Project Grant R01DC021551

OLFACTORY NEUROMODULATION: GENES, CELLS, AND BEHAVIOR - PROJECT SUMMARY DAY/NIGHT CYCLES PROFOUNDLY IMPACT ANIMALS' PHYSIOLOGY AND BEHAVIOR TO ALLOW ADAPTATION TO RHYTHMIC ENVIRONMENTAL CUES. DAILY RHYTHMIC BEHAVIORS ARE BELIEVED TO BE PATTERNED BY CENTRAL CLOCK NEURONS. HOWEVER, THE PHYSIOLOGY OF PRIMARY SENSORY NEURONS, SUCH AS OLFACTORY RECEPTOR NEURONS (ORNS), CAN ALSO EXHIBIT OSCILLATORY CHANGES, BUT WHETHER SUCH CHANGES CAN GUIDE RHYTHMIC BEHAVIORS REMAINS UNDETERMINED. PROGRESS IS FURTHER HINDERED BY THE LACK OF INFORMATION ON WHETHER OR WHICH ODOR-GUIDED BEHAVIORS ARE REGULATED BY DAY/NIGHT CYCLES. THIS PROPOSAL LEVERAGES THE POWERFUL GENETIC TOOLKIT AND TRACTABLE OLFACTORY SYSTEM OF D. MELANOGASTER TO ADDRESS THESE FUNDAMENTAL YET OUTSTANDING QUESTIONS. PRELIMINARY STUDIES SHOWED THAT PHEROMONE-SENSING ORNS EXHIBIT HIGHER RESPONSES IN FLIES AT SUBJECTIVE NIGHT (HENCEFORTH REFERRED TO AS NIGHT FLIES) THAN IN FLIES AT SUBJECTIVE DAY (HENCEFORTH REFERRED TO AS DAY FLIES). IMPORTANTLY, THIS HEIGHTENED PHEROMONE SENSITIVITY IN NIGHT FLIES IN TURN ELEVATES ODOR-GUIDED SOCIAL BEHAVIOR. MECHANISTICALLY, THE DAY OR NIGHT MODULATION IS RESPECTIVELY SIGNALED VIA TWO NEUROMODULATORS. PRELIMINARY EXPERIMENTS FURTHER SHOWED THAT IN THESES ORNS, THE DAY/NIGHT MODULATION OF OLFACTORY ACUITY REQUIRES A CATION CHANNEL SUBUNIT WHOSE EXPRESSION LIKELY REDUCES NEURONAL INPUT RESISTANCE OR CAUSES ACCOMMODATION, THUS LOWERING SPIKE RESPONSE FREQUENCY. THESE FINDINGS LED TO THE HYPOTHESIS THAT DAY/NIGHT CYCLES, THROUGH THE ANTAGONISTIC ACTIONS OF TWO NEUROMODULATORS, UP- OR DOWN-REGULATE THE CATION CHANNEL IN ORNS TO DYNAMICALLY MODULATE OLFACTORY ACUITY AND ODOR-GUIDED BEHAVIOR. TO TEST THIS CENTRAL HYPOTHESIS, THIS RESEARCH WILL DETERMINE HOW THE TWO NEUROMODULATORS ANTAGONISTICALLY REGULATE ORN RESPONSES (AIM 1), CHARACTERIZE THE EFFECTOR(S) CAPABLE OF ALTERING OLFACTORY RESPONSES IN THE TARGET ORNS (AIM 2), AND INVESTIGATE THE GENERALITY OF THE NEUROMODULATORY MECHANISM ACROSS ORN TYPES (AIM 3). THE MECHANISTIC INSIGHTS EXPECTED FROM THIS RESEARCH WILL ADVANCE OUR UNDERSTANDING OF HOW DAY/NIGHT CYCLES INFLUENCE OLFACTORY PHYSIOLOGY AND BEHAVIOR. OF FURTHER SIGNIFICANCE, THIS RESEARCH DEMONSTRATES THAT NEUROMODULATORY IMPAIRMENT AT THE ORN LEVEL PRECLUDES THE POTENTIAL INFLUENCE OF CENTRAL CIRCADIAN MECHANISMS ON ODOR-GUIDED BEHAVIOR. THE IDEA THAT PERIPHERAL SENSORY NEUROMODULATION PLAYS A CRITICAL ROLE IN GATING DAY/NIGHT-REGULATED BEHAVIORS IS CONCEPTUALLY INNOVATIVE. FURTHERMORE, IN RODENTS, THE NEURONAL RESPONSES TO ETHOLOGICALLY RELEVANT ODORS ARE ALSO HEIGHTENED AT SUBJECTIVE NIGHTTIME. THEREFORE, SUCCESS OF THIS RESEARCH WILL LIKELY CARRY BROAD IMPLICATIONS ACROSS ANIMAL SPECIES.