Our brains have a remarkable knack for adaptability. Each day neuronal connections are constantly changing, molded by experiences. Memories made, information learned, and skills acquired spark this dynamic process, causing lasting changes to neuronal circuits.

Along with learning and memory, sensory experiences such as listening to music or appreciating a stunning view also have a similar effect on the brain. Incoming sensory information activates neurons in the cortex, causing long-term modifications to the circuitry depending on what is experienced. This process is called experience dependent plasticity, and it’s part of the reason our brains develop differently due to unique experiences.

But how do our brains convert relatively short-lasting neuronal activity into the long-term changes driven by our sensory experiences? The key lies in specialized proteins called activity-dependent transcription factors. Responding to neuronal activity, these factors activate genes within the cell helping to translate rapid incoming signaling into slower, lasting changes. Although the importance of activity dependent transcription to development and long-term plasticity in the brain is evident, it was impossible to directly monitor transcription factors’ activity. This was mainly due to the lack of available tools to study the interaction between neuronal activity and transcription factor activation that occurs in a living brain.

Scientists in the Yasuda Lab at the Max Planck Florida Institute for Neuroscience (MPFI) have designed and developed novel biosensors that allow the simultaneous study of both sensory evoked neuronal activity and transcription factor dynamics. Coupling the specialized techniques of 2-photon calcium imaging with 2-photon fluorescence lifetime imaging (2pFLIM), scientists for the first time will have the ability to investigate how transcription factors function in a living brain with single cell resolution.

“Transcription factor activity in the brain isn’t a static but rather a very dynamic process that can occur on the order of hours to days after a sensory experience,” explains Dr. Tal Laviv, Research Fellow in the Yasuda Lab. “Traditional methods of studying these proteins involve freezing brain tissue at a single moment in time. So, while these approaches can tell you if a certain factor is activated or not, they aren’t good at capturing how experience shapes transcription factor activity over time. We wanted to develop a new way to study how this process is actually occurring in a living brain and chose to study CREB due to its strong involvement in plasticity, learning, and memory.”

MPFI scientists started by creating sensitive and specific 2pFLIM biosensors designed to report the direct activity of cAMP response-element binding protein or “CREB” for short. Packaging their newly generated sensors using an adeno-associated viral strategy, the team then expressed them in a population of neurons within the somatosensory cortex of mice. The team chronically monitored CREB activity in the same population of neurons while mice experienced an enriched environment. The enriched environment caused a significant increase in overall CREB activity. Interestingly, when mice were removed from the enriched environment for an extended period of time, CREB activity returned to normal levels indicating sensory experience as a driver for the sustained activity.