Sex and cell-specific gene expression in corticolimbic brain regions associated with psychiatric disorders revealed by bulk and single-nuclei RNA sequencingResearch in context
Eamon Fitzgerald,
Danusa Mar Arcego,
Mo Jun Shen,
Nicholas O'Toole,
Xianglan Wen,
Corina Nagy,
Sara Mostafavi,
Kelly Craig,
Patricia Pelufo Silveira,
Nirmala Arul Rayan,
Josie Diorio,
Michael J. Meaney,
Tie-Yuan Zhang
Affiliations
Eamon Fitzgerald
Douglas Mental Health University Institute, Department of Psychiatry, McGill University, Montréal, H4H 1R3, Canada; Ludmer Centre for Neuroinformatics and Mental Health, McGill University, Montréal, H4H 1R3, Canada
Danusa Mar Arcego
Douglas Mental Health University Institute, Department of Psychiatry, McGill University, Montréal, H4H 1R3, Canada; Ludmer Centre for Neuroinformatics and Mental Health, McGill University, Montréal, H4H 1R3, Canada
Mo Jun Shen
Yong Loo Lin School of Medicine, National University of Singapore, Singapore
Nicholas O'Toole
Douglas Mental Health University Institute, Department of Psychiatry, McGill University, Montréal, H4H 1R3, Canada; Ludmer Centre for Neuroinformatics and Mental Health, McGill University, Montréal, H4H 1R3, Canada
Xianglan Wen
Douglas Mental Health University Institute, Department of Psychiatry, McGill University, Montréal, H4H 1R3, Canada; Ludmer Centre for Neuroinformatics and Mental Health, McGill University, Montréal, H4H 1R3, Canada
Corina Nagy
Douglas Mental Health University Institute, Department of Psychiatry, McGill University, Montréal, H4H 1R3, Canada
Sara Mostafavi
Paul G. Allen School of Computer Science and Engineering, University of Washington, 185 E Stevens Way NE, Seattle, WA 9819, USA
Kelly Craig
Douglas Mental Health University Institute, Department of Psychiatry, McGill University, Montréal, H4H 1R3, Canada
Patricia Pelufo Silveira
Douglas Mental Health University Institute, Department of Psychiatry, McGill University, Montréal, H4H 1R3, Canada; Ludmer Centre for Neuroinformatics and Mental Health, McGill University, Montréal, H4H 1R3, Canada; Yong Loo Lin School of Medicine, National University of Singapore, Singapore
Nirmala Arul Rayan
Translational Neuroscience Program, Singapore Institute for Clinical Sciences and Brain – Body Initiative, Agency for Science, Technology and Research (A∗STAR), Singapore
Josie Diorio
Douglas Mental Health University Institute, Department of Psychiatry, McGill University, Montréal, H4H 1R3, Canada
Michael J. Meaney
Douglas Mental Health University Institute, Department of Psychiatry, McGill University, Montréal, H4H 1R3, Canada; Ludmer Centre for Neuroinformatics and Mental Health, McGill University, Montréal, H4H 1R3, Canada; Translational Neuroscience Program, Singapore Institute for Clinical Sciences and Brain – Body Initiative, Agency for Science, Technology and Research (A∗STAR), Singapore; Yong Loo Lin School of Medicine, National University of Singapore, Singapore
Tie-Yuan Zhang
Douglas Mental Health University Institute, Department of Psychiatry, McGill University, Montréal, H4H 1R3, Canada; Ludmer Centre for Neuroinformatics and Mental Health, McGill University, Montréal, H4H 1R3, Canada; Corresponding author. Douglas Mental Health University Institute, Department of Psychiatry, McGill University, Montréal H4H 1R3, Canada.
Summary: Background: There are sex-specific differences in the prevalence, symptomology and course of psychiatric disorders. However, preclinical models have primarily used males, such that the molecular mechanisms underlying sex-specific differences in psychiatric disorders are not well established. Methods: In this study, we compared transcriptome-wide gene expression profiles in male and female rats within the corticolimbic system, including the cingulate cortex, nucleus accumbens medial shell (NAcS), ventral dentate gyrus and the basolateral amygdala (n = 22–24 per group/region). Findings: We found over 3000 differentially expressed genes (DEGs) in the NAcS between males and females. Of these DEGs in the NAcS, 303 showed sex-dependent conservation DEGs in humans and were significantly enriched for gene ontology terms related to blood vessel morphogenesis and regulation of cell migration. Single nuclei RNA sequencing in the NAcS of male and female rats identified widespread sex-dependent expression, with genes upregulated in females showing a notable enrichment for synaptic function. Female upregulated genes in astrocytes, Drd3+MSNs and oligodendrocyte were also enriched in several psychiatric genome-wide association studies (GWAS). Interpretation: Our data provide comprehensive evidence of sex- and cell-specific molecular profiles in the NAcS. Importantly these differences associate with anxiety, bipolar disorder, schizophrenia, and cross-disorder, suggesting an intrinsic molecular basis for sex-based differences in psychiatric disorders that strongly implicates the NAcS. Funding: This work was supported by funding from the Hope for Depression Research Foundation (MJM).
