Proefschrift_Holstein

General discussion

Our environment imposes on us a constant stream of stimuli and potential tasks to engage in. Dealing with this constantly changing environment requires the ability to flexibly adapt our behavioural and cognitive programs to changing task demands. In addition, we adapt our behaviour to changes in potential rewards, which serve both a motivational function, by invigorating and energizing ongoing behaviour and cognition, as well as a directional function, biasing behaviour towards one action or another by influencing choice and learning. In this thesis, I have focused on the motivational function of reward and specifically, on its role in motivating cognitive control. Previous experimental and anatomical work has suggested a role for dopamine, the striatum and connections between the striatum and the prefrontal cortex in motivated cognitive control ( chapters 1 and 2 , (Haber et al., 2000; Haber, 2003; Aarts et al., 2010). Until recently, experimental evidence supporting these hypotheses was either absent, indirect or did not speak to the specific receptor types involved in the underlying process ( chapters 1 and 2 ). In this thesis, I aimed to improve our understanding of the role of dopamine and the corticostriatal network during the integration of reward and flexible cognitive control. More specifically my work aimed to test whether the manipulation of dopamine and specific dopamine receptors ( chapter 3, 4 ), and (prefrontal modulation of) signalling in the striatum ( chapter 6 and 7 ) can alter motivated cognitive control. In addition, I assessed reward- cognition integration across the life span, from adolescence to senescence ( chapter 5 ) and in patients with attention deficit hyperactivity disorder (ADHD) ( chapter 4 ). Summary of findings In chapter 1 , we provided an overview of the state of the relevant literature up until the start of my thesis on how motivation can change cognitive control, how the neural signals associated with these processes may be integrated and how signals in the prefrontal cortex may modulate striatal processing. In that same chapter we also put forward a working hypothesis, suggesting an important role for striatal dopamine in motivated cognitive control. However, which specific dopamine receptor subtype is important for motivated cognitive control had not been assessed, and experimental work thus far had not directly manipulated the striatum and the dopamine system. In chapter 3 , we filled this gap by conducting a pharmacological study to investigate the causal role of dopamine, specifically the dopamine D2 receptor, in task switching and in the integration between reward and task switching. In this study, we replicated the previous observation (Aarts et al., 2010) that inter-individual variation in the dopamine transporter genotype (DAT1/SLC6A3) can modulate the effect of reward on task-switching behaviour, suggesting -again- a role for striatal dopamine in this interaction. However, our pharmacological manipulation did not alter motivated cognitive control. The administration of a dopamine D2 receptor agonist did however change task-switching behaviour, irrespective of reward. This observation is in line with previous theorizing and work in humans and rodents implicating the D2 receptor in flexible behaviour (Mehta et

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