Cellular Diversity in Human Subgenual Anterior Cingulate and Dorsolateral Prefrontal Cortex by Single-Nucleus RNA-Sequencing

被引:2
作者
Kim, Billy [1 ]
Kim, Dowon [1 ]
Schulmann, Anton [2 ]
Patel, Yash [1 ]
Caban-Rivera, Carolina [1 ]
Kim, Paul [1 ]
Jambhale, Ananya [1 ]
Johnson, Kory R. [3 ]
Feng, Ningping [1 ]
Xu, Qing [1 ]
Kang, Sun Jung [4 ]
Mandal, Ajeet [1 ]
Kelly, Michael [5 ]
Akula, Nirmala [2 ]
McMahon, Francis J. [2 ]
Lipska, Barbara [1 ]
Marenco, Stefano [1 ]
Auluck, Pavan K. [1 ]
机构
[1] NIMH, Human Brain Collect Core, Intramural Res Program, Bethesda, MD 20892 USA
[2] NIMH, Human Genet Branch, Intramural Res Program, Bethesda, MD 20892 USA
[3] NINDS, Informat Technol & Bioinformat Program, Intramural Res Program, Bethesda, MD 20892 USA
[4] NIMH, Genet Epidemiol Res Branch, Intramural Res Program, Bethesda, MD 20892 USA
[5] Frederick Natl Lab Canc Res, Canc Res Technol Program, CCR Single Anal Facil, Bethesda, MD 20892 USA
关键词
cingulate; dorsolateral prefrontal cortex; RNA-seq; schizophrenia; single-nucleus; GENOME-WIDE ASSOCIATION; VON ECONOMO NEURONS; GENE-EXPRESSION; WORKING-MEMORY; HUMAN BRAIN; SCHIZOPHRENIA; SEQ; TRANSCRIPTOME; MOOD; NEUROPATHOLOGY;
D O I
10.1523/JNEUROSCI.0830-22.2023
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
Regional cellular heterogeneity is a fundamental feature of the human neocortex; however, details of this heterogene-ity are still undefined. We used single-nucleus RNA-sequencing to examine cell-specific transcriptional features in the dorsolateral PFC (DLPFC) and the subgenual anterior cingulate cortex (sgACC), regions implicated in major psychiat-ric disorders. Droplet-based nuclei-capture and library preparation were performed on replicate samples from 8 male donors without history of psychiatric or neurologic disorder. Unsupervised clustering identified major neural cell classes. Subsequent iterative clustering of neurons further revealed 20 excitatory and 22 inhibitory subclasses. Inhibitory cells were consistently more abundant in the sgACC and excitatory neuron subclusters exhibited consider-able variability across brain regions. Excitatory cell subclasses also exhibited greater within-class transcriptional dif-ferences between the two regions. We used these molecular definitions to determine which cell classes might be enriched in loci carrying a genetic signal in genome-wide association studies or for differentially expressed genes in mental illness. We found that the heritable signals of psychiatric disorders were enriched in neurons and that, while the gene expression changes detected in bulk-RNA-sequencing studies were dominated by glial cells, some alterations could be identified in specific classes of excitatory and inhibitory neurons. Intriguingly, only two excitatory cell classes exhibited concomitant region-specific enrichment for both genome-wide association study loci and transcrip-tional dysregulation. In sum, by detailing the molecular and cellular diversity of the DLPFC and sgACC, we were able to generate hypotheses on regional and cell-specific dysfunctions that may contribute to the development of mental illness.
引用
收藏
页码:3582 / 3597
页数:16
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