This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. We believe that the structure of the cerebellar glomerulus, in particular the glial sheath that envelops the granule cell dendrites and the mossy fiber terminal, leads to the isolation of the extracellular (ec) space outside the glomerulus from the ec space inside the glomerulus. We believe that such geometry would limit access of ec Ca++ into the glomerulus, allowing for conditions where the concentration of Ca++ inside the glomerulus is determined mainly by the activity of the Ca++ channels and pumps localized within the glial ensheathment. We recently proposed a new ICA-like learning rule, which requires that each granule cell be able to measure the sum total activities of other granule cells whose dendrites are localized within the same glomerulus. Since cells have a variety of mechanisms that can directly or indirectly determine the levels of ec Ca++, and since many cellular processes depend on Ca++, we believe that granule cells would have access to the sum total activity through measuring the levels of ec Ca++. In order to more fully appreciate the geometry of the cerebellar glomerulus, and in order to perform more quantitatively correct simulations, we propose to perform EM tomography on several glomeruli. The project will involve obtaining a 3D reconstruction of the cerebellar glomerulus. This reconstruction will be used in MCell simulations to study diffusion of extracellular Ca++ inside the glomerulus. Some of our recent simulations within a stylized cerebellar glomerulus demonstrated that there is a significant difference in the ec Ca++ profiles in simulations where the glial ensheathment is complete vs. simulations with small gaps into the glial ensheathment (1% of the surface area of the glial sheath). In full ensheathment simulations, the drop in ec Ca++ persisted for the entire duration of granule cell activity. In partial ensheathment simulations, there was no persisting drop in ec Ca++. This finding motivated us to take several tomograms of the glial sheath.
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