The functional architecture of the nervous system is usually thought of in terms of groups of neurons with similar functions being clustered together. However, groups of synaptic connections with similar functions also cluster together resulting in a fine-scale (1-10 ?m) functional architecture of nervous tissue. The significance of this fine-scale microcircuitry has been difficult to asses because it can involve dozens of neurons computing signals that are not readily detectable at the level of neuronal cell bodies. Here we propose an approach to studying developmental and functional principles of local microcircuits in the mouse visual thalamus. In the dorsal lateral geniculate nucleus (dLGN), axons from the retina (RGCs) form glia encapsulated clusters of synapses (glomeruli) with thalamocortical relay cells and inhibitory neurons. The functional significance of these local microcircuits is unknown. Based on the diverse patterns of glomerular connectivity we observed in our previous studies of mouse dLGN, we believe these microcircuits are preforming visual-channel-specific computations ranging from simple relay of signals to complex feature detection. We also hypothesize that, central to the organization of these microcircuits, is the use of developmental retinal activity to group functionally related RGCs and inhibitory neurites together in the same glomeruli. Our first step in testing the above hypotheses is to create a detailed mapping of the development of mouse dLGN glomerular microcircuits using serial section electron microscopy that will reveal which cell types initiate glomerulus formation and which aspects of the microcircuit?s connectivity appear during activity dependent synaptic remodeling. We will then test whether visual deprivation or transgenic silencing of subsets of RGC inputs alters the grouping together of neurites or the specificity with which they form synapses. The results of these developmental studies will reveal the extent to which dLGN microcircuit structure is the result of visual experience. We will then probe the function of dLGN glomeruli by first recording the response properties of thalamocortical cells and then reconstructing the glomerular microcircuitry of those same neurons with electron microscopy. By matching receptive field properties to their microcircuit configurations, we will learn whether different glomerular types are specific to different channels of visual processing and will gain insight into the computations likely to be executed by different local microcircuits. We will next use optogenetic stimulation of RGCs to determine how different glomerular configurations integrate signals from converging inputs. The proposed experiments will reveal the origin, organization and function of the fine-scale microcircuitry of an important model system for vision and circuit development.

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One of the biggest weaknesses in our understanding of the nervous system is at the level of local microcircuits; clusters of functionally related synapses that shape the responses of individual dendrites. We propose to study the development and function of the local microcircuitry (synaptic glomeruli) of the mouse visual thalamus. By combining cutting-edge three-dimensional electron microscopy with functional characterization and activity manipulation we will test whether developmental retinal activity shapes the local synaptic organization of the visual thalamus into subcellular feature detectors.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
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Neurotransporters, Receptors, and Calcium Signaling Study Section (NTRC)
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Greenwell, Thomas
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Washington University
Schools of Medicine
Saint Louis
United States
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