Dela Peña Ike, Dela Peña Irene Joy, de la Peña June Bryan, Kim Hee Jin, Shin Chan Young, Han Doug Hyun, Kim Bung-Nyun, Ryu Jong Hoon, Cheong Jae Hoon
Department of Pharmacy, Uimyung Research Institute for Neuroscience, Sahmyook University, 26-21 Kongreung-2-dong, Hwarangro-815, Nowon-gu, Seoul, 139-742, Republic of Korea.
Department of Pharmaceutical and Administrative Sciences, Loma Linda University School of Pharmacy, Loma Linda, CA, 92350, USA.
Behav Genet. 2017 Sep;47(5):564-580. doi: 10.1007/s10519-017-9861-3. Epub 2017 Jul 25.
Impulsivity, the predisposition to act prematurely without foresight, is associated with a number of neuropsychiatric disorders, including attention-deficit/hyperactivity disorder (ADHD). Identifying genetic underpinnings of impulsive behavior may help decipher the complex etiology and neurobiological factors of disorders marked by impulsivity. To identify potential genetic factors of impulsivity, we examined common differentially expressed genes (DEGs) in the prefrontal cortex (PFC) of adolescent SHR/NCrl and Wistar rats, which showed marked decrease in preference for the large but delayed reward, compared with WKY/NCrl rats, in the delay discounting task. Of these DEGs, we examined drug-responsive transcripts whose mRNA levels were altered following treatment (in SHR/NCrl and Wistar rats) with drugs that alleviate impulsivity, namely, the ADHD medications methylphenidate and atomoxetine. Prefrontal cortical genetic overlaps between SHR/NCrl and Wistar rats in comparison with WKY/NCrl included genes associated with transcription (e.g., Btg2, Fos, Nr4a2), synaptic plasticity (e.g., Arc, Homer2), and neuron apoptosis (Grik2, Nmnat1). Treatment with methylphenidate and/or atomoxetine increased choice of the large, delayed reward in SHR/NCrl and Wistar rats and changed, in varying degrees, mRNA levels of Nr4a2, Btg2, and Homer2, genes with previously described roles in neuropsychiatric disorders characterized by impulsivity. While further studies are required, we dissected potential genetic factors that may influence impulsivity by identifying genetic overlaps in the PFC of "impulsive" SHR/NCrl and Wistar rats. Notably, these are also drug-responsive transcripts which may be studied further as biomarkers to predict response to ADHD drugs, and as potential targets for the development of treatments to improve impulsivity.
冲动性，即缺乏远见而过早行动的倾向，与包括注意力缺陷多动障碍（ADHD）在内的多种神经精神疾病有关。确定冲动行为的遗传基础可能有助于解读以冲动性为特征的疾病的复杂病因和神经生物学因素。为了确定冲动性的潜在遗传因素，我们研究了青春期SHR/NCrl和Wistar大鼠前额叶皮层（PFC）中常见的差异表达基因（DEG），在延迟折扣任务中，与WKY/NCrl大鼠相比，它们对大但延迟奖励的偏好显著降低。在这些DEG中，我们研究了药物反应性转录本，其mRNA水平在（SHR/NCrl和Wistar大鼠）用减轻冲动性的药物（即ADHD药物哌甲酯和托莫西汀）治疗后发生了改变。与WKY/NCrl相比，SHR/NCrl和Wistar大鼠前额叶皮层的遗传重叠包括与转录相关的基因（如Btg2、Fos、Nr4a2）、突触可塑性相关的基因（如Arc、Homer2）和神经元凋亡相关的基因（Grik2、Nmnat1）。哌甲酯和/或托莫西汀治疗增加了SHR/NCrl和Wistar大鼠对大的、延迟奖励的选择，并不同程度地改变了Nr4a2、Btg2和Homer2的mRNA水平，这些基因在以冲动性为特征的神经精神疾病中具有先前描述的作用。虽然需要进一步研究，但我们通过识别“冲动性”SHR/NCrl和Wistar大鼠PFC中的遗传重叠，剖析了可能影响冲动性的潜在遗传因素。值得注意的是，这些也是药物反应性转录本，可作为预测对ADHD药物反应的生物标志物以及作为改善冲动性治疗开发的潜在靶点进行进一步研究。
