Human Basal Ganglia Astrocyte Diversity Reflects Evolutionary and Circuit-Level Specialization

Astrocytes play critical roles in neuronal circuit function, yet their diversity and regional specialization in the human basal ganglia (BG) remain poorly defined. Here, we construct a multimodal atlas of BG astrocytes by integrating single nucleus multi-omic data (RNA expression and chromatin accessibility) with spatial transcriptomic profiling. We identify 21 transcriptionally distinct subtypes, which resolve into three major groups -- striatal gray matter, non-striatal gray matter, and white matter -- each marked by differential expression of neurotransmitter transporters and synapse-associated genes. These patterns reflect input circuit architecture rather than local neuronal identity, revealing a circuit-aligned mode of astrocyte specialization. Within the striatum, we uncover previously unrecognized dorsal and ventral subtypes, spatially segregated and supported by DNA methylation and 3D chromatin conformation (snm3C-seq) and histone modification (Paired-Tag) data. Comparative analysis with macaque and marmoset BG atlases, generated using matched profiling depth and modalities, revealed a human-specific astrocyte subtype enriched in the substantia nigra, characterized by elevated gliotransmission signatures and expression of genes linked to Parkinson's disease vulnerability. Finally, integration with whole-brain atlases positioned BG astrocytes within the broader spectrum of human astroglial specialization, defining a molecular landscape shaped by evolutionary and circuit-level pressures.

Data citation

No data citation listed

Funding agency

NIMH

Grant numbers

1U01MH114812, UM1MH130981

Access

open

License

CC BY 4.0