Sholler Dennis J, Merritt Christina R, Davis-Reyes Brionna D, Golovko George, Anastasio Noelle C, Cunningham Kathryn A
Center for Addiction Research, University of Texas Medical Branch, 301 University Boulevard, Galveston, TX 77555, USA; Department of Pharmacology and Toxicology, University of Texas Medical Branch, 301 University Boulevard, Galveston, TX 77555, USA.
Center for Addiction Research, University of Texas Medical Branch, 301 University Boulevard, Galveston, TX 77555, USA.
Neuroscience. 2020 May 21;435:161-173. doi: 10.1016/j.neuroscience.2020.03.045. Epub 2020 Mar 30.
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.
高冲动性是众多神经精神疾病的特征，确定用于减少冲动性的神经药理学干预靶点可能会揭示跨诊断治疗策略。运动冲动（冲动行为）部分反映了内侧前额叶皮质（mPFC）“自上而下”执行控制的失败。本研究对雄性远交大鼠mPFC中基于单选择序列反应时（1-CSRT）任务中的过早反应稳定表达高（HI）或低（LI）运动冲动的基因所表达的全套mRNA分子（转录组）进行了分析。RNA测序确定了18个基因在HI大鼠与LI大鼠的mPFC中表达更高。功能基因富集分析表明，与钙稳态和G蛋白偶联受体（GPCR）信号通路相关的生物学过程，特别是谷氨酸能信号通路，在HI大鼠与LI大鼠的mPFC中过度富集。转录因子富集分析确定，相对于LI大鼠，母亲对十二指节蛋白同源物4（SMAD4）和RE1沉默转录因子（REST）在HI大鼠的mPFC中过度富集，而计算机分析预测在电压门控钙通道亚基α1E（CACNA1E）启动子区域内有一个保守的SMAD结合位点。qRT-PCR分析证实，HI大鼠与LI大鼠相比，CACNA1E的mRNA表达以及亮氨酰和胱氨酰氨肽酶（LNPEP）的表达在mPFC中更高。这些结果建立了与运动冲动个体差异相关的mPFC转录组图谱，并为未来的冲动性研究提出了新的基因靶点。
