Neuronal Networks in Health and Disease (AG Istvan Mody)
The Bonner Mody lab “Neuronal Networks in Health and Disease” was established in 2014 and is funded by an ERC Advanced Grant awarded to Prof. Istvan Mody. Prof. Mody is Tony Coelho Professor of Neurology and Professor of Physiology at The David Geffen School of Medicine, University of California, Los Angeles. In 2014, he was appointed part-time as Professor for Synaptic Physiology and Pathophysiology at the Department of Epileptology, University of Bonn.
The main focus of our lab is to establish genetically encoded voltage sensors that will allow the precise and direct measurement of ultrafast membrane potential changes. The development of these techniques is highly important out of the following reasons:
Both physiological and pathological neuronal processes are based on temporally and spatially complex patterns of neuronal activity. Understanding these processes requires the simultaneous measurement of large numbers of neurons with high temporal precision. Classical electrophysiological techniques such as patch clamp recordings provide high temporal resolution and enable the experimenter to identify the recorded cells unequivocally. However, they can only be applied to a small number of neurons at a time. Other techniques such as Ca2+ imaging provide the ability to monitor larger populations of neurons, while identifying the recorded neurons by genetic means. However, Ca2+ sensors report neuronal activity only indirectly, and, based on the inherent properties and slower kinetics of underlying Ca2+ transients, are not able to report fast changes in membrane potential, (e.g., action potentials), hyperpolarizations (e.g., IPSPs), or subthreshold depolarizing events (e.g. EPSPs). Fluorescent voltage sensors measure changes in membrane potential and thus are optimal to monitor the activity of populations of neurons. However, the available voltage sensors show severe shortcomings in terms of signal to noise ratio and kinetics. We are devoted to develop fluorescent voltage indicators with a high signal to noise ratio and fast kinetics that follow sub- and suprathreshold changes in membrane potential with high temporal precision.
We, and others, strongly believe that techniques for reliably measuring at a high spatial-temporal resolution the well-orchestrated simultaneous activity of many distinct but identified neurons are within the realm of possibilities. The following quote, from Charles S. Sherrington’s book Man on His Nature, that describes what happens in one’s brain upon awakening, is a prescient allegory of what we expect to see when optical voltage sensing of neuronal activity will be developed to its full potential:
”The great topmost sheet of the mass, that where hardly a light had twinkled or moved, becomes now a sparkling field of rhythmic flashing points with trains of traveling sparks hurrying hither and thither. The brain is waking and with it the mind is returning. It is as if the Milky Way entered upon some cosmic dance. Swiftly the head mass becomes an enchanted loom where millions of flashing shuttles weave a dissolving pattern, always a meaningful pattern though never an abiding one; a shifting harmony of subpatterns”.
We have set out to improve a promising technique to provide the means of visualizing the “meaningful patterns” and the “harmony of subpatterns” of neuronal activity so vividly described by Sherrington. But the impact of the GEVOS approach proposed here will reach well beyond the boundaries of neuroscience. This technique should be equally applicable to research on muscle, heart and other tissue and organs that use changes in Vm as an integral part of their cellular signaling mechanisms. The ability to faithfully measure Vm with optogenetic tools will advance knowledge in all fields of the life sciences.