Dendritome Mapping Unveils Spatial Organization of Striatal D1/D2-Neuron Morphology

Abstract

Morphology is a cardinal feature of a neuron that mediates its functions, but profiling neuronal morphologies at scale remains a formidable challenge. Here we describe a generalizable pipeline for large-scale brainwide study of dendritic morphology of genetically-defined single neurons in the mouse brain. We generated a dataset of 3,762 3D-reconstructed and reference-atlas mapped striatal D1- and D2- medium spiny neurons (MSNs). Integrative morphometric analyses reveal distinct impacts of anatomical locations and D1/D2 genetic types on MSN morphologies. To analyze striatal regional features of MSN dendrites without prior anatomical constraints, we assigned MSNs to a lattice of cubic boxes in the reference brain atlas, and summarized morphometric representation ("eigen-morph") for each box and clustered boxes with shared morphometry. This analysis reveals 6 modules with characteristic dendritic features and spanning contiguous striatal territories, each receiving distinct corticostriatal inputs. Finally, we found aging confers robust dendritic length and branching defects in MSNs, while Huntington's disease (HD) mice exhibit selective length-related defects. Together, our study demonstrates a systems-biology approach to profile dendritic morphology of genetically-defined single-neurons; and defines novel striatal D1/D2-MSN morphological territories and aging- or HD-associated pathologies.