Visualizing circuits and systems using transgenic reporters of neural activity

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 15 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 level and system level analysis. This review will focus on genetically encoded sensors. A primary advantage of these indicators is that they can be nonselectively introduced to large populations of cells using either transgenic-mediated or viral-mediated approaches. This ability removes the nontrivial 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: first, reporters of immediate-early gene (IEG) activation using promoters such as c-fos and arc; second, voltage-based sensors, such as GFP-coupled Na+ and K+ channels; third, Cl*-based sensors; fourth, Ca2+-based sensors, such as Camgaroo and the troponin-based TN-L15; and fifth, 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, because 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-level and system-level functional mapping.