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Research led by Associate Professor Rebecca Burton at Oxford, together with Associate Professor Gil Bub at McGill University (Canada) and Professor Emilia Entcheva at George Washington University (USA), has demonstrated a purely optical method that makes it possible to stimulate cells and to directly observe both the effects of spatial distribution and functional connectivity between neurons and heart muscle cells. This model system provides a unique window into the relationship between the tissue health, neuron density and the excitability of the heart muscle. These insights are particularly relevant to understanding complications that arise after damage to the heart tissue, such as potentially lethal heart arrhythmias after a heart attack.

Clockwise, the sections of the figure show the co-culture of cardiac myocytes (nuclei stained in blue) and sympathetic neurons (red); Cardiac wave dynamics in co-culture; Optical stimulation of sympathetic ganglion cells to drive cardiac behaviour using “Optochemical” versus “Optoelectric” stimulation of neurons. Optochemical stimulation achieved by photo-uncaging of nicotine using a flash of blue light leading to the release of noradrenaline by the sympathetic neurons resulting in increase in myocyte beat rate. Optogenetic neural stimulation of cardiac tissue performed via Channelrhodopsin-2 selectively expressed only in the neurons.
Clockwise, the sections of the figure show the co-culture of cardiac myocytes (nuclei stained in blue) and sympathetic neurons (red); Cardiac wave dynamics in co-culture; Optical stimulation of sympathetic ganglion cells to drive cardiac behaviour using “Optochemical” versus “Optoelectric” stimulation of neurons. Optochemical stimulation achieved by photo-uncaging of nicotine using a flash of blue light leading to the release of noradrenaline by the sympathetic neurons resulting in increase in myocyte beat rate. Optogenetic neural stimulation of cardiac tissue performed via Channelrhodopsin-2 selectively expressed only in the neurons.

Cardiac stimulation via sympathetic neurons can potentially trigger arrhythmias.

We have co-cultured stellate ganglion sympathetic neurons with cardiac myocytes and have used optical methods to study their interactions and electrophysiology.

In this study, we demonstrate the utility of optical interrogation of sympathetic neurons and their effects on macroscopic cardiomyocyte network dynamics to address research targets such as the effects of adrenergic stimulation via the release of neurotransmitters, the effect of neuronal numbers on cardiac behaviour, and the applicability of optogenetics in mechanistic in vitro studies. As arrhythmias are emergent behaviours that involve the coordinated activity of millions of cells, we image at macroscopic scales in order to capture complex dynamics.

In healthy tissue, the presence of neurons acts to stabilise the excitation patterns within the heart. However, when tissue has become damaged, it becomes much more excitable, and neural activity can establish an aberrant wave that could lead to a sustained heart arrhythmia. Our cell culture results imply that the sensitivity of cardiac tissue to neural activity is much higher than previously thought, as very few neurons are needed to disrupt normal propagation. This method provides an optimal high-throughput approach to screen for new drugs that will limit the influence of these border zones on normal heart rhythm.

Link to the paper: https://www.sciencedirect.com/science/article/pii/S2589004220305216