Thesis defense Mieke van Holstein (Donders series 232)

22 September 2016

Promotor: prof. dr. R. Cools, copromotor :dr. E. Aarts

Neural circuitry and neurochemistry of motivated cognitive control
A cross-species approach

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. This requires the transformation of information about reward into abstract cognitive decisions, which in turn need to be translated into specific actions. The mechanisms underlying this hierarchy are not well understood. 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. Until recently, experimental evidence supporting these hypotheses was either absent or indirect. Therefore, the research in this thesis aimed to elucidate the causal role for striatal dopamine and the corticostriatal network during the integration of reward and flexible cognitive control. We showed that dopaminergic manipulation with methylphenidate indeed changed motivation-cognition signalling in the striatum. In addition, a causal role for the ventral striatum in motivated cognitive control was established, followed by evidence for frontal modulation of striatal processing during the integration of signals related to motivation, cognition, and action across subparts of the striatum. Together, these results are in line with a role for striatal dopamine in motivated cognitive control, and they show that integration across corticostriatal circuits is involved in this process. Many psychiatric disorders are associated with deficits in cognitive control and/or reward processing (e.g. ADHD, schizophrenia, addiction and OCD). These psychiatric disorders are also associated with changes in the cortico-striatal circuit and dopamine signalling. Overall, the work in this thesis contributes to a better understanding of the role of dopamine in the cortico-striatal-nigral circuitry, thereby contributing to our understanding of the underlying neuropathology in at least ADHD, schizophrenia, addiction and OCD.