The mesolimbic dopaminergic system exerts a crucial influence on incentive processing. However, the contribution of dopamine in dynamic, ecological situations where reward rates vary, and decisions evolve over time, remains unclear. In such circumstances, current (foreground) reward accrual needs to be compared continuously with potential rewards that could be obtained by traveling elsewhere (background reward rate), to determine the opportunity cost of staying versus leaving. We hypothesized that dopamine specifically modulates the influence of background, but not foreground, reward information when making a dynamic comparison of these variables for optimal behavior. On a novel foraging task based on an ecological account of animal behavior (marginal value theorem), human participants of either sex decided when to leave locations in situations where foreground rewards depleted at different rates, either in rich or poor environments with high or low background reward rates. In line with theoretical accounts, people's decisions to move from current locations were independently modulated by changes in both foreground and background reward rates. Pharmacological manipulation of dopamine D2 receptor activity using the agonist cabergoline significantly affected decisions to move on, specifically modulating the effect of background reward rates. In particular, when on cabergoline, people left patches in poor environments much earlier. These results demonstrate a role of dopamine in signaling the opportunity cost of rewards, not value per se. Using this ecologically derived framework, we uncover a specific mechanism by which D2 dopamine receptor activity modulates decision-making when foreground and background reward rates are dynamically compared.

Research has indicated a major role of dopamine in decision-making processes, but the underlying mechanisms remain largely unknown due to inconsistency in effects of dopaminergic drugs. To clarify the impact of dopamine on impulsive choice, we administered 150 mg L-DOPA to 87 healthy adults in a randomized, placebo-controlled, double-blind, crossover study, evaluating performance in four value-based decision-making tasks. We predicted that baseline impulsivity would moderate L-DOPA effects. In support of our hypothesis, L-DOPA had no main effect on impulsive choice, but reduced risk-seeking for gains in more-impulsive subjects. Because L-DOPA effects may be influenced by body weight, we repeated our analyses on data from half of the sample (n = 44) with lower weight, anticipating a stronger effect. In addition to the effect on risk-seeking for gains, low-weight participants also exhibited baseline-dependent effects of L-DOPA on loss aversion and delay discounting. Our results are consistent with the hypothesis of an inverted U-shaped dopamine function in which both low and high extremes of dopamine signaling are associated with high-impulsive choice. Consideration of differential baseline impulsivity and body weight may resolve previous seemingly paradoxical pharmacological results and might deepen our understanding of dopaminergic mechanisms underlying impulsivity.

It has recently been proposed that short-term memory (STM) binding deficits might be an important feature of Alzheimer's disease (AD), providing a potential avenue for earlier detection of this disorder. By contrast, work in Parkinson's disease (PD), using different tasks, has suggested that the STM impairment in this condition is characterised by increased random guessing, possibly due to fluctuating attention. In the present study, to establish whether a misbinding impairment is present in sporadic late-onset AD (LOAD) and increased guessing is a feature of PD, we compared the performance of these patient groups to two control populations: healthy age-matched controls and individuals with subjective cognitive impairment (SCI) with comparable recruitment history as patients. All participants performed a sensitive task of STM that required high resolution retention of object-location bindings. This paradigm also enabled us to explore the underlying sources of error contributing to impaired STM in patients with LOAD and PD using computational modelling of response error. Patients with LOAD performed significantly worse than other groups on this task. Importantly their impaired memory was associated with increased misbinding errors. This was in contrast to patients with PD who made significantly more guessing responses. These findings therefore provide additional support for the presence of two doubly dissociable signatures of STM deficit in AD and PD, with binding impairment in AD and increased random guessing characterising the STM deficit in PD. The task used to measure memory precision here provides an easy-to-administer assessment of STM that is sensitive to the different types of deficit in AD and PD and hence has the potential to inform clinical practice.

1 The mesolimbic dopaminergic system exerts a crucial influence on normal motivated 2 behaviour, but the mechanism of this action in dynamic situations where decisions evolve 3 over time remains unclear. In such circumstances, current (foreground) reward accrual rate 4 needs to be compared continuously with potential rewards that could be obtained elsewhere 5 (background reward rate) in order to determine the opportunity cost of staying or leaving. We 6 hypothesised that dopamine levels specifically modulate the influence of background -but 7 not foreground -reward information in a decision-making task that requires dynamic 8 comparison of these variables for optimal behaviour, and that this effect would be disrupted 9in individuals with loss of motivation -apathy. We developed a human foraging task based 10 on a normative theory of animal behaviour (marginal value theorem), in which participants 11 decide when to leave locations in which rewards decreased over time in order to pursue 12 greater returns in their environment. People's decisions to move from current locations 13 conformed closely to foraging principles. Pharmacological manipulation of dopamine D2 14 receptor activity in healthy individuals using the agonist cabergoline significantly modulated 15 background, but not foreground, reward sensitivity. In a separate study, this same effect was 16 observed in patients with Parkinson's disease, dependent on presence of apathy. Using an 17 ecologically derived framework we demonstrate a specific mechanism by which dopamine 18 modulates dynamic human decision-making, and how impairment of this mechanism can 19 contribute to pathological loss of motivation. 20 21 KEY WORDS 22