GENETIC DETERMINANTS OF LOCAL CIRCUIT ORGANIZATION

Yale University, New Haven CT

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Abstract

The continuing objective of this proposal is to identify and characterize fundamental mechanisms that underlie the organization of synaptic circuits in the central nervous system. Of particular interest is how synapses may segregate into local versus projection circuits and thus support the parcellation of the nervous system into delineated functional domains. Durin the period of support we continued to develop the olfactory system as an efficacious and widely applicable model for addressing these questions. The current proposal builds on our prior observations and seeks to test specific hypotheses regarding the organization of olfactory bulb glomeruli and the molecular determinanants of glomerular target by olfatory receptor cell axons. The potential mechanisms involved in pathfinding by olfactory receptor cell (ORC) axons remains controversial. While a number of potentially important molecules have been identified, they have not been tested for their ability to influence the behavior of olfactory receptor cell axons. A similarly controversial area of much interest is the olfactory bulb glomerulus, the site of primary afferent terminations in the olfactory bulb. While some recent evidence suggests that the olfactory receptor cell axons converging on individual glomeruli are homogeneous, additional lines of evidence suggest that several molecularly defined subtypes can innervate a single glomerulus. Thus, we have two primary lines of investigation that are the source of continuing debate. First, mechanisms, of axons guidance and second, intrinsic organization of their target area. To address these controversies we propose to test the following hypotheses:1 ) A differential distribution of glial processes in the inner and outer sublaminae of the olfactory nerve layer contributes to the fasciculation of ORC axons; 2) The molecular specificity of ORC axons becomes homogeneous within fascicles as they approach their target glomerulus; 3) Extracellular matrix molecules in the olfactory nerve and glomerular layers differentially influence growth and pathfinding by ORC axons; 4) ORC axons within specific subglomerular compartments share molecular specificity and synaptic targets; 5) The distribution of dendritic targets within glomeruli mirrors the subcompartmental distribution seen in ORC axons; 6) The distribution of synaptic circuits within glomeruli is non-uniform and includes the segregation of dendrodendritic local circuits from axodendritic primary afferent circuits. Together, these analyses will utilize light and electron microscopic localization of antibody probes, tissue culture and measures of neuronal activity in response to specific stimulants. The results will be widely applicable to diseases of the olfactory system and more broadly to diseases associated with developmental anomalies.