Spatial patterning of transcriptional and regulatory programs in the primate subcortex

Abstract Mammalian brain cell identity is shaped by intrinsic factors and external context. We present a spatially resolved transcriptomic and gene regulatory atlas of cell types across all subcortical regions in a primate, the common marmoset. Dense sampling and cross-species integration revealed spatially precise neuronal assemblies, including in complex midbrain and diencephalic structures. Chromatin accessibility and transcriptional identity are spatially tuned within and across subcortical structures; spatial gradients within hippocampal subfields are orchestrated by graded transcription factors acting through graded enhancers. The primate-expanded thalamic GABAergic population shares transcriptional and regulatory syntax with conserved midbrain populations, reflecting an evolutionary adaptation compared with rodents. Similar regional expression across cell types can arise by distinct regulatory architectures, as for telencephalic astrocytes and neurons. Conversely, distant cell types can share regulatory programs despite divergent identities: striatal GABAergic medium spiny neurons and telencephalic glutamatergic neurons share a postsynaptic regulatory program despite divergent lineage, region, and neurotransmitter identity. Competing Interest Statement H.Z. is on the scientific advisory board of MapLight Therapeutics, Inc. The other authors declare no competing interests. Footnotes ↵8 Lead Contact Figure 4, 5, 6 revised; author affiliations updated.