The role of a neuronal cell type in the generation of perception and behavior depends on three major factors. These are: the sources of synaptic input, how synaptic inputs are integrated to give rise to spiking output, and the population of neurons that receive the output. This Research Segment (Segment 2 - Anatomy. Linking Cell Types Defined by Epigenetic Profiling to Neural Circuits) will link putative cell types defined by epigenetic profiling (Segment 1) to their inputs and outputs. This knowledge will link genetically targetable cell types to circuits, allowing future manipulative studies to assess their functional roles within intact neural circuits. Nearly all brain regions, including those that will be dissected and subject to epigenetic profiling in Segment 1, either contain multiple intermingled cell types or they are composed of nuclei too small to be selectively dissected. However, because individual nuclei or intermingled cell types typically project axons to unique distant brain structures, they can be identified based on their axonal outputs. Efforts here will generate epigenetic profiles of neurons with known projections, to link profiled populations to their outputs. Monosynaptic rabies tracing will then be used to link inputs across the entire brain to cell types defined based on their outputs. Finally, putative cell type specific enhancers, whose ability to drive cell type specific expression will be initially evaluated in Research Segment 4, will be further characterized. This includes further characterization of the cell types that drive expression from identified enhancers using anatomical analysis of their distributions within the brain, as well as the patterns of projections of their axonal arbors. The ability to use enhancers to target cell types for selective gene expression and anatomical characterization of the targeted cell types will make available the full arsenal of molecular and genetic tools for interrogating the functional roles of these cell types within intact neural circuits.
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