Project Grant F32DC022517

UTILIZING RECEPTOR-DEFINED ODOR CODING CHANNELS TO UNDERSTAND INHIBITORY CIRCUIT ORGANIZATION - PROJECT SUMMARY UNDERSTANDING HOW SENSORY RECEPTORS RESPOND TO A RANGE OF STIMULI IS ESSENTIAL FOR DELINEATING HOW SENSORY INFORMATION IS ENCODED, BUT NEURONAL RESPONSE FEATURES ARE NOT DETERMINED SOLELY BY THE INTERACTION BETWEEN STIMULI AND RECEPTORS. INHIBITORY CIRCUITS PLAY A FUNDAMENTAL ROLE IN SHAPING RESPONSE FEATURES TO SENSORY STIMULI, THEREFORE IMPACTING THE INFORMATION THAT IS RELAYED TO HIGHER LEVELS OF PROCESSING. WITHIN THE OLFACTORY SYSTEM, RESPONSES ARE INFLUENCED BY A DIVERSITY OF INHIBITORY CIRCUITS BUT WE STILL LACK AN UNDERSTANDING OF THE FUNCTIONAL ORGANIZATION OF THESE CIRCUITS. ARE INHIBITORY CONNECTIONS RANDOMLY ORGANIZED OR IS THERE STRUCTURE THAT REFLECTS RECEPTOR DOMAINS AND CHEMICAL SPACE? IT REMAINS CHALLENGING TO MAP RESPONSES FROM THE RECEPTOR LEVEL TO THEIR PRINCIPAL OUTPUT NEURONS AND QUANTIFY INHIBITORY RESPONSES OF THE SAME NEURONS ACROSS INDIVIDUALS. THE PROPOSED PROJECT OVERCOMES THIS CHALLENGE BY TAKING ADVANTAGE OF THREE RECEPTOR-TAGGED MOUSE LINES TO DELINEATE HOW INHIBITION IS FUNCTIONALLY ORGANIZED IN THE OLFACTORY BULB AND HOW INHIBITORY RESPONSES MANIFEST IN POSTSYNAPTIC NEURONS. IN AIM 1, I WILL TEST ALTERNATE MODELS OF LATERAL INHIBITORY ORGANIZATION AND ASK HOW INHIBITION IS ORGANIZED RELATIVE TO EXISTING STRUCTURE IN THE OLFACTORY BULB. WHILE IT IS KNOWN THAT LATERAL INHIBITION IS ODOR-DEFINED AND SELECTIVE, LITTLE IS KNOWN REGARDING HOW THIS SELECTIVITY IS ORGANIZED WITHIN AND ACROSS INDIVIDUALS. IN AIM 2, I WILL THEN ASK HOW INHIBITION MANIFESTS IN POSTSYNAPTIC CELLS THAT TRANSMIT SENSORY INFORMATION TO CORTICAL REGIONS. PREVIOUS WORK SUGGESTS THAT THE TWO TYPES OF POSTSYNAPTIC OUTPUT NEURONS IN THE OLFACTORY BULB ARE DIFFERENTIALLY INFLUENCED BY INHIBITION, BUT THERE IS CONFLICTING EVIDENCE REGARDING WHETHER SISTER CELLS RECEIVING THE SAME RECEPTOR-DEFINED INPUTS ARE HOMOGENOUSLY MODULATED BY INHIBITION. TO TEST THESE QUESTIONS, I WILL CHARACTERIZE PRE- AND POSTSYNAPTIC EXCITATORY AND SUPPRESSIVE TUNING IN VIVO USING OLFACTORY RECEPTOR-DEFINED NEURONS AND THE MOST UP-TO-DATE OPTICAL REPORTERS TO IMAGE NEURONAL RESPONSES IN AWAKE, HEAD-FIXED MICE. I WILL ALSO IMAGE FROM THE SOMA OF POSTSYNAPTIC OLFACTORY RECEPTOR-DEFINED NEURONS BY USING A DIAGNOSTIC LIGAND. THIS PROJECT WILL IDENTIFY NOVEL PRINCIPLES UNDERLYING INHIBITORY CIRCUIT ORGANIZATION, WHICH HAS IMPLICATIONS FOR SENSORY PROCESSING ACROSS MODALITIES AND WILL BROADEN OUR INSIGHT INTO THE RELATIONSHIP BETWEEN SENSORY RECEPTORS, STIMULUS IDENTITY, AND THE ORGANIZATION OF SENSORY CIRCUITS. THE PROPOSED PROJECT WILL PROVIDE ME WITH TRAINING IN THE TECHNICAL SKILLS AND CONCEPTUAL KNOWLEDGE NEEDED FOR MY FUTURE CAREER GOAL OF BECOMING A TENURE-TRACK RESEARCHER INVESTIGATING HOW DEVELOPMENTAL DEVIATIONS IMPACT THE EVOLUTION AND FUNCTION OF CHEMOSENSORY SYSTEMS. THIS RESEARCH WILL TAKE PLACE IN MY SPONSOR'S LAB AT THE UNIVERSITY OF UTAH, BUT I WILL SPEND A MONTH IN SPRING 2025 IN MY CO-SPONSOR'S LAB AT DUKE UNIVERSITY LEARNING IN VITRO TECHNIQUES TO ASSAY ODORANT RECEPTOR ACTIVATION. BOTH INSTITUTIONS HAVE COLLABORATIVE RESEARCH ENVIRONMENTS THAT WILL PROVIDE ME WITH THE NECESSARY RESOURCES TO COMPLETE MY RESEARCH TRAINING GOALS.