Current Research and Scholarly Interests
1. Organization of the olfactory system
The olfactory systems from flies to mammals use a similar organizational principle. Olfactory receptor neurons (ORNs) expressing the same odorant receptor project their axons to the same glomerulus. Projection neurons (PNs) send dendrites to individual glomeruli, and relay olfactory information via their axons to high olfactory centers. Using MARCM (see below) to label individual fly PNs, we found that PN axon terminals exhibit striking stereotypy at the lateral horn according to the glomeruli they send dendrites to. Axon terminals of PNs representing food odors are spatially segregated from those that represent mating pheromones. By contrast, PN axon terminal arborizations in the mushroom body, the olfactory learning and memory center, exhibit much less stereotypy. We are currently using two-photon calcium imaging, optogenetics, and quantitative behavioral assays to identify principles of information processing at the antennal lobe and in higher olfactory centers suggested by previous anatomical studies. We are also investigating how the glomerular map in the mouse olfactory bulb is represented in olfactory cortex using virus-mediated trans-synaptic tracing.
2. Development of wiring specificity in the fly olfactory system
The assembly of the fly olfactory system requires precise glomerular targeting of axons from each of the 50 ORN classes, as well as dendrites of each of the 50 PN classes. We are using this neural circuit as a model to investigate the general principles by which precise wiring specificity arises during development. Our previous studies have shown that PN dendrite patterning precedes ORN axon targeting. PN dendrite targeting relies on global cues in the form of gradients, as well as local cues distributed in a salt-and-pepper fashion on dendrites projecting to different glomeruli. Targeting of ORN axons may use the same molecules as PN dendrite targeting, but via distinct mechanisms including axon-axon interactions and axon-target interactions. We are currently performing systematic genetic studies to identify the cell-surface code ORNs and PNs use to form specific connections at stereotypically organized glomeruli.
3. Developmental neurobiology
In addition to our focus on the olfactory system, we are investigating several other developmental neurobiological problems. These include mechanisms of axon pruning, the roles of neuronal activity in neuronal maturation and incorporation into functional circuits, and cell autonomous functions of genes that are implicated in human neurological disorders. We are using both fly and mouse systems to study these problems.
4. Creating genetic tools
In the process of dissecting the adult organization and developmental assembly of complex neural circuits, we have created several useful genetic tools. The MARCM method (Mosaic Analysis with a Repressible Cell Marker) enables the visualization and genetic manipulation of small populations of cells or single neurons in a mosaic fly. We have developed a new repressible binary expression system, the Q system, which has many applications and is helping us to study several problems described above.
We have also developed a mosaic method in the mouse called MADM (Mosaic Analysis with Double Markers) that allows sparse labeling and genetic manipulation of individual cells or cells that share the same lineage with distinct colors in mosaic animals. We have used MADM as trace lineages and study cell autonomous gene functions in neural developmental processes. We are currently expanding the MADM technique to other mouse chromosomes, and will use MADM to study several developmental neurobiological problems (see above). We have also developed other useful mice, such as a double fluorescent Cre reporter and synapse labeling tools in vivo.