IntroductionWhile several theories have highlighted the importance of the noradrenergic system for behavioral flexibility, a number of recent studies have also shown a role for noradrenaline in motivation, particularly in effort processing. Here, we designed a novel sequential cost/benefit decision task to test the causal influence of noradrenaline on these two functions in rhesus monkeys.MethodsWe manipulated noradrenaline using clonidine, an alpha-2 noradrenergic receptor agonist, which reduces central noradrenaline levels and examined how this manipulation influenced performance on the task. ResultsClonidine had two specific and distinct effects: first, it decreased choice variability, without affecting the cost/benefit trade-off; and second, it reduced force production, without modulating the willingness to work.ConclusionsTogether, these results support an overarching role for noradrenaline in facing challenging situations in two complementary ways: by modulating behavioral volatility, which would facilitate adaptation depending on the lability of the environment, and by modulating the mobilization of resources to face immediate challenges.Electronic supplementary materialThe online version of this article (10.1007/s00213-018-4963-z) contains supplementary material, which is available to authorized users.

Humans have been shown to strategically explore. They can identify situations in which gathering information about distant and uncertain options is beneficial for the future. Because primates rely on scarce resources when they forage, they are also thought to strategically explore, but whether they use the same strategies as humans and the neural bases of strategic exploration in monkeys are largely unknown. We designed a sequential choice task to investigate whether monkeys mobilize strategic exploration based on whether that information can improve subsequent choice, but also to ask the novel question about whether monkeys adjust their exploratory choices based on the contingency between choice and information, by sometimes providing the counterfactual feedback about the unchosen option. We show that monkeys decreased their reliance on expected value when exploration could be beneficial, but this was not mediated by changes in the effect of uncertainty on choices. We found strategic exploratory signals in anterior and mid-cingulate cortex (ACC/MCC) and dorsolateral prefrontal cortex (dlPFC). This network was most active when a low value option was chosen, which suggests a role in counteracting expected value signals, when exploration away from value should to be considered. Such strategic exploration was abolished when the counterfactual feedback was available. Learning from counterfactual outcome was associated with the recruitment of a different circuit centered on the medial orbitofrontal cortex (OFC), where we showed that monkeys represent chosen and unchosen reward prediction errors. Overall, our study shows how ACC/MCC-dlPFC and OFC circuits together could support exploitation of available information to the fullest and drive behavior towards finding more information through exploration when it is beneficial.

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Humans have been shown to strategically explore. They can identify situations in which gathering information about distant and uncertain options is beneficial for the future. Because primates rely on scare resources when they forage, they are also thought to strategically explore, but whether they use the same strategies as humans and the neural bases of strategic exploration in monkeys are largely unknown. We designed a sequential choice task to investigate whether monkeys mobilize strategic exploration based on whether that information can improve subsequent choice, but also to ask the novel question about whether monkeys adjust their exploratory choices based on the contingency between choice and information, by sometimes providing the counterfactual feedback, about the option not chosen. We show that monkeys decreased their reliance on expected value when exploration could be beneficial, but this was not mediated by changes in the effect of uncertainty on choices. We found strategic exploratory signals in anterior and mid-cingulate cortex (ACC/MCC) and dorsolateral prefrontal cortex (dlPFC). This network was most active when a low value option was chosen which suggests a role in counteracting expected value signals, when exploration away from value should to be considered. Such strategic exploration was abolished when the counterfactual feedback was available. Learning from counterfactual outcome was associated with the recruitment of a different circuit centered on the medial orbitofrontal cortex (OFC), where we showed that monkeys represent chosen and unchosen reward prediction errors. Overall, our study shows how ACC/MCC-dlPFC and OFC circuits together could support exploitation of available information to the fullest and drive behavior towards finding more information through exploration when it is beneficial.

The two catecholamines, noradrenaline and dopamine, have been shown to play comparable roles in behavior. Both noradrenergic and dopaminergic neurons respond to cues predicting reward availability and novelty. However, even though both are thought to be involved in motivating actions, their roles in motivation have seldom been directly compared. We therefore examined the activity of putative noradrenergic neurons in the locus coeruleus and putative midbrain dopaminergic neurons in monkeys cued to perform effortful actions for rewards. The activity in both regions correlated with engagement with a presented option. By contrast, only noradrenaline neurons were also (i) predictive of engagement in a subsequent trial following a failure to engage and (ii) more strongly activated in nonrepeated trials, when cues indicated a new task condition. This suggests that while both catecholaminergic neurons are involved in promoting action, noradrenergic neurons are sensitive to task state changes, and their influence on behavior extends beyond the immediately rewarded action.

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Cognition is flexible, allowing for different behaviors on a moment-by-moment basis. Such flexibility is thought to rely on the brain's ability to route information through different networks of brain regions in order to support different cognitive computations. However, the mechanisms that determine which network of brain regions is engaged are unknown. To address this, we combined cortex-wide calcium imaging with high-density electrophysiological recordings in eight cortical and subcortical regions of mice. Different dimensions within the population activity of each brain region were functionally connected with different cortex-wide 'subspace networks' of regions. These subspace networks were multiplexed, allowing a brain region to simultaneously interact with multiple independent, yet overlapping, networks. Alignment of neural activity within a region to a specific subspace network dimension predicted how neural activity propagated between regions. Thus, changing the geometry of the neural representation within a brain region could be a mechanism to selectively engage different brain-wide networks to support cognitive flexibility.

16The two catecholamines, noradrenaline and dopamine, have been shown to play 17 comparable roles in behaviour. Both noradrenergic and dopaminergic neurons 18 respond to salient cues predicting reward availability and to stimulus novelty, and 19 shape action selection strategies. However, their roles in motivation have seldom been 20 directly compared. We therefore examined the activity of noradrenergic neurons in the 21 locus coeruleus and putative midbrain dopaminergic neurons in monkeys cued to 22 perform effortful actions for rewards. The activity in both regions correlated with the 23 likelihood of engaging with a presented option. By contrast, only noradrenaline neurons 24 were also (i) predictive of engagement in a subsequent trial following a failure to 25 engage and (ii) sensitive to the task state change, the discovery of the new task 26 condition in unrepeated trials. This indicates that while dopamine is primarily important 27 for the promotion of actions directed towards currently available rewards, 28 noradrenergic neurons play a crucial complementary role in mobilizing resources to 29 promote future engagement. 30 frame, the magnitude of LC responses to sensory stimuli increases when these stimuli 54 are unexpected, and therefore provide information about the state of the world that 55 may be useful to guide subsequent behaviour. By contrast, perfectly expected stimuli 56 provide little information, and so their presentation should not require the updating of 57 behaviour. In other words, such a function could allow the activation of LC neurons to 58 promote the adaptation of behaviour in response to a change in the state of the world 59