Computational Modeling of Optogenetic Control of Neuronal Signaling

Abstract

Precise control of activity patterns of densely connected neurons in the brain is necessary to understand the functioning of the brain, a goal of the 21st century. Optogenetics has revolutionized neuroscience research by allowing manipulation and recording of neuronal activity in cultured tissue and living animals with unprecedented spatiotemporal resolution. It has proven its potential for a wide range of applications in and beyond neuroscience, significantly improved the way many neuroscience studies were performed earlier, and contributed to our understanding of the mechanism and biology underlying several neurological diseases. For optogenetic control, the light-sensitive proteins are genetically inserted into the desired neural populations, thus allowing for precise control of the activity of these genetically modified neurons with light. newlineA major challenge in optogenetics is to achieve low-power, high-frequency, and high-fidelity control of neuronal signaling. Although each component of optogenetics continues to evolve rapidly to meet the challenge, computational optogenetics has tremendous scope of research and guiding capabilities for designing better components. newlineThis thesis is focused on formulating accurate computational models of ultrafast optogenetic excitation with vf-Chrimson, temporally precise inhibition with light-driven chloride pumps, namely eNpHR3.0 and Jaws, low-power high-fidelity high-frequency bidirectional control with experimentally reported and newly discovered opsin pairs, and improved optogenetic retinal prostheses with newly discovered opsins, namely CsChrimson, ChRmine and bReaChES. The accuracy of theoretical models has been validated by comparing simulated results with reported experimental results. Using the formulated models, a detailed theoretical study of the effect of light irradiance, pulse width, pulse frequency, pulse timing, and wavelength, opsin expression density and other physiological conditions has been carried out. Further, efforts have been made to determine optimal conditions to address the present challenges in optogenetics. newlineThe study provides new insights into the complex mechanism behind reported experimental results, and is important for designing new experiments with desired spatiotemporal resolution and would prove beneficial for optogenetic-based prosthetic circuits and devices. newline newline