Biology subjects

Bouret, S.

Publications and source records attributed to Bouret, S..

11 recordsLinked to original sources

bioRxiv2026

Pharmacogenetic manipulation of Locus coeruleus activity in monkeys demonstrates its role in cognitive effort

The noradrenergic nucleus locus coeruleus (LC) is involved in numerous cognitive functions. Its activation often enhances sensory and motor performance and its activity correlates with arousal, which altogether suggest a general role in the mobilization of resources for cognition and action. We recently showed its strong and specific implication in physical effort and indirect evidence suggest that it might also be involved in cognitive effort. To address this question directly, we used a pharmacogenetic approach in rhesus macaques to selectively and reversibly inhibit LC neurons in a cognitively challenging task. Two monkeys were injected with viral vectors expressing inhibitory DREADDs (hM4Di) specifically in noradrenergic LC neurons, allowing reversible suppression of LC activity via systemic administration of deschloroclozapine (DCZ, 0.1 mg/kg). A third monkey served as a control and only received DCZ injections. Monkeys performed a simple hole-board task in which they searched for food rewards (raisins) hidden in a 5x5 grid of wells. In the transparent condition, rewards were visible, requiring minimal cognitive effort. In the opaque condition, rewards were hidden, such that monkey had to rely upon working memory to avoid revisiting empty wells. Thus, performance in opaque condition required more cognitive effort. Behavioral analysis showed that LC inhibition had no effect on performance in the transparent condition. However, in the opaque condition, it significantly impaired performance by increasing errors (revisits), without affecting the total number of rewards obtained, response times, or overall motivation. Monkeys compensated the decrease in success rate by performing more trials, indicating reduced efficiency rather than disengagement. These findings demonstrate that the LC plays a critical causal role in mobilizing cognitive resources for a demanding task. This is in line with the idea that the noradrenergic system contributes broadly to cognitive control and effort, extending previous findings on its involvement in physical effort. Overall, the study provides strong evidence linking LC activity to cognitive effort regulation, thereby complementing non-invasive studies in humans.

neuroscience↗

bioRxiv2025

Inhibition of oxytocin neurons during key periods of development has long-term behavioural and body composition effects

BackgroundOxytocin (OT) is a key neuromodulator of social behavior in mammals, and accumulating evidence supports the existence of a critical period for OT action during infancy. However, other developmental windows remain poorly explored, and it remains unclear whether OT exert distinct functions depending on the timing of its activity. In this study, we aimed to determine whether specific developmental stages exist during which OT-expressing neurons play a decisive role with long-term consequences. MethodsWe used a chemogenetic approach to transiently inhibit OT-expressing neurons during three postnatal developmental periods: infancy, the juvenile period, and young adulthood in male and female mice. Behavioral and metabolic outcomes were then assessed longitudinally. We also examined the effects of inhibiting OT neurons during late fetal stages and at birth. ResultsSocial memory was consistently impaired in males, regardless of the timing of neuronal inactivation. The most pronounced behavioral effects were observed following inhibition during infancy in both sexes. Metabolically, adult males from all cohorts exhibited increased body weight, whereas increased fat mass and adipocyte size hypertrophy were specifically observed following inhibition during the juvenile period. Notably, inhibition of OT-expressing neurons around the time of birth resulted in delayed parturition and altered neonatal feeding behavior. LimitationsOT-expressing neurons release multiple signaling molecules. However, converging evidence suggests that the observed phenotypes are primarily attributable to OT deficiency. Although this study demonstrates long-term behavioral and metabolic consequences of transient OT neuron inhibition, further experiments are required to elucidate underlying mechanisms and identify additional effects. ConclusionsTransient inhibition of OT-expressing neurons during distinct postnatal developmental periods leads to long-lasting effects on social behavior and metabolism, with outcomes depending on both the timing of inhibition and sex. Furthermore, our findings reveal an unexpected role for fetal/neonatal OT neurons in regulating the timing of birth and early feeding behavior.

neuroscience↗

bioRxiv2025

Reference Point-Dependent Reinforcement Learning in Humans and Rats

Previous studies indicate that rewards and punishments in reinforcement learning are encoded in a relative manner. Reference point-dependence, a valuation bias shared by eminent adaptation level and prospect theories, is often cited as the underlying computational mechanism. However, whether these behavioural and computational mechanisms are preserved across species is unknown. To fill this gap, we designed a reinforcement learning task that was adapted for both humans (homo sapiens sapiens) and rats (rattus norvegicus). Behavioural analyses indicated robust relative value encoding in both species. At the computational level, reference point-dependence provided a reliable account of reinforcement learning behaviour in humans and rats. Despite these major similarities between species, some distinct differences in behavioural and computational modelling parameters were also observed. Overall, our study demonstrates that relative value encoding is a robust feature of reinforcement learning that is conserved across human and rat species.

molecular biology↗

bioRxiv2023

Linking the evolution of two prefrontal brain regions to social and foraging challenges in primates

The diversity of cognitive skills across primates remains both a fascinating and a controversial issue. Recent comparative studies provided conflicting results regarding the contribution of social vs ecological constraints to the evolution of cognition. Here, we used an interdisciplinary approach combining comparative cognitive neurosciences and behavioral ecology. Using brain imaging data from 16 primate species, we measured the size of two prefrontal brain regions, the frontal pole (FP) and the dorso-lateral prefrontal cortex (DLPFC), respectively involved in metacognition and working memory, and examined their relation to a combination of socio-ecological variables. The size of these prefrontal regions, as well as the whole brain, was best explained by three variables: body mass, daily traveled distance (an index of ecological constraints) and population density (an index of social constraints). The strong influence of ecological constraints on FP and DLPFC volumes suggests that both metacognition and working memory are critical for foraging in primates. Interestingly, FP volume was much more sensitive to social constraints than DLPFC volume, in line with laboratory studies showing an implication of FP in complex social interactions. Thus, our data highlights the relative weight of social vs ecological constraints on the evolution of specific prefrontal brain regions and their associated cognitive operations in primates. FundingThis work was supported by recurrent funding from CNRS to SB, SP and CG. It was also supported by the ANR-17-CE27-0005 (HOMTECH).

neuroscience↗

bioRxiv2023

The online metacognitive control of decisions

Difficult decisions typically involve mental effort, which scales with the deployment of cognitive (e.g., mnesic, attentional) resources engaged in processing decision-relevant information. But how does the brain regulate mental effort? A possibility is that the brain optimizes a resource allocation problem, whereby the amount of invested resources balances its expected cost (i.e. effort) and benefit. Our working assumption is that subjective decision confidence serves as the benefit term of the resource allocation problem, hence the "metacognitive" nature of decision control. Here, we present a computational model for the online metacognitive control of decisions or oMCD. Formally, oMCD is a Markov Decision Process that optimally solves the ensuing resource allocation problem under agnostic assumptions about the inner workings of the underlying decision system. We demonstrate how this makes oMCD a quasi-optimal control policy for a broad class of decision processes, including -but not limited to- progressive attribute integration. We disclose oMCDs main properties (in terms of choice, confidence and response time), and show that they reproduce most established empirical results in the field of value-based decision making. Finally, we discuss the possible connections between oMCD and most prominent neurocognitive theories about decision control and mental effort regulation.

animal behavior and cognition↗

bioRxiv2022

Strategic exploration in the macaque prefrontal cortex

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.

neuroscience↗

bioRxiv2020

Differential Contribution of Dopaminergic Transmission at D1- and D2-like Receptors to Cost/Benefit Evaluation for Motivation in Monkeys

It has been widely accepted that dopamine (DA) plays a major role in motivation, yet the specific contribution of DA signaling at D1-like receptor (D1R) and D2-like receptor (D2R) to cost-benefit trade-off remains unclear. Here, by combining pharmacological manipulation of DA receptors (DARs) and positron emission tomography imaging, we assessed the relationship between the degree of D1R/D2R blockade and changes in benefit- and cost-based motivation for goal-directed behavior of macaque monkeys. We found that the degree of blockade of either D1R or D2R was associated with a reduction of the positive impact of reward amount and increasing delay-discounting. Workload-discounting was selectively increased by D2R antagonism. In addition, blocking both D1R and D2R had a synergistic effect on delay-discounting but an antagonist effect on workload-discounting. These results provide fundamental in-sight into the distinct mechanisms of DA action in the regulation of the cost and benefit-based motivation, which have important implications for motivational alterations in both neurological and psychiatric disorders.

neuroscience↗

bioRxiv2019

Pharmacological evidence for the implication of noradrenaline in effort

The trade-off between effort and reward is one of the main determinants of behavior and its alteration is at the heart of major disorders such as depression or Parkinsons disease. Monoaminergic neuromodulators are thought to play a key role in this trade-off, but their relative contribution remains unclear. Rhesus monkeys (Macaca mulatta) performed a choice-task requiring a trade-off between the volume of fluid reward and the amount of force to be exerted on a grip. In line with a causal role of noradrenaline in effort, decreasing noradrenaline levels with systemic clonidine injections (0.01mg/kg) decreased exerted force and enhanced the weight of upcoming force on choices, without any effect on reward sensitivity. Computational modeling demonstrated that NA acted on a single hidden variable, which affected both choices (as a variable of decision) and force production (as a driving force). Thus, our data strongly support noradrenalines implication in effort processing.

neuroscience↗

bioRxiv2019

Noradrenergic but not dopaminergic neurons signal task state changes and predict re-engagement after a failure

The two catecholamines, noradrenaline and dopamine, have been shown to play comparable roles in behaviour. Both noradrenergic and dopaminergic neurons respond to salient cues predicting reward availability and to stimulus novelty, and shape action selection strategies. However, their roles in motivation have seldom been directly compared. We therefore examined the activity of 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 the likelihood of engaging 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) sensitive to the task state change, the discovery of the new task condition in unrepeated trials. This indicates that while dopamine is primarily important for the promotion of actions directed towards currently available rewards, noradrenergic neurons play a crucial complementary role in mobilizing resources to promote future engagement.

neuroscience↗

bioRxiv2017

Contributions of different prefrontal cortical regions to abstract rule acquisition and reversal in monkeys

The ability to learn and follow abstract rules relies on intact prefrontal regions including the lateral prefrontal cortex (LPFC) and the orbitofrontal cortex (OFC). Here, we investigate the specific roles of these brain regions in learning rules that depend critically on the formation of abstract concepts as opposed to simpler input-output associations. To this aim, we tested monkeys with bilateral removals of either LPFC or OFC on a rapidly learned task requiring the formation of the abstract concept of same vs. different. While monkeys with OFC removals were significantly slower than controls at both acquiring and reversing the concept-based rule, monkeys with LPFC removals were not impaired in acquiring the task, but were significantly slower at rule reversal. Neither group was impaired in the acquisition or reversal of a delayed visual cue-outcome association task without a concept-based rule. These results suggest that OFC is essential for the implementation of a concept-based rule, whereas LPFC seems essential for its modification once established.

neuroscience↗

bioRxiv2017

Independent contributions of noradrenaline to behavioural flexibility and motivation

Among neuromodulatory systems, the noradrenergic system remains one of the least understood. Several theories have pointed out its implication in behavioural flexibility and more recently in motivation, with a strong role in effort processing. Here, we designed a sequential cost/benefit decision task to test the causal role of noradrenaline in these two functions. We manipulated noradrenaline using clonidine, an alpha-2 noradrenergic receptor agonist, which reduces central noradrenaline levels. Clonidine had two distinct effects: it decreased choice volatility (without affecting the cost/benefit trade off) and reduced force production. Because the effects were independent, they cannot be accounted for by a non-specific effect on arousal. Altogether, these results support the global implication of noradrenaline in facing challenging situations in two complementary ways: by modulating behavioural volatility, which would facilitate adaptation depending on the lability of the environment, and by modulating the mobilization of resources to face immediate challenges.

neuroscience↗