Despite its well-known capacity for regeneration, damage to the peripheral olfactory system causes permanent olfactory dysfunction in selected clinical populations, which includes patients that become dysosmic after upper respiratory infection. Permanent replacement of olfactory by respiratory epithelium occurs after injury to the periphery and is a candidate mechanism for producing dyosmia. Less is known about the effect of peripheral destruction on the accuracy of reinnervation of the bulb by neurons that are newly generated during reconstitution of the epithelium. The principal investigator is proposing three specific aims to extend the principal investigator's and his colleagues' previous work on regeneration and development of the rat olfactory system. First, the principal investigator and colleagues will assess the distribution of distinct subsets of olfactory neurons (defined by the odorant receptor they express or by their expression of specific polysaccharide and peptide antigens) across the epithelium after the cycle of MeBr-induced destruction and regeneration is completed. The proposed experiments will demonstrate whether or not disordered expression of odorant receptors occurs in the periphery and contributes to dysfunction after reversible damage to the epithelium. Second, the principal and colleagues will assess the accuracy with which two subsets of neurons selectively reinnervate their defined targets among the set of """"""""necklace"""""""" glomeruli at the posterior margin of the glomerular sheet. Their preliminary evidence indicates that destruction of greater than 95% of the epithelium prevents specific reinnervation of both necklace and non-necklace glomeruli, despite the substantial restoration of input to the bulb as a whole after lesion; in contrast, slightly less severe damage allows the target glomeruli to be reinnervated correctly. Third, the principal investigator and colleagues will test the hypothesis emerging from these results, that targeting of reinnervating fibers in the adult requires the sparing of some fibers of the same type to act as guides directing the newly-growing axons to the correct glomerulus. The principal investigator and colleagues will make lesions of varying severity, and correlate the extent of sparing neurons that were connected to the target glomerulus before lesion with the accuracy and specificity of reinnervation. Successful completion of these aims will document the importance of fasciculation along pre-existing axons as a cell biological mechanism subserving targeted regrowth in the adult olfactory system. The results will also significantly improve our understanding of the process of regeneration in the primary olfactory projection and the reasons for its not infrequent failure in humans.
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