PROJECT SUMMARY A fundamental challenge in neuroscience is in understanding which circuits and cells in the brain contribute to specific behaviors, perceptions, and functions. One class of tools that can help to unveil complex brain circuitry are activity integrators that can record the history of neural activity over a user-specified window of time. Technologies that not only record and map neural activity but enable genetic access to ‘playback’ neural activity can provide an unparalleled understanding of brain circuit structures. This project will develop and validate new optogenetic tools allowing permanent genetic access to recently activated neurons in vivo, within a time frame specified using light. This project builds on a previously developed and validated optogenetic tool: a photoactivatable DNA recombinase technology that shows low background, high induced activity, and a narrow time window for activation. We will validate these tools in cultured cells and in vivo in mouse brain. With these tools, users could apply a brief pulse of light during a behavior, resulting in a permanent genetic modification in neurons active during the behavior. These precision tools will extend the genetic toolkit for neuroscientists and enable a variety of new studies interrogating and manipulating complex brain circuitry in the normal and diseased brain.

PROJECT NARRATIVE The goal of this work is to develop new tools to allow genetic access to recently active neurons. These tools will enable visualization and manipulation of neural circuit activity selectively in neurons that have recently fired, allowing researchers to modulate specific neural circuits in the brain with high temporal precision. These tools will lead to better understanding of the neural circuitry giving rise to perception, memory, complex thought, and behavior, and how these are altered by disease states and neurological disorders.