Probing neural codes with two-photon holographic optogenetics

Optogenetics ushered in a revolution in how neuroscientists interrogate brain function. Because of technical limitations, the majority of optogenetic studies have used low spatial resolution activation schemes that limit the types of perturbations that can be made. However, neural activity manipulations at finer spatial scales are likely to be important to more fully understand neural computation. Spatially precise multiphoton holographic optogenetics promises to address this challenge and opens up many new classes of experiments that were not previously possible. More specifically, by offering the ability to recreate extremely specific neural activity patterns in both space and time in functionally defined ensembles of neurons, multiphoton holographic optogenetics could allow neuroscientists to reveal fundamental aspects of the neural codes for sensation, cognition and behavior that have been beyond reach. This Review summarizes recent advances in multiphoton holographic optogenetics that substantially expand its capabilities, highlights outstanding technical challenges and provides an overview of the classes of experiments it can execute to test and validate key theoretical models of brain function. Multiphoton holographic optogenetics could substantially accelerate the pace of neuroscience discovery by helping to close the loop between experimental and theoretical neuroscience, leading to fundamental new insights into nervous system function and disorder.