In studies of neural plasticity, one of the outstanding challenges is to connect our growing understanding of cellular and synaptic mechanisms to their consequences for plasticity of whole neuronal circuits. A promising approach is to use optical microscopy to observe the changes in activity that accompany learning; however, conventional methods like multiphoton microscopy cannot monitor neuronal events over large regions at high speeds. A new technique, Objective-Coupled Planar Illumination (OCPI) microscopy, promises orders-of- magnitude increases in the sensitivity and speed of optical physiology. This proposal focuses on extending the spatiotemporal resolution of OCPI microscopy to observe neuronal activity and plasticity at subcellular resolution in thousands of neurons simultaneously. PUBLIC HEALTH RELEVANCE: The mechanisms of learning are among the great unsolved mysteries of the brain, and memory deficits are a major medical problem. To better understand the neuronal basis of learning, we will develop new instruments for observing the changes in the brain during memory formation.