Neural and psychological mediators of trait impulsivity: cortico-striatal circuitry and catecholaminergic neuromodulation

Abstract

Impulsivity is a multidimensional trait in humans and other mammalian species. It is widely regarded as the tendency to act rapidly, without appropriate foresight and underlies many psychiatric disorders, including attention-deficit/hyperactivity disorder (ADHD), mood disorders such as depression and mania, and substance use disorder (SUD). Research has shown that impulsivity is a non-unitary construct, characterised by distinct behavioural manifestations and, accordingly, distinct neural substrates. This thesis focuses on elucidating the psychological and neural mechanisms of waiting impulsivity in experimental rats trained on the 5-choice serial reaction time task (5CSRTT). The psychological processes involved in this behaviour are yet to be fully understood. However, aspects of sustained attention, urgency, motivation, and delay-aversion are all likely to play a role in shaping this behaviour. Although the neural substrates and neurotransmitter systems underlying waiting impulsivity have been extensively investigated, there are still many unanswered questions. Some of the questions that this work aims to address are: 1) can we refine our understanding of the psychological mechanism that influence premature responses, specifically the extent to which these are driven by motivated behaviour or, instead, negative urgency? 2) Does waiting impulsivity confer advantages in specific experimental contexts and what are the neurotransmitter mechanisms regulating this? 3) Can we refine our understanding of the precise neural circuits involved in the execution of a premature response? 4) How does impulsivity and attention on the 5CSRTT compare with performance on other tasks of sustained attention? Are there any shared neural processes? To investigate these questions, I used a range of experimental approaches spanning behavioural testing to systemic and local (intra-cerebral) pharmacology, brain lesions and chemogenetics. In chapter 2, I show that premature responses are influenced by reinforcement rate and motivation, and that negative urgency does not seem to play an important role in the genesis of these responses. In chapter 3, I found that high levels of trait impulsivity confer an advantage in contexts that require rapid focusing and action. I also showed that this advantage might be conferred putatively by elevated striatal dopamine (DA) release in the striatum. In chapter 4, I 6 show that inhibition of the mesolimbic DA system reduces premature responses but was unable to pinpoint the midbrain-striatal loop responsible for this effect. Finally, in chapter 5, two tasks were compared that assess sustained visual attention. PFC lesions effected using the excitotoxin quinolinic acid profoundly affected performance on the 5CSRTT but had negligible effects on a signal detection attentional task. Taken together, these findings suggest that impulsive (premature) responding in the 5CSRTT is linked with the motivation to perform the task but does appear to depend on negative urgency. Trait impulsivity confers an advantage in specific contexts and depends on striatal DA function. Finally, sustained attention on the 5CSRTT is distinct from other forms of sustained attention both at the psychological and neural levels. Some of these findings are consistent with studies on impulsive individuals, thus highlighting the potential for translational research between rodents and humans. Ultimately, this work expands our understanding of the psychological and neural circuit mechanisms underlying waiting impulsivity.