Department of Anatomy & Neuroscience, University College Cork, Cork, Ireland; APC Microbiome Ireland, University College Cork, Cork, Ireland.
Department of Anatomy & Neuroscience, University College Cork, Cork, Ireland.
Behav Brain Res. 2019 May 17;364:193-204. doi: 10.1016/j.bbr.2019.01.022. Epub 2019 Feb 6.
Impulsivity is an important component of many psychiatric illnesses and has been associated with a number of psychiatric disorders such as bipolar disorder and attention deficit / hyperactivity disorder (ADHD). Exploring the different aspects of impulsive behaviour and assigning these to specific neurobiological pathways would advance our interpretation of disorders for which impulsivity is key. Pharmacological studies have implicated a number of neurotransmitters in impulsivity, which in turn have been shown to be affected by several genes in both rodent and human studies of impulsivity. Here, we examine impulsivity-related differences in gene expression in finer detail, using the 2-choice serial reaction time task (2-CSRTT) to assess the molecular signature of impulsivity in brain regions previously linked to impulsive behaviour. Wistar rats were rated as high, (n = 6), intermediate, (n = 12) or low impulsive (n = 6), based on premature responses in the 2-CSRTT, after which RNA was extracted from the nucleus accumbens core (NAcc) and ventral prefrontal cortex (vPFC). RNA from the NAcc and vPFC of high and low impulsivity rats (n = 6 per group) was analysed for differential gene expression patterns and exon usage using RNA poly-A tail sequencing. Pnisr, Mal, and Tspan2 were significantly increased in the NAcc of highly impulsive rats, whereas Ube3a was significantly decreased. No differences were seen in the vPFC. In addition to changes in gene expression, Tspan2 displayed differential exon usage in impulsive rats, while functionally, gene expression changes were related to membrane depolarisation and changes in exon usage were linked to sphingolipid breakdown. The changes in gene expression and exon usage observed in this study represent an important step towards defining the molecular architecture of impulsivity. This study therefore represents an important starting point for analysis of the biological role of impulsivity in addiction and other neurological conditions associated with impulsive phenotypes.
冲动是许多精神疾病的一个重要组成部分，与许多精神障碍有关，如双相情感障碍和注意缺陷/多动障碍（ADHD）。探索冲动行为的不同方面，并将这些方面分配到特定的神经生物学途径，将有助于我们对冲动是关键的障碍进行解释。药理学研究表明，许多神经递质与冲动有关，而这些递质在啮齿动物和人类的冲动研究中，又受到几个基因的影响。在这里，我们更详细地检查了与冲动相关的基因表达差异，使用 2 选择连续反应时间任务（2-CSRTT）来评估与冲动行为相关的大脑区域的分子特征。根据 2-CSRTT 中的过早反应，Wistar 大鼠被分为高（n=6）、中（n=12）或低冲动（n=6）组，然后从伏隔核核心（NAcc）和腹侧前额叶皮层（vPFC）中提取 RNA。从高和低冲动大鼠的 NAcc 和 vPFC（每组 n=6）中分析 RNA 多聚-A 尾测序的差异基因表达模式和外显子使用。在高度冲动的大鼠中，Pnisr、Mal 和 Tspan2 在 NAcc 中显著增加，而 Ube3a 则显著减少。vPFC 中未见差异。除了基因表达的变化外，Tspan2 在冲动大鼠中显示出不同的外显子使用，而在功能上，基因表达的变化与膜去极化有关，外显子使用的变化与鞘脂分解有关。本研究中观察到的基因表达和外显子使用的变化代表了定义冲动分子结构的重要一步。因此，本研究代表了分析冲动在成瘾和其他与冲动表型相关的神经疾病中的生物学作用的重要起点。
