Genetically encoded sensors of neural activity enable visualization of circuit-level function in the central nervous system. Although our understanding of the molecular events that regulate neuronal firing, synaptic function, and plasticity has expanded rapidly over the past fifteen years, an appreciation for how cellular changes are functionally integrated at the circuit level has lagged. A new generation of tools that employ fluorescent sensors of neural activity promises unique opportunities to bridge the gap between cellular and system-levels analysis.This review will focus on genetically-encoded sensors. A primary advantage of these indicators is that they can be non-selectively introduced to large populations of cells using either transgenic or viral-mediated approaches. This ability removes the non-trivial obstacles of how to get chemical indicators into cells of interest, a problem that has dogged investigators who have been interested in mapping neural function in the intact CNS. Five different types of approaches and their relative utility will be reviewed here: 1) reporters of immediate-early gene (IEG) activation using promoters such as c-fos and arc, 2) voltage-based sensors, such as GFPcoupled Na + and K + channels, 3) Cl − based sensors, 4) Ca ++ -based sensors, such as Camgaroo and the troponin-based TN-L15, and 5) pH-based sensors, which have been particularly useful for examining synaptic activity of highly convergent afferents in sensory systems in vivo. Particular attention will be paid to reporters of IEG expression, since these tools employ the built-in threshold function that occurs with activation of gene expression, provoking new experimental questions by expanding the timescale of analysis for circuit and system-level functional mapping.
Fluorescent reporters of inducible gene expressionImmediate-early gene expression (IEG) can be a reliable marker of elevated neuronal firing, reporting activity over time scales that range from minutes to hours compared to ms and seconds for voltage-or ion-based sensors. In ion-based approaches, indicators are constitutively present in the cell, and the fluorescent protein must be engineered to be a sensor with rapid onset and offset kinetics to achieve temporal fidelity with the process being measured. In contrast, monitoring IEG expression can be directly coupled to transcription of the reporter gene. However, because maturation of the fluorophore is required for detection, a temporal delay may be introduced into reporter detection. This delay in reporting activity is advantageous in that it expands the types of experimental questions that can be addressed. For example, do IEGexpressing cells remain more excitable after stimulus cessation? Are cells activated by two temporally distinct stimuli (i.e. training and recall in a memory task) overlapping or distinct?