PROJECT SUMMARY Moment-to-moment fluctuations in behavioral and brain states have been shown to have profound effects on perception and behavior in both humans and experimental animals. The variability in behavioral responses caused by these fluctuations have real world effects because they can cause an individual to respond inappropriately in high stakes and demanding situations, such as driving a car or operating on a patient. In addition, if not accounted for, the fluctuations can be a source of increased variability in both clinical therapies and systems neuroscience research, reducing the effectiveness of treatments and the robustness of experimental results. So far, much of the progress in understanding the effects of state on neural processing has come from experiments in sensory circuits. But knowing how state affects sensory processing isn’t enough to understand how it affects behavior because there are many additional downstream stages of neural circuit processing before the final motor output. The goal of this project is to examine the effects of state on both sensory and motor systems for the same behavior. This will be accomplished by taking advantage of a sensorimotor task (delay eyeblink conditioning, dEBC) in which much of the processing between sensory and motor systems occurs within a single brain area (the cerebellum). The experiments will involve first developing novel quantitative methods based on psychophysics to test the effects of state on dEBC. Two different types of behavioral state will be examined—locomotion and arousal—and the experiments are designed to tease apart the relative effects of these two states on dEBC. The experiments will then use large scale imaging and electrophysiology to test if and how the input (sensory) and output (motor) neurons of the cerebellum are affected by state. The results of these experiments will provide the first glimpse of how an entire neural system and behavior are dynamically modulated by state on a subsecond to second timescale. A greater understanding of the impact of state on the neural processing underlying behavioral performance will provide critical information for optimizing experimental design and therapies.

PROJECT NARRATIVE When we are awake our brain activity is in a constant state of flux due to things like changing levels of arousal and alertness, and these fluctuations in activity can have big effects on our ability to perform skilled actions, like driving a car. The proposed experiments will examine how brain activity fluctuations affect processing in the cerebellum, which is a brain area essential for producing skilled actions. The results will provide important information about how our brains control movement, which in addition to advancing our understanding of fundamental principles of brain function, will be useful for creating more effective therapies for movement disorders such as ataxia and dystonia.