Voltage imaging to understand connections and functions of neuronal circuits

Understanding of the cellular mechanisms underlying brain functions, such as cognition and emotions, requires monitoring of membrane voltage at the cellular, circuit and system levels. Seminal voltage-sensitive dye and calcium-sensitive dye imaging studies have demonstrated parallel detection of electrical activity across populations of interconnected neurons in a variety of preparations. A game-changing advance made in recent years has been the conceptualization and development of the optogenetic tools, including genetically encoded indicators of voltage (GEVI) or calcium (GECI), and genetically encoded light-gated ion channels (actuators, e.g. channelrhodopsin2). Compared to low molecular weight calcium and voltage indicators (dyes), the optogenetic imaging approaches are: (i) cell-type specific, (ii) less invasive, (iii) able to relate activity and anatomy and (iv) they facilitate long-term recordings of individual cells' activities over weeks, thereby allowing direct monitoring of the emergence of learned behaviors and underlying circuit mechanisms. We highlight the potential of novel approaches based on genetically encoded voltage indicators and compare those to calcium imaging approaches. We also discuss how novel approaches based on genetically encoded voltage (and calcium) indicators coupled with genetically encoded actuators will promote progress in our knowledge of brain circuits and systems.

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