Inherent Motor Impulsivity Associates with Specific Gene Targets in the Rat Medial Prefrontal Cortex

• Published in: Neuroscience 2020-05, Vol.435, p.161-173
• Main Authors: Sholler, Dennis J., Merritt, Christina R., Davis-Reyes, Brionna D., Golovko, George, Anastasio, Noelle C., Cunningham, Kathryn A.
• Format: Article
• Language: English
• Subjects: Animals; Choice Behavior; choice serial reaction time; Executive Function; Impulsive Behavior; Male; medial prefrontal cortex; motor impulsivity; Prefrontal Cortex; Rats; Rats, Sprague-Dawley; RNA-sequencing; transcriptomics
• ISSN: 0306-4522; 1873-7544
• DOI: 10.1016/j.neuroscience.2020.03.045

•RNA-sequencing and bioinformatics enable target discovery in impulsivity, a feature of several neuropsychiatric diseases.•Inherent motor impulsivity associated with 18 gene targets in the medial prefrontal cortex of male rats.•G protein-coupled receptor and calcium signaling pathways associated with the variation in inherent motor impulsivity.•High motor impulsivity may associate with differences in voltage-gated calcium channel (e.g. CACNA1E) gene expression. High impulsivity characterizes a myriad of neuropsychiatric diseases, and identifying targets for neuropharmacological intervention to reduce impulsivity could reveal transdiagnostic treatment strategies. Motor impulsivity (impulsive action) reflects in part the failure of “top-down” executive control by the medial prefrontal cortex (mPFC). The present study profiled the complete set of mRNA molecules expressed from genes (transcriptome) in the mPFC of male, outbred rats stably expressing high (HI) or low (LI) motor impulsivity based upon premature responses in the 1-choice serial reaction time (1-CSRT) task. RNA-sequencing identified expression of 18 genes that was higher in the mPFC of HI vs. LI rats. Functional gene enrichment revealed that biological processes related to calcium homeostasis and G protein-coupled receptor (GPCR) signaling pathways, particularly glutamatergic, were overrepresented in the mPFC of HI vs. LI rats. Transcription factor enrichment identified mothers against decapentaplegic homolog 4 (SMAD4) and RE1 silencing transcription factor (REST) as overrepresented in the mPFC of HI rats relative to LI rats, while in silico analysis predicted a conserved SMAD binding site within the voltage-gated calcium channel subunit alpha1 E (CACNA1E) promoter region. qRT-PCR analyses confirmed that mRNA expression of CACNA1E, as well as expression of leucyl and cystinyl aminopeptidase (LNPEP), were higher in the mPFC of HI vs. LI rats. These outcomes establish a transcriptomic landscape in the mPFC that is related to individual differences in motor impulsivity and propose novel gene targets for future impulsivity research.