Proefschrift_Holstein

General discussion

updating of task-sets in the high reward condition ( chapter 6 ) or in maintaining the new strategy after new learning has taken place (after a successful set-shift and the receipts of a reward). Rewarded task-switching In the rewarded task-switching paradigm presented in chapter 6 , two discrimination tasks alternate unpredictably on a trial by trial basis and the use of cues is required to determine the relevant stimulus dimension. This paradigm is the first rodent paradigm that manipulates and compares reward conditions (i.e. high vs. low reward) and cognitive conditions (i.e. switch vs. repeat trials). The paradigm parallels the human paradigm ( chapters 3, 4, 5, and 7 ; but see limitations ) and the pattern of results in chapter 6 is generally congruous with our previous work: Reward can improve cognitive flexibility both in (a genetically determined subset of) humans and in rodents. The results from the rodent work ( chapter 6 ) also fit remarkably well with the pattern of results in the aging work ( chapter 5 ): A reduction in the reward benefit on task switching was observed both in older adults and in animals with lesions of the ventral striatum, strengthening the hypothesis that the age-related effects observed in chapter 5 were related to age-related changes in striatal dopamine. Implications for neuropsychiatry In chapter 4 and 5 we tested the hypothesis that cognitive deficits in ADHD and aging may be grounded in a deficit to use information about potential gains to adequately allocate cognitive processes. A similar deficit could underlie cognitive deficits observed in other neuropsychiatric disorders such as schizophrenia, addiction, Parkinson’s disease and obsessive compulsive disorder (OCD). For example, both schizophrenia and OCD have been associated with cognitive deficits ( chapter 2 ) and changes in the corticostriatal circuitry (Shepherd, 2013). Cognitive deficits in schizophrenia are thought to be related to hypoactivity in the mesocortical dopamine system, whereas positive symptoms (e.g. hallucinations and delusions) are thought to be related to hyperactivity in the dopaminergic nigro-striatal connections and increased dopamine D2 receptor signalling (Simpson et al., 2010). In line with the work in this thesis, excessive dopamine D2 receptor stimulation may induce a flexible state, at the expense of the ability to maintain stable representations (Barch and Ceaser, 2012) decreasing the ability of patients with schizophrenia to filter out irrelevant input. The repetitive behaviours typically observed inOCDon the other hand are thought to originate from increased activity in the corticostriatal circuitry, in particular hyperactivity in the cortex and hypoactivity in the striatum. Combined with the potential involvement of (at least) dopamine D1 receptor in OCD (Nordstrom and Burton, 2002), this underlying pathology may yield excessive maintenance of prefrontal representations, causing the inflexible, repetitive behaviours observed in OCD. In addition,

173