Project Grant R35NS137329

INVESTIGATING SLEEP REGULATION AND FUNCTION DURING EARLY DEVELOPMENT - PROJECT SUMMARY SLEEP CHARACTERISTICS CHANGE DRAMATICALLY ACROSS DEVELOPMENT. IN EARLY LIFE, SLEEP DURATION AND DEPTH ARE ELEVATED, AND SLEEP LACKS A STRONG CIRCADIAN PATTERN. WITH MATURATION, SLEEP DURATION TAPERS TO ADULT LEVELS AND CLEAR SLEEP RHYTHMS EMERGE. THE GENES, MOLECULES, AND NEURAL CIRCUITS GOVERNING DEVELOPMENTAL CHANGES TO SLEEP ARE LARGELY UNKNOWN. SLEEP IN EARLY LIFE IS HYPOTHESIZED TO FACILITATE STRUCTURAL MATURATION OF THE BRAIN, AND SLEEP ABNORMALITIES DURING DEVELOPMENT MAY CONTRIBUTE TO ABERRANT NEURAL CIRCUIT FORMATION. MOREOVER, SLEEP DISORDERS ARE HIGHLY PREVALENT IN NEURODEVELOPMENTAL DISORDERS (NDDS). IMPROVING SLEEP BY TARGETING REGULATORY PATHWAYS MAY THUS REPRESENT A NEW THERAPEUTIC AVENUE IN NDDS; HOWEVER, THE KNOWLEDGE GAP REGARDING FACTORS CONTROLLING EARLY LIFE SLEEP HINDERS DESIGN OF SLEEP-RELATED STRATEGIES. OUR RESEARCH USES THE POWERFUL MODEL SYSTEM DROSOPHILA TO GAIN NOVEL INSIGHTS INTO SLEEP REGULATION AND FUNCTION ACROSS DEVELOPMENTAL PERIODS. OUR STUDIES HAVE LED TO 1) IDENTIFICATION OF GENES THAT SPECIFICALLY COORDINATE SLEEP MATURATION, 2) FUNCTIONAL INSIGHTS INTO THE ROLE OF SLEEP DURING EARLY DEVELOPMENT, AND 3) MECHANISMS COUPLING SLEEP TO NDDS. BUILDING ON THESE EFFORTS, THIS RESEARCH PROGRAM IS COMPRISED OF THREE HIGHLY INTEGRATED DOMAINS THAT SEEK TO DEFINE SLEEP REGULATORY MECHANISMS DURING DEVELOPMENT AND UNDERSTAND HOW SLEEP INFLUENCES BRAIN MATURATION IN NORMAL AND PATHOLOGICAL STATES. FIRST, IN STUDIES SPANNING LARVAL TO ADULT STAGES, WE WILL DETERMINE SLEEP CELLULAR AND CIRCUIT PROPERTIES ACROSS DEVELOPMENT. WE PROPOSE TO IDENTIFY SLEEP/WAKE REGULATORY NEURONS OF INTEREST IN EARLY DEVELOPMENT, CHARACTERIZE THESE CELLS, MAP CONNECTIVITY, AND TRACE/CHARACTERIZE THE CELLS IN THE ADULT. SECOND, WE WILL EXAMINE MECHANISMS CONTROLLING EMERGENCE OF CIRCADIAN SLEEP. OUR RECENT WORK HAS PINPOINTED WHEN SLEEP RHYTHMS FIRST EMERGE DURING DROSOPHILA DEVELOPMENT. WE WILL DETERMINE MECHANISMS CONTROLLING ONSET OF SLEEP RHYTHMS, FUNCTIONAL CONSEQUENCES OF CIRCADIAN SLEEP, AND HOW DEVELOPMENT OF CLOCK-SLEEP CIRCUITS TIES INTO BROADER SLEEP REGULATORY MECHANISMS. THIRD, WE PROPOSE TO UTILIZE GENETIC SCREENS TO INVESTIGATE MOLECULAR/CELLULAR COUPLING OF SLEEP AND NDDS. SPECIFICALLY, WE WILL PURSUE A COMPREHENSIVE ASSESSMENT OF HOW NDD-ASSOCIATED GENE MANIPULATIONS AFFECT SLEEP ACROSS NUMEROUS DEVELOPMENTAL STAGES, EACH OF WHICH HAS UNIQUE BEHAVIORAL AND MOLECULAR FEATURES THAT MIGHT BE SPECIFICALLY SENSITIVE TO PARTICULAR PERTURBATIONS. GENETIC FINDINGS WILL BE PLACED INTO CONTEXT OF SLEEP/CIRCADIAN CIRCUIT PRINCIPLES IN AN ONGOING, INTEGRATED MANNER. COLLECTIVELY, OUR RESEARCH PROGRAM WILL GENERATE NEW INSIGHTS INTO THE REGULATION OF EARLY LIFE SLEEP, DEEPENING OUR UNDERSTANDING OF THE LINK BETWEEN SLEEP, BRAIN DEVELOPMENT, AND NEURODEVELOPMENTAL PATHOLOGY.