Overlapping yet distinct spatiomolecular profiles across mood disorders and biological sex in the human prefrontal cortex
- 1Lieber Institute for Brain Development
Abstract
Major depressive disorder (MDD) and bipolar disorder (BD) exhibit both overlapping and distinct clinical features, including sex differences in prevalence and symptomatology, but how these similarities and differences are reflected at the molecular and cellular level in the human brain remains poorly understood. Here, we applied spatial transcriptomics to the human dorsolateral prefrontal cortex from individuals with MDD, BD, and neurotypical controls to resolve molecular programs associated with diagnosis and biological sex. Our analysis revealed sex- and diagnosis-specific differences across white matter, the neurovascular unit (NVU), and neuronal compartments. Within white matter, we identified female-specific survival-response programs shared in both MDD and BD, and divergent myelin-related gene expression patterns across disorders (CLDN11, CNDP1). Within the NVU, transcriptional evidence of impaired vascular integrity was accompanied by astrocytic response profiles in females with MDD and males with BD, with inflammatory responses further evident in females with MDD (IFITM3, CEBPD, IL1R1). In donors with BD of both sexes and in females with MDD, inhibitory neurons exhibited impaired neuropeptide expression (SST, CORT, CRH). Integration with donor genotype information highlighted that genetic risk for mood disorders influences MAPK3 expression, implicating altered ERK signaling, which was further supported by disorder-associated changes in Ras/MEK/ERK pathway components in neurons (MAPK3, DUSP6, RASD1, ELK1). Together, these findings reveal coordinated, cell type- and spatial domain-specific molecular programs that distinguish shared and disorder-specific transcriptomic changes across mood disorders in a sex-dependent manner.
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BibTeX
@misc{thompson2026overlapping,
title = {{Overlapping yet distinct spatiomolecular profiles across mood disorders and biological sex in the human prefrontal cortex}},
author = {J. R. Thompson and S. Oh and S. E. Maguire and S. V. Bach and B. J. Mulvey and G. Pertea and M. R. Abramson and R. A. Miller and S. H. Kwon and M. Tippani and M. R. Valentine and A. Deep-Soboslay and Y. Du and A. B. Nguyen and J. E. Kleinman and K. R. Maynard and T. M. Hyde and S. Han and L. Collado-Torres and K. Martinowich and S. C. Hicks and S. C. Page},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.22.761067},
url = {https://www.biorxiv.org/content/10.64898/2026.10.22.761067v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Overlapping yet distinct spatiomolecular profiles across mood disorders and biological sex in the human prefrontal cortex
AU - J. R. Thompson
AU - S. Oh
AU - S. E. Maguire
AU - S. V. Bach
AU - B. J. Mulvey
AU - G. Pertea
AU - M. R. Abramson
AU - R. A. Miller
AU - S. H. Kwon
AU - M. Tippani
AU - M. R. Valentine
AU - A. Deep-Soboslay
AU - Y. Du
AU - A. B. Nguyen
AU - J. E. Kleinman
AU - K. R. Maynard
AU - T. M. Hyde
AU - S. Han
AU - L. Collado-Torres
AU - K. Martinowich
AU - S. C. Hicks
AU - S. C. Page
PY - 2026
DA - 2026/10/22
PB - bioRxiv
DO - 10.64898/2026.10.22.761067
UR - https://www.biorxiv.org/content/10.64898/2026.10.22.761067v1
AB - Major depressive disorder (MDD) and bipolar disorder (BD) exhibit both overlapping and distinct clinical features, including sex differences in prevalence and symptomatology, but how these similarities and differences are reflected at the molecular and cellular level in the human brain remains poorly understood. Here, we applied spatial transcriptomics to the human dorsolateral prefrontal cortex from individuals with MDD, BD, and neurotypical controls to resolve molecular programs associated with diagnosis and biological sex. Our analysis revealed sex- and diagnosis-specific differences across white matter, the neurovascular unit (NVU), and neuronal compartments. Within white matter, we identified female-specific survival-response programs shared in both MDD and BD, and divergent myelin-related gene expression patterns across disorders (CLDN11, CNDP1). Within the NVU, transcriptional evidence of impaired vascular integrity was accompanied by astrocytic response profiles in females with MDD and males with BD, with inflammatory responses further evident in females with MDD (IFITM3, CEBPD, IL1R1). In donors with BD of both sexes and in females with MDD, inhibitory neurons exhibited impaired neuropeptide expression (SST, CORT, CRH). Integration with donor genotype information highlighted that genetic risk for mood disorders influences MAPK3 expression, implicating altered ERK signaling, which was further supported by disorder-associated changes in Ras/MEK/ERK pathway components in neurons (MAPK3, DUSP6, RASD1, ELK1). Together, these findings reveal coordinated, cell type- and spatial domain-specific molecular programs that distinguish shared and disorder-specific transcriptomic changes across mood disorders in a sex-dependent manner.
ER -