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Genetic Induction of the Olfactory Bulb and Regulation of Olfactory Axon Guidepost Cells

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The proposed research focuses on development of the olfactory bulb (OB), the most rostral division of cerebral cortex. The OB has a single layer of mitral cell projection neurons. Mitral cells receive olfactory information from olfactory receptor neurons, and send their axons along one major output pathway, the lateral olfactory tract (LOT), directed in part by guidepost cells, called ?lot? cells. The LOT carries olfactory input to olfactory cortex, and to a variety of brain structures concerned with motor behavior, memory and mood. The OB develops adjacent to an embryonic source of Fibroblast Growth Factors (FGFs) in the rostral telencephalon. In Preliminary Studies, introducing FGF8 ectopically into the lateral cortical primordium (CP) created OB-like structures (OBLSs) in the lateral wall of the cerebral hemisphere. An FGF8-induced OBLS was composed of mitral cells, but also attracted interneurons characteristic of the OB. The highly ectopic mitral cells sent compact axon bundles (tributary LOTs or ?tLOTS?) ventrally to join the LOT. Meanwhile, lot guidepost cells migrated rostrally from their source at the telencephalic/diencephalic boundary to surround the OB, diverging from their main pathway to surround each OBLS as well. Axons in the tLOTs grew out to the main LOT through funnels of ectopic lot cells. These preliminary findings prompt Aims 1 and 2 of the present proposal, to determine the role of FGF8 in inducing the OB. In Aim 3, the function of lot cells in guiding axons of the LOT will be explored, testing, in particular, the hypothesis that the OB itself guides the migration of lot cells. These studies should provide a wealth of new information on the development of the OB and its major output pathway. Reduction or loss of the sense of smell in humans causes depression, anxiety and diminished pleasure in life. Understanding how the OB is induced and how it communicates with the rest of the brain is a topic of basic and clinical significance. Notably, the combination of an underestimated frequency of olfactory dysfunction in the human population, and the rarity with which clinicians image central olfactory structures in anosmic patients, suggests the role of central developmental defects may be greatly underappreciated. Investigation of the normal development of the OB therefore has the potential to drive new discoveries concerning OB development and function in human syndromes.
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