Multi-omic spatial mapping of the human habenula reveals cell type-specific gene regulation across medial and lateral subregions

Dysregulation of the habenula (Hb), a small epithalamic midline structure critical for reward processing and mood, is implicated in neuropsychiatric disorders and addiction. The Hb has been extensively characterized in rodents and fish, but little is known about the molecular anatomy of the human Hb, especially the transcriptomic and epigenetic signatures of spatially-organized lateral (LHb) and medial (MHb) cell types. Here, we present a high resolution spatiomolecular map of the human Hb using multiomic single nucleus sequencing (snMultiome) and spatially-resolved transcriptomics. We measured gene expression and chromatin accessibility in individual nuclei across MHb and LHb cell types from 10 adult neurotypical control donors and defined cell type-specific regulatory relationships between transcription factors, target genes, and open chromatin regions. We performed high resolution spatial transcriptomics on a subset of the same donors and identified the anatomical location of heterogeneous LHb subpopulations, including two putative inhibitory populations located within the LHb. We further characterized cell-type relationships between Hb neurons and glial subtypes and predicted ligand-receptor interactions between LHb and MHb neurons. Finally, we identified Hb cell types and spatial domains enriched in genes associated with risk for neuropsychiatric disorders, including substance use disorders. Together, we present a landmark molecular neuroanatomical atlas of transcriptionally distinct human Hb cell-types that are conserved across species and enriched in genes associated with risk for brain disorders.

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