Genetic Determinants of Local Circuit Organization

Yale University, New Haven CT

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Abstract

[unreadable] DESCRIPTION (provided by applicant): Progress in understanding the mechanisms that underlie the highly specific targeting of olfactory sensory neuron axons to olfactory bulb glomeruli has advanced significantly in the past decade. As a consequence, our understanding of functional representation, odor coding, within the olfactory bulb continues to undergo refinement. In stark contrast to our progress in understanding of how axon targeting contributes to functionally defined domains in the olfactory bulb, our understanding of the mechanisms underlying the spatial organization of their dendritic targets, mitral cells, is almost non-existent. It is clearly essential that for interpretable neuronal signaling to occur, the targeting and arborization of mitral cell dendrites must be correct. Not only is it necessary for the apical dendrites to correctly target a specific giomerulus, the secondary dendrites as well must be appropriately distributed within the deeper sublamina of the external plexiform layer. Although direct evidence has not been reported, it seems plausible that the targeting and arborization of the apical and lateral dendrites utiiize different mechanisms. As a first step toward understanding the mechanisms that may influence these processes we propose a series of hypotheses and experiments that build on our prior and ongoing studies of OSN axon development and targeting. We propose three overall aims: 1) To test the hypothesis that in mice the spatio-temporal differentiation of mitral cell dendrites varies across the zones of the olfactory bulb; 2) To test the hypothesis that candidate molecules we have identified are differentially expressed by mitral cells, or within the external plexiform and glomerular layers, during dendritic differentiation; 3) To test the hypothesis that changes in functional activity can influence the specificity with which mitral cell dendrites target specific glomeruti. The proposed studies build on both our own progress over the past several years as well as that of other labs and should provide a more complete picture of the critical interface between sensory axons and their dendritic targets in the olfactory bulb. Because diseases such as Kallman's involve perturbation of this primary pathway, the results are likely to be important for understanding the mechanisms mediating the altered migration of mitral cells in Kallman's disorder.