Chemogenetic voltage-sensitive imaging

Understanding the fundamentals of the molecules responsible for neuronal electrical signals is crucial, but to extend our understanding of this signaling to the systems level of the brain will require the development of novel recording tools. My remaining projects focused on recording membrane potential changes, specifically using light. Since the 1960s, investigators have worked to improve our ability to optically measure changes in cellular electrical excitability. The two most successful avenues of optically measuring membrane potential changes have been chemical, with voltage-sensitive dyes, and genetic, with voltage-sensitive fluorescent proteins. Chemical methods have been limited by phototoxic effects and penetration depth. I and my colleagues discovered that indocyanine green, an infrared FDA-approved dye, is voltage-sensitive and capable of measuring electrical activity in mammalian tissue. Genetic methods have been limited by a lack of probes that combine brightness with narrow spectral bandwidth, high signal-to-noise, and rapid kinetics. One genetically encoded voltage indicator with the first three desired characteristics is ArcLight. After better characterizing ArcLight’s voltage-sensitive responses, I used a rational design approach to develop a novel optogenetic voltage indicator called ArcLightning. My work in this field should be of utility to researchers seeking to optically record neuronal and cardiac activity in the years to come.