Project Summary! How the brain combines sensory stimuli from different modalities to guide behavior is currently not understood at a single-cell level. Here we propose to use the model organism Drosophila to investigate the neural circuit basis of multi-sensory integration in the context of two specific orientation behaviors developed in our lab. In one paradigm, odor switches the orientation of walking flies to a wind (mechanosensory) cue: flies orient downwind in the absence of odor and upwind in the presence of an attractive odor. In the second paradigm, an aversive wind stimulus and attractive visual stimulus sum to guide orientation of a tethered flying fly. We have discovered a novel mechanosensory pathway that computes wind direction from movements of the fly's antennae, and transmits this information to the central complex, a region of the brain implicated in navigation. Combined with information from the literature and preliminary data from our own lab, this suggests a model for how different sensory streams might be aligned and integrated within the central complex. We propose to use optogenetic activation, chemogenetic silencing, whole-cell electrophysiology, and functional imaging to test the role of candidate central complex neurons in multi-sensory control of orientation. We will additionally test the alternative hypothesis that multi-sensory integration in descending neurons is required for the two behaviors. This study will provide a comprehensive cellular-level account of how sensory streams are combined to control the orientation of a model organism.!