Abstract
Metabolic and functional alterations of neurons in the dorsolateral prefrontal cortex (dlPFC) are thought to contribute to impulsivity, which is a hallmark of addictive behaviors that underlie compulsive drug seeking and taking in humans. To determine if there is a transcriptional signature in dlPFC neurons of humans with cocaine use disorder, we performed total RNA-sequencing on neuronal nuclei isolated from post-mortem dlPFC of cocaine addicts and healthy controls. Our results point toward a transcriptional mechanism whereby cocaine alters specific gene networks in dlPFC neurons. In particular, we identified an AP-1 regulated transcriptional network in dlPFC neurons associated with cocaine use disorder that contains several differentially expressed hub genes. Several of these hub genes are GWAS hits for traits that might involve dysfunction of brain reward circuitry (Body-Mass Index, Obesity) or dlPFC (Bipolar disorder, Schizophrenia). Further study is warranted to determine their potential pathophysiological role in cocaine addiction.
Highlights
To address this, we performed total RNA-sequencing on fluorescent-activated cell sorting (FACS)-isolated dorsolateral prefrontal cortex (dlPFC) neuronal nuclei from humans who were chronic users of cocaine with severe patterns of use and from healthy controls
Cell type-specific total RNA-sequencing from human post-mortem dlPFC neurons
We performed total RNA-sequencing on dlPFC neuronal nuclei isolated from humans with chronic cocaine use disorder who died from cocaine intoxication and from healthy controls (Table 1) (Supplementary Table 1)
Summary
We performed total RNA-sequencing on fluorescent-activated cell sorting (FACS)-isolated dlPFC neuronal nuclei from humans who were chronic users of cocaine with severe patterns of use and from healthy controls. All cases selected for analysis met criteria for cocaine dependence with intoxication at autopsy (ICD-10 F14.22) and DSM-IV diagnostic criteria for cocaine abuse or dependence (replaced by cocaine use disorder in DSM-5). After we validated the cell type-specificity of our approach, we identified 883 differentially expressed transcripts in dlPFC neurons of cocaine addicts, several of which have known roles in neuroplasticity underlying drug addiction. We performed Weighted Gene Co-Expression Network Analysis (WGCNA) and identified a gene network in dlPFC neurons whose expression is altered in cocaine users compared to healthy controls. Our results corroborate previous studies identifying increased AP-1 mediated transcription in the brain after cocaine administration and provide an important translational step forward by showing these same signaling pathways are altered in neurons of human addicts
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