Project Summary Flexible behavior is central to virtually all cognitive and social abilities. Recent technical advances have opened an unprecedented opportunity to comprehensively dissect the neural circuit mechanisms of this ability across multiple brain areas in freely behaving animals. This proposal focuses on the cerebellum, a structure that is a major site of pathology in autism spectrum disorder. Damage to the cerebellum at birth leads to a 36fold increase in the risk of autism, and this region is also a principal site for coexpression of autism risk genes. Thus cerebellar development may act as an intermediate mechanistic step in transducing inherited autism risk into neurodevelopmental phenotypes. In this project, a multidisciplinary team of leading experts proposes to investigate the neural basis of this disorder using advanced technologies, including unbiased automatic classification of behavior, largescale cellularresolution imaging in behaving rodents, mouse genetic models for autism, and manipulation of neural activity in specific cerebellar areas and cell types. In genetic mouse models of autism, the researchers will identify modes of behavior based on physical poses, and relate these modes to classical behavioral tests, such as eyeblink conditioning, and to cerebellar circuit dysfunction. In adult wildtype and autism model mice, the researchers will use optogenetic methods to perturb specific cerebellar lobules while quantifying the effects on behavioral dynamics and learning. In juvenile model mice, the researchers will use chemogenetic methods to identify longlasting patterns of behavioral disruption and relate these patterns across behaviors to build a quantitative map of these perturbations. In addition, they will use in vivo dendritic imaging to evaluate the influences of cerebellar perturbation on neocortical neuron structure. All of these results will inform modeling of cerebellarneocortical interactions to better understand how these differently wired regions interact during learning and development. The longterm goal of this project is to arrive at a chain of explanation, centered on principles of convergent neuroscience, to understand causal mechanisms of neurodevelopmental disorders. This project will join genetics with circuit function, local cerebellar anatomy with behavioral outcomes, and classical behavioral tests with modern unbiased methods. This project is expected to produce an accurate and detailed understanding of cerebellar contributions to normal and aberrant neurodevelopment. In addition, the proposed research will enable researchers to generate and test a variety of hypotheses about the neural basis of flexible behavior. Taken together, these achievements will represent a crucial step toward a mechanistic understanding...