Mesoscale molecular architecture of the human striatum across cell types and lifespan

The human striatum is a central hub for diverse motor, cognitive, and affective behaviors, yet it lacks obvious cytoarchitectural boundaries defining functional territories. Here, we uncover a robust and molecularly defined mesoscale architecture in the human striatum. Using Slide-tags, a scalable single-nucleus spatial transcriptomics technology, we profiled 1.1 million cells across the striatum of 19 postmortem donors. Our data uncover a natural subdivision into six zones, each defined by distinct medium spiny neuron (MSN) populations and coordinated neuron-astrocyte signaling. Dorsal zone MSNs exhibit higher expression of synaptic remodeling and plasticity genes, while ventral zones are enriched for semaphorin, chaperone, and hedgehog signaling. Imputing these identities onto a larger 131-donor RNA-seq cohort, we find dorsal zones show greater age-related transcriptional changes, and spatial zonation attenuates with age. This atlas provides a mesoscale molecular definition of striatal anatomy, linking cell identity to functional specialization and aging susceptibility.