Project Grant R15EY031539

GENETIC AND CIRCUIT CONTROL OF VISUO-ACOUSTIC BEHAVIOR AND INTEGRATION - FUNCTION-DISRUPTING AP2S1 ALLELES HAVE RECENTLY BEEN LINKED TO LEARNING DISABILITIES AND AUTISM SPECTRUM DISORDERS (ASD), THOUGH THE MECHANISMS UNDERLYING THIS GENE'S IMPACT ON HUMAN BEHAVIOR ARE UNKNOWN. UNDERSTANDING HOW, WHEN, AND WHERE THIS GENE REGULATES VERTEBRATE BEHAVIOR IS KEY TO ADDRESSING DEFICITS OBSERVED IN THESE AND OTHER NEUROPSYCHIATRIC CONDITIONS, YET VIABLE VERTEBRATE MODELS ARE LACKING. OUR LAB HAS ISOLATED VIABLE ZEBRAFISH AP2S1 MUTANTS AND HAS BEGUN TO CHARACTERIZE AP2S1'S ROLE IN COGNITIVE PROCESSES SUCH AS INTEGRATING MULTISENSORY INFORMATION, APPROPRIATE SELECTION OF BEHAVIORS, AND HABITUATION LEARNING. GIVEN THAT DEFICITS IN INFORMATION PROCESSING AND BEHAVIORAL SELECTION ARE CHARACTERISTICS SHARED BY MANY NEUROPSYCHIATRIC CONDITIONS, INCLUDING ASD AND SCHIZOPHRENIA, OUR GENETICALLY-ACCESSIBLE MODEL CAN BE LEVERAGED TO DETERMINE THE MOLECULAR AND NEURAL MECHANISMS UNDERLYING THESE CONDITIONS AS WELL AS MORE BROADLY CHARACTERIZE AP2S1'S ROLE IN MULTISENSORY INTEGRATION, BEHAVIOR SELECTION, AND LEARNING. WE WILL USE OUR ZEBRAFISH MODEL TO REVEAL THE NEURAL MECHANISMS BY WHICH AP2S1 MODULATES VISUAL AND ACOUSTIC BEHAVIOR AND SENSORY INTEGRATION. IN AIM 1, WE WILL DETERMINE WHAT ASPECTS OF VISUALLY GUIDED LEARNING, VISUAL BEHAVIOR SELECTION, AND VISUO-ACOUSTIC INTEGRATION REQUIRE AP2S1. OUR RESULTS WILL TEST THE HYPOTHESIS THAT AP2S1 DIRECTLY MODULATES VISUAL PROCESSING AND VISUO-ACOUSTIC INTEGRATION, BEYOND ITS ROLE IN ACOUSTIC BEHAVIOR. IN AIM 2, WE WILL DETERMINE THE TEMPORAL AND SPATIAL REQUIREMENTS FOR AP2S1 TO MODULATE VISUALLY AND ACOUSTICALLY EVOKED BEHAVIOR USING INDUCIBLE AND CELL-SPECIFIC TRANSGENES. OUR RESULTS WILL TEST THE HYPOTHESES THAT THE BEHAVIORAL ROLE OF AP2S1 IS 1) TO REGULATE APPROPRIATE CIRCUIT DEVELOPMENT, AND/OR 2) TO REGULATE ACUTE NEURONAL FUNCTION, AND WILL DISTINGUISH IF AP2S1 REGULATES VISUAL AND ACOUSTIC RESPONSES THROUGH DISTINCT OR SHARED CIRCUITS. IN AIM 3, WE WILL FOCUS ON THE PAIR OF COMMAND-LIKE MAUTHNER NEURONS THAT INTEGRATE VISUAL AND ACOUSTIC INFORMATION TO DRIVE ESCAPE BEHAVIOR, AND DETERMINE HOW ITS FUNCTION IS MODULATED BY AP2S1. THROUGH SUBCELLULAR CALCIUM IMAGING IN BEHAVING FISH, OUR RESULTS WILL TEST THE HYPOTHESIS THAT AP2S1 MODULATES ESCAPE BEHAVIOR SELECTION THROUGH A SPATIALLY-SPECIFIC IMPACT ON MAUTHNER DENDRITIC INTEGRATION, REVEALING THE DYNAMICS OF VISUAL AND ACOUSTIC INFORMATION INTEGRATION IN THESE CENTRAL NEURONS. OVERALL, THESE AIMS WILL POSITIVELY IMPACT HUMAN HEALTH INITIATIVES BY ADVANCING OUR KNOWLEDGE OF THE GENETIC AND NEURAL MECHANISMS GOVERNING MULTISENSORY INFORMATION PROCESSING AND BEHAVIORAL SELECTION, AND THE DIRECT ROLES OF THE ASD-LINKED GENE AP2S1. FURTHERMORE, OUR PROPOSED WORK WILL VALIDATE THE USE OF THESE BEHAVIORAL ASSAYS AS A ZEBRAFISH MODEL FOR VERTEBRATE MULTISENSORY INTEGRATION THAT WILL BE USED TO CHARACTERIZE OTHER GENES AS THEY BECOME CLINICALLY RELEVANT.