RT Journal Article
SR Electronic
T1 Cellular Diversity in Human Subgenual Anterior Cingulate and Dorsolateral Prefrontal Cortex by Single-Nucleus RNA-Sequencing
JF The Journal of Neuroscience
JO J. Neurosci.
FD Society for Neuroscience
SP 3582
OP 3597
DO 10.1523/JNEUROSCI.0830-22.2023
VO 43
IS 19
A1 Billy Kim
A1 Dowon Kim
A1 Anton Schulmann
A1 Yash Patel
A1 Carolina Caban-Rivera
A1 Paul Kim
A1 Ananya Jambhale
A1 Kory R. Johnson
A1 Ningping Feng
A1 Qing Xu
A1 Sun Jung Kang
A1 Ajeet Mandal
A1 Michael Kelly
A1 Nirmala Akula
A1 Francis J. McMahon
A1 Barbara Lipska
A1 Stefano Marenco
A1 Pavan K. Auluck
YR 2023
UL http://www.jneurosci.org/content/43/19/3582.abstract
AB Regional cellular heterogeneity is a fundamental feature of the human neocortex; however, details of this heterogeneity 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 psychiatric 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 considerable variability across brain regions. Excitatory cell subclasses also exhibited greater within-class transcriptional differences 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 transcriptional 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.SIGNIFICANCE STATEMENT Dysfunction of the subgenual anterior cingulate cortex has been implicated in mood disorders, particularly major depressive disorder, and the dorsolateral PFC, a subsection of the PFC involved in executive functioning, has been implicated in schizophrenia. Understanding the cellular composition of these regions is critical to elucidating the neurobiology underlying psychiatric and neurologic disorders. We studied cell type diversity of the subgenual anterior cingulate cortex and dorsolateral PFC of humans with no neuropsychiatric illness using a clustering analysis of single-nuclei RNA-sequencing data. Defining the transcriptomic profile of cellular subpopulations in these cortical regions is a first step to demystifying the cellular and molecular pathways involved in psychiatric disorders.