Many pathways that carry signals from one neuron to another involve calcium as a messenger molecule. By examining changes in calcium concentration within individual neurons, researchers can learn how these neurons interact within circuits. A long-term goal of this laboratory is to produce indicators that can track the full rang of calcium changes in large numbers of neurons in behaving animals across days to weeks. In particular, the proposed experiments will produce new technology that can follow activity in neuronal cell types that are involved in important brain functions, from fine motor control to reward learning. The overall objective of this application is to design probes that can follow rapi neural activity in awake, behaving animals and to demonstrate their usefulness in studying cell types whose activity cannot be recorded using currently available techniques. This contribution is significant because it will allow researchers to investigate the function of important neural circuits under realistic conditions. This approach is innovative because this laboratory will develop tools that allow the study of cells that previously could not be examined in awake animals. The work proposed in this application will therefore advance our ability to understand how the brain functions in health and disease. In the long run, this information could lead to new approaches to diagnosis, treatment, and prevention of a variety of brain disorders.