Gene Network Dysregulation in Dorsolateral Prefrontal Cortex Neurons of Humans with Cocaine Use Disorder

• Published in: Scientific reports Vol. 7; no. 1; pp. 5412 - 10
• Main Authors: Ribeiro, Efrain A., Scarpa, Joseph R., Garamszegi, Susanna P., Kasarskis, Andrew, Mash, Deborah C., Nestler, Eric J.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 14.07.2017; Nature Publishing Group; Nature Portfolio
• Subjects: 13; 13/31; 45/43; 45/91; 631/378/1689/5; 631/378/340; 692/308/575; Addictions; Addictive behaviors; Addicts; Adult; Autopsy; Bipolar disorder; Brain - metabolism; Brain - pathology; Cocaine; Cocaine-Related Disorders - genetics; Drug abuse; Drug addiction; Gene Expression Profiling; Gene Expression Regulation; Gene Regulatory Networks; Genes; Humanities and Social Sciences; Humans; Impulsive behavior; Male; Mental disorders; Middle Aged; multidisciplinary; Neurons; Neurons - metabolism; Prefrontal cortex; Prefrontal Cortex - metabolism; Prefrontal Cortex - pathology; Reinforcement; Ribonucleic acid; RNA; Schizophrenia; Science; Science (multidisciplinary); Sequence Analysis, RNA; Transcription factors; Young Adult
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-017-05720-3

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.