The olfactory system of mammals is thought to be capable of distinguishing among thousands of odors. Subtle differences in the molecular structure of some odors can lead to a dramatic change in odor perception. It is now known that the first step in olfactory discrimination involves the interaction of odors with odorant receptors on sensory neurons in the nasal cavity. How the brain determines which receptors have been activated remains a mystery. However, as in most sensory systems, the olfactory system probably uses defined spatial patterns of receptor activation to make connections in the brain. The overall objectives of this proposal are to determine the identity, structure and function of molecules that participate in the spatial organization of connections between the olfactory sensory neurons in the nasal cavity and their axon termination sites in the olfactory bulb. The investigators have proposed three different mechanisms that may be important in the formation of specific olfactory connections, and during the continual neural renewal that occurs in the olfactory system. 1) A coarse topographic map divides the main olfactory system into at least four compartments and the accessory olfactory system into two compartments. They will analyze the determinants of compartmentalization by isolating and characterizing the molecules that restrict the termination sites of axon subsets. The ability of these molecules to influence axon trajectories will be tested on primary cell cultures of olfactory neurons. The structural determinants of compartmentalization will be investigated using light and electron microscopy in conjunction with immunocytochemical studies of intact olfactory bulbs. 2) There is a spatial and temporal pattern of expression of axonal and extracellular matrix adhesion molecules that provides a basis for subsets of axons to grow along designated pathways. One of these adhesion mechanisms in the olfactory system utilizes an endogenous carbohydrate binding protein, L-14, that is capable of inducing axon-axon and axon-matrix interactions. The investigators will analyze the role of this adhesion mechanism during development of olfactory connections, using mutant mice deficient in the extracellular matrix glycoprotein merosin, a key component of this adhesion mechanism. 3) Neuronal activity plays a role in stabilizing specific connections, leading to refinement of a coarse olfactory map. They will analyze the effects of changing neuronal activity through sensory deprivation on the precision of connections made by a small group of chemically defined neurons. The developmental relationship of the olfactory system and the forebrain is clinically significant. X-linked Kallmann syndrome is caused by a defect in the development of the olfactory system. These studies will provide insight into the molecular and cellular basis of olfactory structure and function and will illuminate specific mechanisms of axonal growth in normal and abnormal nervous systems.
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