Axons (the long, tube-like extensions of nerve cells that carry electrical and molecular signals) are a particularly critical feature of brain circuit architecture. This project examines how functionally diverse populations of nerve cells coordinate their axonal architecture during fruit fly brain development to produce precisely-organized brain circuits. Fruit flies have more than 50 different types (classes) of olfactory receptor neurons that make precise axonal connections to the first upstream processing station in the brain. This project combines molecular, cell-biological and developmental techniques with genomic, bioinformatics and statistical approaches to identify the mechanisms through which olfactory receptor neurons form class-specific axonal connections with their targets. Understanding how olfactory receptor neurons decide upon which class-specific combinations of path-finding and cell adhesion molecules to express on their cell surfaces will further understanding of how the physical wiring diagram at the initial stage of brain odor-processing circuitry gets set up. This research will also lead to fundamental insights into evolutionarily-conserved mechanisms that assemble brain cells with highly-diverse functional properties into functionally integrated brain circuits, and further understanding of how the structure of olfactory circuits and olfactory behaviors evolves along with changes in olfactory receptor sequence, expression pattern and function. This award also supports advanced research training for graduate, undergraduate, and high school students, as well as scientific outreach programs for 6th-12th grade students attending schools in low-income areas with a high percentage of students from groups who are traditionally underrepresented in science, technology, engineering and mathematics.

As neurons are born, they organize their axons into large tracts (clumps of axons) that extend for long distances. Once axons arrive at a target site, they defasciculate from these main tracts, sort themselves out based on their molecular and/or functional identity, and selectively synapse with target cells. Combinations of genes encoding cell adhesion molecules (CAMs) act as adhesive or repulsive cues to regulate axonal behavior. Nevertheless, how diverse neuronal populations coordinate axonal organization to regulate circuit architecture remains unclear. The Drosophila olfactory system provides an excellent model to investigate molecular mechanisms of axonal organization. Olfactory receptor neurons (ORNs) of the same class express the same olfactory receptor (OR) genes, and their axons converge onto class-specific glomeruli in the antennal lobes to synapse with projection neurons (PNs). Previous research has identified interacting CAM families expressed in ORN class-specific combinations. Genetic perturbations of a subset of CAMs in differentiated ORNs exhibited defects in glomerular position, morphology and context; simultaneous disruption of function in ORN classes targeting neighboring glomeruli resulted in similar defects with reduced expression of some CAMs. This project tests the hypothesis that signaling in ORNs regulate the expression of CAM combinations to organize axonal projections to class-specific glomeruli. First, the function of OR signaling pathways and ORN activity in glomerular organization will be tested. Next, transcriptional changes in CAMs will be studied in OR mutant flies using RNA profiling. Finally, developmental and genetic analyses will be used to elucidate the ORN-specific function of CAMs in axonal and glomerular organization.

This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

National Science Foundation (NSF)
Division of Integrative Organismal Systems (IOS)
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Evan Balaban
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Duke University
United States
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