Intercellular interactions in the developing nervous system; neuron-glia relationships; functional organization of olfactory systems

Research in my laboratory focuses on the development and functional organization of the olfactory system, studied in convenient model organisms, the moth Manduca sexta and, very recently, the fruitfly Drosophila melanogaster. Several different lines of investigation have led us to focus much of our attention on roles for glial cells in development and in mature function.

Development of the olfactory pathway. Over the years, our research has been aimed primarily at elucidating key intercellular interactions during development of the olfactory system. My coworkers and I have been especially interested in the mechanisms underlying the wide-spread phenomenon that sensory neurons guide many aspects of development in their target areas in the brain. Using the olfactory system of Manduca, we found in 1987 that glial cells must be present in order for the axons of olfactory receptor neurons, whose cell bodies are located in the antenna, to induce the formation of synaptic glomeruli in the antennal lobes of the brain.

Much of our work since then has built on the hypothesis that glial cells act as intermediaries in the developmental influence that olfactory axons exert upon their targets - i.e. that glial cells, which are induced by axons to surround developing glomeruli, form a necessary scaffold within which receptor neurons and target neurons subsequently differentiate their glomerular arbors. We have discovered that neuronal activity is not necessary for the formation of a glomerular architecture, so we are focusing our attention on cell-surface and extracellular signaling molecules, such as fasciclin II, tenascin, and nitric oxide, that could be involved.

We also are interested in another issue, that of axon guidance, as we seek to understand how olfactory receptor axons sort into glomerulus-specific bundles and then find their correct glomerular targets in the antennal lobe. We have discovered a glia-rich "sorting zone" in the antennal nerve (Fig. 1), and, using methods that deplete the developing system of glial cells, we have found that those glial cells must be present for the axons to sort properly. We use in vitro methods and live-cell video microscopy to explore in detail the interactions between the growth cones of olfactory receptor axons and glia from the sorting zone (Fig. 2) and from other parts of the olfactory pathway.

In collaborative experiments with the groups of Drs. John Hildebrand and Alan Nighorn, we have extended these studies to include examination of how male-specific olfactory receptor axons find their unique targets in the antennal lobe, taking particular advantage of the ability to transplant developing antennae between sexes. Further, in collaboration with investigators at other universities, we are exploring how adhesion molecules, present on subsets of olfactory receptor axons, help to guide the axons to their specific targets; we are particularly interested in whether expression of adhesion molecules is influenced by neuron-glia interactions.

Recently, in collaboration with Dr. Konrad Zinsmaier, we have begun to use the simpler olfactory system of Drosophila for molecular genetic investigations of neuron-glia interactions that are similar to those we have explored in Manduca.

In the long run, we hope to understand the intercellular interactions between developing receptor neurons, their target neurons in the brain, and glial cells at a molecular level. We expect that the knowledge we gain will offer insights into intercellular influences in less accessible developing mammalian sensory systems.

Function of olfactory glomeruli. A separate line of experiments addresses the functional architecture of olfactory glomeruli. Our long-standing collaboration with Dr. John Hildebrand has revealed aspects of the synaptic organization of neurons in the mature antennal lobe of Manduca, and a collaboration with Drs. Ed Arbas and Mark Willis revealed that glomerular architecture is not necessary for odor-modulated flight behavior.

In collaboration with Drs. Timothy Secomb and Anita Goriely, we have developed mathematical models, based on data from the Manduca antennal system, of ionic diffusion within mature glomeruli and across the glial boundaries between glomeruli. From these models, we learned that the glial borders of glomeruli are likely to limit the diffusion of potassium ions sufficiently to have a substantial impact on electrical activity within activated glomeruli. Again, the goal is to use the experimental advantages and our detailed knowledge of the moth antennal system to shed light on the organization of olfactory systems in general.