Multi-omic spatial mapping of the human habenula defines the molecular and anatomical organization of medial and lateral subregions
- 1Lieber Institute for Brain Development
Abstract
The habenula (Hb) is a small epithalamic midline structure critical for reward processing and mood regulation that is implicated in many complex brain disorders, including depression and addiction. The molecular anatomy of the Hb has been well-characterized in model organisms, but little is known about its organization in the human brain, including the transcriptomic and epigenetic signatures of spatially-organized lateral (LHb) and medial (MHb) cell types. Here, we generated a high resolution spatiomolecular map of the human Hb using both multiomic single nucleus sequencing (snMultiome) and spatially-resolved transcriptomics. We measured gene expression and chromatin accessibility across 4 MHb and 5 LHb neuronal cell types as defined by transcriptomic conservation with rodents and zebrafish. We identified cell type-specific molecular specializations related to GABAergic and glutamatergic signaling as well as regulatory relationships between open chromatin regions, transcription factors, and target genes associated with depression and addiction. High resolution spatial transcriptomics identified the anatomical location of heterogeneous LHb subpopulations, including two putative inhibitory populations in 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 delineated Hb cell types and spatial domains enriched in genes associated with genetic risk for psychiatric disorders, identifying the strongest enrichment in the MHb. Collectively, the generated data and analyses resolve the spatiomolecular organization of the human Hb and identify molecular-genetic associations with neuropsychiatric disease.
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BibTeX
@misc{montgomery2026multiomic,
title = {{Multi-omic spatial mapping of the human habenula defines the molecular and anatomical organization of medial and lateral subregions}},
author = {K. D. Montgomery and J. M. Werner and N. J. Eagles and C. Liu and C. S. Cardinault and S. V. Bach and A. Chandra and R. Zhang and S. E. Maguire and H. R. Divecha and A. Deep-Soboslay and R. A. Miller and L. A. Huuki-Myers and R. A. Bharadwaj and J. E. Kleinman and T. M. Hyde and B. S. Maher and L. Collado-Torres and K. R. Maynard},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.30.755667},
url = {https://www.biorxiv.org/content/10.64898/2026.09.30.755667v1},
note = {CC BY-NC},
}
RIS
TY - UNPB
TI - Multi-omic spatial mapping of the human habenula defines the molecular and anatomical organization of medial and lateral subregions
AU - K. D. Montgomery
AU - J. M. Werner
AU - N. J. Eagles
AU - C. Liu
AU - C. S. Cardinault
AU - S. V. Bach
AU - A. Chandra
AU - R. Zhang
AU - S. E. Maguire
AU - H. R. Divecha
AU - A. Deep-Soboslay
AU - R. A. Miller
AU - L. A. Huuki-Myers
AU - R. A. Bharadwaj
AU - J. E. Kleinman
AU - T. M. Hyde
AU - B. S. Maher
AU - L. Collado-Torres
AU - K. R. Maynard
PY - 2026
DA - 2026/09/30
PB - bioRxiv
DO - 10.64898/2026.09.30.755667
UR - https://www.biorxiv.org/content/10.64898/2026.09.30.755667v1
AB - The habenula (Hb) is a small epithalamic midline structure critical for reward processing and mood regulation that is implicated in many complex brain disorders, including depression and addiction. The molecular anatomy of the Hb has been well-characterized in model organisms, but little is known about its organization in the human brain, including the transcriptomic and epigenetic signatures of spatially-organized lateral (LHb) and medial (MHb) cell types. Here, we generated a high resolution spatiomolecular map of the human Hb using both multiomic single nucleus sequencing (snMultiome) and spatially-resolved transcriptomics. We measured gene expression and chromatin accessibility across 4 MHb and 5 LHb neuronal cell types as defined by transcriptomic conservation with rodents and zebrafish. We identified cell type-specific molecular specializations related to GABAergic and glutamatergic signaling as well as regulatory relationships between open chromatin regions, transcription factors, and target genes associated with depression and addiction. High resolution spatial transcriptomics identified the anatomical location of heterogeneous LHb subpopulations, including two putative inhibitory populations in 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 delineated Hb cell types and spatial domains enriched in genes associated with genetic risk for psychiatric disorders, identifying the strongest enrichment in the MHb. Collectively, the generated data and analyses resolve the spatiomolecular organization of the human Hb and identify molecular-genetic associations with neuropsychiatric disease.
ER -