From insects to mammals, olfactory receptor neurons (ORNs) expressing the same odorant receptor target their axonal projections to specific glomerular destinations in the antennal lobe/olfactory bulb, creating an odor map in these first olfactory structures of the central nervous system. In the fly, axons of 50 classes of ORNs match precisely with dendrites of corresponding 50 classes of second order olfactory projection neurons (PNs) to form the 50 glomeruli of the antennal lobe. Olfactory information is thus faithfully delivered from sensory organs in the periphery to higher brain centers, enabling innate and learned olfactory behavior. Thanks to the continual support of this grant since 2003, our studies have made the Drosophila antennal lobe one of the best-understood circuits in terms of the molecular, cellular, and developmental underpinnings of wiring specificity. We provided a detailed description of the wiring process with single-cell resolution, finding that PN dendrites pre-pattern the antennal lobe prior to ORN axon invasion. We discovered the importance of PN dendrite-dendrite, ORN axon-axon, and PN dendrite-ORN axon interactions and some of the underlying molecular mechanisms. Moreover, we recently developed methods to profile the transcriptomes of individual olfactory neurons, and to visualize them as they make wiring decisions using time-lapse imaging. In this renewal, we propose to combine live imaging, single-cell RNA-sequencing, proteomic approaches with state-of-the-art genetic manipulations to address the following three questions: 1) how do ORN axons choose a specific trajectory when they first reach the antennal lobe? 2) How do PN dendrites establish discrete boundaries and targeting specificity? 3) How do ORN axons find their partner PN dendrites? The completion of the proposed studies will allow us to gain a more comprehensive understanding of the combinatorial codes that determine wiring specificity, and cell biological mechanisms that underlying the execution of wiring decisions. These studies will contribute to our understanding of a central problem in developmental neurobiology: how wiring specificity of neural circuits is achieved during development. By uncovering the molecules and mechanisms inherent to the fly olfactory circuit, we have already provided insight into constructing more complex neural circuits in the mammalian brain, and established links between neural circuit wiring and disorders of the human brain.
Understanding how neural circuits are assembled during normal development is a prerequisite for understanding many human neurological and psychiatric disorders that disrupt this assembly process. Indeed, some of the human versions of genes that we have discovered in flies to play important roles in neural circuit wiring are implicated in disorders of the brain, including peripheral neuropathy, bipolar disorders, and intellectual disabilities. In addition, knowledge of insect olfactory system organization and development can be used to design strategies to combat malaria, which is transmitted by mosquitos that primarily utilize olfaction to find both their mates and human hosts.
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