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Single-nucleus transcriptomics of the prefrontal cortex in major depressive disorder implicates oligodendrocyte precursor cells and excitatory neurons

Abstract

Major depressive disorder (MDD) has an enormous impact on global disease burden, affecting millions of people worldwide and ranking as a leading cause of disability for almost three decades. Past molecular studies of MDD employed bulk homogenates of postmortem brain tissue, which obscures gene expression changes within individual cell types. Here we used single-nucleus transcriptomics to examine ~80,000 nuclei from the dorsolateral prefrontal cortex of male individuals with MDD (n = 17) and of healthy controls (n = 17). We identified 26 cellular clusters, and over 60% of these showed differential gene expression between groups. We found that the greatest dysregulation occurred in deep layer excitatory neurons and immature oligodendrocyte precursor cells (OPCs), and these contributed almost half (47%) of all changes in gene expression. These results highlight the importance of dissecting cell-type-specific contributions to the disease and offer opportunities to identify new avenues of research and novel targets for treatment.

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Fig. 1: Experimental flow.
Fig. 2: Identification of cell types.
Fig. 3: DEGs.
Fig. 4: Differential expression and biological associations.
Fig. 5: WGCNA.
Fig. 6: Contributions of OPC2 and Ex7.

Data availability

Raw sequencing data, annotated gene–barcode matrix and lists of cells used for differential gene expression analysis are accessible on GEO using the accession number GSE144136. RNAScope and high-throughput qPCR data are available upon request.

Code availability

A sample custom R script (Supplementary_R_Script_1.R) used for analyzing high-throughput qPCR data is provided and an R script used to test the statistical significance of CCInx interactions is provided (Supplementary_R_Script_2.R) along with this paper.

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Acknowledgements

G.T. holds a Canada Research Chair (Tier 1) and a NARSAD Distinguished Investigator Award. He is supported by grants from the Canadian Institute of Health Research (CIHR) (FDN148374 and EGM141899). We acknowledge the expert help of the Douglas–Bell Canada Brain Bank staff (J. Prud’homme, M. Bouchouka and A. Baccichet), and H. Djambazian at the MUGQIC. The work was also supported by CFI projects 32557 and 33408 (to J.R.). The Douglas–Bell Canada Brain Bank is supported in part by funding from the Canada First Research Excellence Fund, awarded to McGill University for the Healthy Brains for Healthy Lives project, and from the Fonds de recherche du Québec–Santé (FRQS) through the Quebec Network on Suicide, Mood Disorders and Related Disorders. The present study used the services of the Molecular and Cellular Microscopy Platform (MCMP) at the Douglas Institute.

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Authors

Contributions

C.N. conceptualized, performed experiments and wrote the manuscript. M.M. performed experiments, bioinformatics and wrote the manuscript. A.T., V.Y., M.A.D. and Y.C.W. performed experiments and wrote the manuscript. M.S., K.P., J.-F.T., S.J.T. and P.P. contributed to data analyses and reviewed the manuscript. N.M. contributed to tissue processing, data interpretation and manuscript preparation. J.R. provided technical single-cell expertise and experimental support, and aided in manuscript preparation. G.T. provided general oversight of the study, including in experimental design, data interpretation and manuscript preparation.

Corresponding author

Correspondence to Gustavo Turecki.

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The authors declare no competing interests.

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Peer review information Nature Neuroscience thanks Ronald Duman (deceased), Matthew Girgenti, and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Supplementary information

Supplementary Information

Supplementary Methods and Supplementary Figs. 1–14.

Reporting Summary

Supplementary Tables

Supplementary Tables 1–52.

Supplementary Software

Supplementart_R_Script_1.R for analyzing high-throughput qPCR data and Supplementary_R_Script_2.R for generating P values for CCInx interactions.

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Nagy, C., Maitra, M., Tanti, A. et al. Single-nucleus transcriptomics of the prefrontal cortex in major depressive disorder implicates oligodendrocyte precursor cells and excitatory neurons. Nat Neurosci 23, 771–781 (2020). https://doi.org/10.1038/s41593-020-0621-y

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