Reverse engineering and energetics of high frequency action potential generation

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***The proposal focuses on understanding cell excitability in challenging and extreme situations as a laboratory to understanding strategies devised by living systems to optimize energetics and maintain homeostasis, or a state of dynamical equilibrium. Cellular electrical signaling is based, with few exceptions, on a universal principle: controlled dissipation of ion gradients across a membrane that sustains low intracellular Na+ and extracellular K+ concentrations. These gradients provide the driving force for voltage spikes, or action potentials (APs). To maintain excitability, ion gradients must be restored by the chemical work of (ATP-fueled) Na+/K+ pumps, a process that preserves cellular homeostasis. This universal mode of operation is the basis of operation for axons in the central nervous system, and, in weakly electric fish such as Eigenmannia, it produces external electric currents by which the fish senses its environment. Operating under challenging conditions raises issues of energetics and strategies to maintain homeostasis.*******Remarkably, throughout their lifetime, Eigenmannia continuously produce an oscillating dipole-like electric organ discharge (EOD) at a fixed individual specific frequency originating from columns of electrocyte cells. The species range is 200-500Hz. The organ's 1000 or so non-contractile cells are driven by releases of acetylcholine through the synaptic gap. The neural input ensures that APs fire synchronously, producing a highly regular EOD. Our first short term goal is to determine how this complex high frequency “device” produces an energy-efficient dipole oscillator. Our approach is to construct EODs from the cell up to the whole organ, remembering that understanding the cellular logistics of ion homeostasis is mandatory if the EOD is to be understood. In parallel, measurements of the EOD signal are being carried out in my collaborator's lab. The low intrinsic EOD variability has received little attention so far, but our examination promises fresh insights into EO design. The brain's input into the EO provides a high frequency signal via myelinated axons which must be robust. This connects to our second short term goal, investigating the response to sustained high frequency firing in axons not designed for that purpose, including those that have suffered mild damage. We want to understand how these myelinated neurons recover excitability and homeostasis.*******The weakly electric fish is a fascinating model system for studying not only the energetics but the subcellular and broader level dynamics of high frequency excitability. The study of axons subjected to sustained abnormal firing or mildly damaged will reveal homeostatic design features. Our work guided by experiment and with continuous input from several biologists ensures that the predictions are well grounded and their impact extends beyond the realms of biophysics.*****