Differential gene expression in the mesocorticolimbic system of innately high- and low-impulsive rats

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.