the nanostructure of the quasi-synaptic approaches between nerve cells and CM will be determined using electron microscopic tomography, and the macrostructure and interrelation of the efferent nerves will be quantitatively analysed across all walls of the heart. In the second task, we will image the dynamics of vesicle release and neurotransmitter-mediated signal transmission after optogenetic neuronal stimulation, using stimulus-timed sample preservation for electron tomography and fluorescent cAMP and Ca2+ sensor imaging coupled with electromechanical measurements. Optogenetic and pharmacological experiments will be carried out on whole hearts (including extracardiac ganglia) to investigate the effects of different neuronal inputs on electrophysiology. In the third task, we will characterize structural and functional changes in neuron–CM signaling pathways in middle-aged and old mice, and use a biophysically detailed computer model to elucidate how spatially heterogeneous neuronal activity influences ventricular arrhythmia development. In close collaboration with the other FOR 5807 teams, we will provide a comprehensive picture of neuron → CM communication in the heart, thus enhancing our understanding of GPCR-mediated control of organ function.
