In Vivo Imaging of Cellular Excitation-Transcription Coupling in the Mouse Brain

Regulation of gene transcription is essential for long-term plasticity in the brain. However, it has not been possible to monitor dynamics of neuronal transcription in vivo and to correlate them to neuronal activity patterns at cellular resolution. Here we present a technique to image in vivo signaling of cAMP response element binding protein (CREB), an activity-dependent transcription factor important for synaptic plasticity, using 2-photon fluorescence lifetime imaging (2pFLIM) in combination with new FRET biosensors. This allowed for long-term simultaneous imaging of CREB and neuronal activity in cortical neurons of awake animals. We found that, on average, CREB activity is positively correlated with behavioral performance in a motor learning task. Further, we performed chronic dual-imaging of CREB and neuronal activity in primary visual cortex, identifying a correlation between CREB and neuronal activity dynamics following sensory deprivation. This approach will allow researchers to unravel transcriptional dynamics underlying experience-dependent plasticity in the brain.