Biology subjects

Cools, R.

Publications and source records attributed to Cools, R..

At least 19 recordsLinked to original sources

bioRxiv2026

Dopamine modulates striatal activity when controlling the output of working memory

Cognitive control depends on capacity-limited mechanisms that require selection. Working memory (WM) therefore relies on an input-gate to filter information into WM and an output-gate to transform current WM representations into a prioritised state to guide behaviour. According to current theory, such WM gating processes are modulated by dopamine in the striatum, yet empirical evidence for this hypothesis remains sparse. We fill this gap by directly testing the role of dopamine for both WM input-and output-gating in a double-blind, placebo-controlled within-subject fMRI study (N = 34; 23 female, 11 male human subjects), using a 400 mg oral dose of the dopamine D2 receptor antagonist sulpiride. In our cued delayed-response task, which separated input-from output-gating, sulpiride altered neural activity in the striatum during output-gating. This effect was accompanied by a sulpiride-induced de-crease in the neural stimulus selectivity of gated sensory representations in visual association cortex, with greater decreases in stimulus selectivity correlating with reduced behavioural accuracy in the task. Together, the results establish a role for striatal dopamine during the control of cortical outflow of WM. Significance StatementTo act on a goal, the brain holds information in mind and brings the important parts into focus to guide what we do next. Scientists believe that this "selection" process involves dopamine, a chemical messenger, in a brain area called the striatum. We tested this by giving people a drug that alters dopamine activity in the brain. The drug changed how the striatum reacted when people selected information from memory. It also made the brains visual areas represent this information less clearly, and this change affected peoples behaviour. Therefore, we conclude that dopamine in the striatum plays a role when our brain controls which information in working memory is sent to other parts of the brain to guide actions.

neuroscience↗

bioRxiv2025

Long-read single-cell genome, transcriptome and open chromatin profiling links genotype to phenotypes.

Current single-cell multiomics methods typically provide limited genomic information, constraining genotype-phenotype studies. To address this gap, we developed SPLONGGET (Single-cell Profiling of LONG-read Genome, Epigenome, and Transcriptome), which integrates 10X Genomics barcoding with Oxford Nanopore sequencing to simultaneously profile genome, chromatin accessibility, and full-length transcriptomes in thousands of single cells. By retaining all tagmentation fragments during library preparation, SPLONGGET delivers whole-genome coverage, supports target enrichment for effective single-cell genotyping, and remains backwards compatible with existing short-read workflows. SPLONGGET enables comprehensive calling of small variants, structural variants, and copy number alterations. Applying SPLONGGET to paediatric B-cell acute lymphoblastic leukaemia revealed clonal dynamics and the phenotypic effects of somatic variants. Notably, we evidence parallel evolution of immune escape variants with four distinct splice site mutations and loss of heterozygosity in the CAR T-cell therapy CD19 target. In conclusion, SPLONGGET enables integrated high-throughput analysis of genetic variation and molecular phenotypes using off-the-shelf kits, offering a timely and powerful tool to study genetically heterogeneous samples, such as tumours but also ageing normal tissues.

genomics↗

bioRxiv2025

Validating molecular target-enriched fMRI for disentangling drug effects on dopamine

The psychostimulant methylphenidate may exert its effects on cognition and associated brain signals via action on the dopamine or noradrenaline transporter (DAT/NET). A recently developed and increasingly popular dual-regression approach (REACT; Dipasquale et al. (2019)) attempts to hone in on the molecular mechanisms underlying (drug-induced) changes in fMRI signal by enriching the analysis with information about the spatial distribution of molecular targets of interest. This method has great potential, but hitherto lacked validation of its molecular specificity and functional relevance. Here we leverage a unique pharmaco-fMRI dataset with established dopamine-dependent methylphenidate effects on neural reward prediction error (RPE) signaling, the canonical functional signature of dopamine. Using REACT we found that methylphenidate significantly modulated both DAT and NET-related functional connectivity networks, but only the effect on the DAT network varied with interindividual differences in striatal dopamine synthesis capacity, as measured with [18F]FDOPA PET. Furthermore, methylphenidate affected DAT-related connectivity in the prefrontal cortex in the same location where it affected neural RPE signaling. Together, these findings firmly establish the validity of REACT as a tool for isolating the role of dopamine from that of noradrenaline in methylphenidates effects on brain function.

neuroscience↗

bioRxiv2025

Anxiety state-related task disengagement varies with trait anxiety

Cognitively demanding tasks are often perceived as costly due to the cognitive control resources they require, leading to effort avoidance, particularly in psychiatric populations with motivational impairments. Research on anxiety and cognitive effort are mixed: some studies suggest anxiety increases the perceived effort cost and avoidance, while others indicate that cognitive effort engagement can serve as an adaptive coping strategy. To reconcile these perspectives, we examined the interaction between state and trait anxiety on cognitive effort evaluation and engagement in two experiments. We hypothesized that state anxiety enhances task engagement as difficulty increases, and that this effect is diminished in individuals with high trait anxiety. Experiment 1 assessed self-reported anxiety in an online sample, while Experiment 2 manipulated state anxiety through autobiographical recall. Both experiments employed flow induction and effort discounting paradigms. Across both studies, the effect of state anxiety on task engagement depended on trait anxiety, but the direction of the state anxiety effect was opposite to the effect we predicted. In Experiment 1, participants with low trait anxiety reported reduced task engagement, as indexed by lower flow scores, when state anxiety was higher, but only in easy tasks. This effect was attenuated in participants with higher trait anxiety. The same pattern was observed in Experiment 2, but this time the interaction between trait and state anxiety was present regardless of task difficulty. These findings suggest that trait anxiety may reflect reduced impact of state anxiety on task disengagement. Public significance statementThis study demonstrated that effects of state anxiety on task disengagement depend on individual differences in trait anxiety. People with higher trait anxiety reported reduced effects of state anxiety on task disengagement.

neuroscience↗

bioRxiv2024

Abstract rule generalization for composing novel meaning recruits the frontoparietal control network

The ability to generalize previously learned knowledge to novel situations is crucial for adaptive behavior, representing a form of cognitive flexibility that is particularly relevant in language. Humans excel at combining linguistic building blocks to infer the meanings of novel compositional words, such as "un-reject-able-ish". How do we accomplish this? While recent research on compositional generalization in relational memory, action planning and vision strongly implicates a medial prefrontal-hippocampal network (Baram et al., 2021; Barron et al., 2020; Schwartenbeck et al., 2023), it remains unclear whether the same network supports compositional inference in language. To this end, we trained participants on an artificial language in which the meanings of compositional words could be derived from known stems and unknown affixes, using abstract affixation rules (e.g., "good-kla" which means "bad", where "-kla" reverses the meaning of the stem word "good"). According to these rules, word meaning depended on the sequential relation between the stem and the affix (i.e., pre- vs. post-stem). During fMRI, participants performed a semantic priming task, with novel compositional words as either sequential order congruent (e.g., "white-kla") or incongruent primes (e.g., "kla-white"), and synonyms of the composed meaning as targets ("black"). Our results show that the compositional process engages a broad temporoparietal network, including the hippocampus, while the composed meanings are represented in left-lateralized language areas. Notably, newly composed meanings were decodable already at the time of the prime. Finally, we found that the composition process recruits abstract structure rule representations in a lateral frontoparietal network, rather than the predicted medial frontotemporal network, perhaps because abstract rules in language are more readily formatted as production rules rather than as relational map structures.

neuroscience↗

bioRxiv2024

Multiple paralogues and recombination mechanisms drive the high incidence of 22q11.2 Deletion Syndrome

The 22q11.2 deletion syndrome (22q11.2DS) is the most common microdeletion disorder. Why the incidence of 22q11.2DS is much greater than that of other genomic disorders remains unknown. Short read sequencing cannot resolve the complex segmental duplicon structure to provide direct confirmation of the hypothesis that the rearrangements are caused by non-allelic homologous recombination between the low copy repeats on chromosome 22 (LCR22s). To enable haplotype-specific assembly and rearrangement mapping in LCR22 regions, we combined fiber-FISH optical mapping with whole genome (ultra-)long read sequencing or rearrangement-specific long-range PCR on 24 duos (22q11.2DS patient and parent-of-origin) comprising several different LCR22-mediated rearrangements. Unexpectedly, we demonstrate that not only different paralogous segmental duplicon but also palindromic AT-rich repeats (PATRR) are driving 22q11.2 rearrangements. In addition, we show the existence of two different inversion polymorphisms preceding rearrangement, and somatic mosaicism. The existence of different recombination sites and mechanisms in paralogues and PATRRs which are copy number expanding in the human population are a likely explanation for the high 22q11.2DS incidence.

genetics↗

bioRxiv2024

Striatal Dopamine Can Enhance Learning, Both Fast and Slow, and Also Make it Cheaper

Associations can be learned incrementally, via reinforcement learning (RL), or stored instantly in working memory (WM). While WM is fast, it is also capacity-limited and effortful. Striatal dopamine may promote RL plasticity, and WM, by facilitating updating and effort exertion. Yet, prior studies have failed to distinguish between dopamines effects on RL versus WM. N = 100 participants completed a paradigm isolating these systems in a double-blind study measuring dopamine synthesis with [18F]-FDOPA imaging and manipulating dopamine with methylphenidate and sulpiride. Learning is enhanced among high synthesis capacity individuals and by methylphenidate, but impaired by sulpiride. Methylphenidate also blunts effort cost learning. Computational modeling reveals that individuals with high dopamine synthesis rely more on WM, while methylphenidate boosts their RL rates. The D2 antagonist sulpiride reduces accuracy due to diminished WM involvement and faster WM decay. We conclude that dopamine enhances both slow RL, and fast WM, by promoting plasticity and reducing effort sensitivity. These results also highlight the need to control for dopamines effects on WM when testing its effects on RL.

animal behavior and cognition↗

bioRxiv2023

Reinforcement learning in Parkinson disease is not associated with inflammatory tone

Parkinsons disease (PD) is associated with large variability in the development and severity of both motor and nonmotor symptoms, including depression and impulse control disorder. Neuroinflammation might contribute to this heterogeneity, given its association with dopaminergic signalling, neuropsychiatric symptoms, and reward versus punishment learning. Here, we assessed the effect of inflammatory tone on probabilistic reinforcement learning and impulse control disorders in PD. We measured computational learning model-based neural reward prediction error and expected value signals in frontostriatal circuity during reinforcement learning using functional MRI. In addition, we acquired cerebral spinal fluid of 74 PD patients and screened for 13 inflammatory factors, including our primary marker of interest IL-6, previously implicated in reward learning signaling in the ventral striatum. In contrast to our prediction, we found no association between inflammatory tone and any of the behavioural or neural reinforcement learning parameters. Furthermore, we did we not find any correlation between inflammatory tone and depressive or impulsive PD symptoms. Exploratory analyses revealed a negative association between MCP-1 and reward prediction error signals in the ventral striatum, an observation that should be replicated in future work. The null findings might reflect the fact that measurements were taken ON medication, or that our sample consists of an early disease stage cohort that may be too small to detect these effects, or that IL-6 is a suboptimal marker for inflammatory tone, or a combination of these factors.

neuroscience↗

bioRxiv2022

Parallel cognitive maps for short-term statistical and long-term semantic relationships in the hippocampal formation

The hippocampal-entorhinal system uses cognitive maps to represent spatial knowledge and other types of relational information, such as the transition probabilities between objects. However, objects can often be characterized in terms of different types of relations simultaneously, e.g. semantic similarities learned over the course of a lifetime as well as transitions experienced over a brief timeframe in an experimental setting. Here we ask how the hippocampal formation handles the embedding of stimuli in multiple relational structures that differ vastly in terms of their mode and timescale of acquisition: Does it integrate the different stimulus dimensions into one conjunctive map, or is each dimension represented in a parallel map? To this end, we reanalyzed functional magnetic resonance imaging (fMRI) data from Garvert et al. (2017) that had previously revealed an entorhinal map which coded for newly learnt statistical regularities. We used a triplet odd-one-out task to construct a semantic distance matrix for presented items and applied fMRI adaptation analysis to show that the degree of similarity of representations in bilateral hippocampus decreases as a function of semantic distance between presented objects. Importantly, while both maps localize to the hippocampal formation, this semantic map is anatomically distinct from the originally described entorhinal map. This finding supports the idea that the hippocampal-entorhinal system forms parallel cognitive maps reflecting the embedding of objects in diverse relational structures.

neuroscience↗

bioRxiv2022

Evidence for absence of links between striatal dopamine synthesis capacity and working memory capacity, spontaneous eye-blink rate, and trait impulsivity

Individual differences in striatal dopamine synthesis capacity have been associated with working memory capacity, trait impulsivity and spontaneous eye-blink rate (sEBR), as measured with readily available and easily administered, off-the-shelf tests. Such findings have raised the suggestion that individual variation in dopamine synthesis capacity, estimated with expensive and invasive brain positron emission tomography (PET) scans, can be approximated with simple, more pragmatic tests. However, direct evidence for the relationship between these simple trait measures and striatal dopamine synthesis capacity has been limited and inconclusive. We measured striatal dopamine synthesis capacity using [18F]-FDOPA PET in a large sample of healthy volunteers (N=94) and assessed the correlation with simple, short tests of working memory capacity, trait impulsivity, and sEBR. We additionally explored the relationship with an index of subjective reward sensitivity. None of these trait measures correlated significantly with striatal dopamine synthesis capacity, nor did they have out-of-sample predictive power. Bayes Factor analyses indicated the evidence was in favour of absence of correlations for all but subjective reward sensitivity. These results warrant caution for using these off-the-shelf trait measures as proxies of striatal dopamine synthesis capacity.

neuroscience↗

bioRxiv2021

Pupillary dynamics of optimal effort

While a substantial body of work has shown that cognitive effort is aversive and costly, a separate line of research on intrinsic motivation suggests that people spontaneously seek challenging tasks. According to one prominent account of intrinsic motivation, the Learning Progress Motivation theory, the preference for difficult tasks reflects the dynamic range that these tasks yield for changes in task performance (Oudeyer, Kaplan & Hafner, 2007). Here we test this hypothesis, by asking whether greater engagement with intermediately difficult tasks, indexed by subjective ratings and objective pupil measurements, is a function of trial-wise changes in performance. In a novel paradigm, we determined each individuals capacity for task performance and used difficulty levels that are too low, intermediately challenging or high for that individual. We demonstrated that challenging tasks resulted in greater liking and engagement scores compared with easy tasks. Pupil size tracked objective task difficulty, where challenging tasks were associated with greater pupil responses than easy tasks. Most importantly, pupil responses were predicted by trial-to-trial changes in average accuracy as well as learning progress (derivative of average accuracy), while greater pupil responses also predicted greater subjective engagement scores. Together, these results substantiate the Learning Progress Motivation hypothesis stating that the link between task engagement and cognitive effort is mediated the dynamic range for changes in task performance.

neuroscience↗

bioRxiv2021

Biased credit assignment in motivational learning biases arises through prefrontal influences on striatal learning

Actions are biased by the outcomes they can produce: Humans are more likely to show action under reward prospect, but hold back under punishment prospect. Such motivational biases derive not only from biased response selection, but also from biased learning: humans tend to attribute rewards to their own actions, but are reluctant to attribute punishments to having held back. The neural origin of these biases is unclear; in particular, it remains open whether motivational biases arise primarily from the architecture of subcortical regions or also reflect cortical influences, the latter being typically associated with increased behavioral flexibility and emancipation from stereotyped behaviors. Simultaneous EEG-fMRI allowed us to track which regions encoded biased prediction errors in which order. Biased prediction errors occurred in cortical regions (dACC, PCC) before subcortical regions (striatum). These results highlight that biased learning is not a mere feature of the basal ganglia, but arises through prefrontal cortical contributions, revealing motivational biases to be a potentially flexible, sophisticated mechanism.

neuroscience↗

bioRxiv2021

Social framing effects in decision making

Human decisions are known to be strongly influenced by the manner in which options are presented, the "framing effect". Here, we ask whether decision-makers are also influenced by how advice from other knowledgeable agents are framed, a "social framing effect". For example, do students learn better from a teacher who often frames advice by emphasizing appetitive outcomes, or do they learn better from another teacher who usually emphasizes avoiding options that can be harmful to their progress? We study the computational and neural mechanisms by which framing of advice affect decision-making, social learning, and trust. We found that human participants are more likely to trust and follow an adviser who often uses an appetitive frame for advice compared with another one who often uses an aversive frame. This social framing effect is implemented through a modulation of the integrative abilities of the ventromedial prefrontal cortex. At the time of choice, this region combines information learned via personal experiences of reward with social information, but the combination differs depending on the social framing of advice. Personally-acquired information is weighted more strongly when dealing with an adviser who uses an aversive frame. The findings suggest that social advice is systematically incorporated into our decisions, while being affected by biases similar to those influencing individual value-based learning.

neuroscience↗

bioRxiv2020

Stress-sensitive brain computations of task controllability

Estimating the controllability of the environment enables agents to better predict upcoming events and decide when to engage controlled action selection. How does the human brain estimate controllability? Trial-by-trial analysis of choices, decision times, and neural activity in an explore-and-predict task demonstrate that humans solve this problem by comparing the predictions of an "actor" model with those of a reduced "spectator" model of their environment. Neural BOLD responses within striatal and medial prefrontal areas tracked the instantaneous difference in the prediction errors generated by these two statistical learning models. BOLD activity in the posterior cingulate, temporoparietal, and prefrontal cortices covaried with changes in estimated controllability. Exposure to inescapable stressors biased controllability estimates downward and increased reliance on the spectator model in an anxiety-dependent fashion. Taken together, these findings provide a mechanistic account of controllability inference and its distortion by stress exposure.

neuroscience↗

bioRxiv2020

Does dopamine synthesis capacity predict individual variation in curiosity?

Curiosity, which can be defined as "intrinsically motivated information-seeking", is an important driving force in our everyday lives. Based on previous evidence demonstrating a link between information prediction errors and dopamine neuronal firing rates, we asked whether the drive to seek information varies with individual differences in dopamine synthesis capacity. In order to investigate this, we let participants perform a lottery task in which we independently manipulated outcome uncertainty, outcome valence (gains versus losses) and expected value, and asked participants to indicate their curiosity for each presented lottery. In a separate session, participants underwent an [18F]DOPA PET scan to quantify their dopamine synthesis capacity. We replicate previous behavioral results, showing that curiosity is a function of outcome uncertainty as well as outcome valence (gain versus loss). However, we found no evidence that curiosity or the sensitivity to outcome uncertainty, outcome valence and expected value was related to participants dopamine synthesis capacity in the ventral striatum, the caudate nucleus or the putamen. These findings stress the need for further studies into the role of dopamine in (different types of) curiosity.

neuroscience↗

bioRxiv2020

Striatal BOLD and midfrontal theta power express motivation for action

Action selection is biased by the valence of anticipated outcomes. To assess mechanisms by which these motivational biases are expressed and controlled, we measured simultaneous EEG-fMRI during a motivational Go/NoGo learning task (N=36), leveraging the temporal resolution of EEG and subcortical access of fMRI. VmPFC BOLD encoded cue valence, importantly predicting trial-by-trial valence-driven response speed differences and EEG theta power around cue onset. In contrast, striatal BOLD encoded selection of active Go responses and correlated with theta power around response time. Within trials, theta power ramped in the fashion of an evidence accumulation signal for the value of making a Go response, capturing the faster responding to reward cues. Our findings reveal a dual nature of midfrontal theta power, with early components reflecting the vmPFC contribution to motivational biases, and late components reflecting their striatal translation into behavior, in line with influential recent "value of work" theories of striatal processing.

neuroscience↗

bioRxiv2020

The cognitive effects of a promised bonus do not depend on dopamine synthesis capacity

Reward motivation is known to enhance cognitive control. However, detrimental effects have also been observed, which have been attributed to overdosing of already high baseline dopamine levels by further dopamine increases elicited by reward cues. Aarts et al. (2014) indeed demonstrated, in 14 individuals, that reward effects depended on striatal dopamine synthesis capacity, measured with [18F]FMT-PET: promised reward improved Stroop control in low-dopamine individuals, while impairing it in high-dopamine individuals. Here, we aimed to assess this same effect in 44 new participants, who had previously undergone an [18F]DOPA-PET scan to quantify dopamine synthesis capacity. This sample performed the exact same rewarded Stroop paradigm as in the prior study. However, we did not find any correlation between reward effects on cognitive control and striatal dopamine synthesis capacity. The discrepancy between the current and our previous findings might reflect the use of different radiotracers for indexing dopamine synthesis capacity. STATEMENT OF RELEVANCEReward motivation is generally thought to enhance cognitive control, but paradoxical negative effects of rewards on cognitive control have also been observed. A previous PET study demonstrated that reward effects on Stroop control depended on baseline striatal dopamine synthesis capacity, indexed by uptake of the radiotracer [18F]FMT. The sample size is this study was very small for a between-subject correlational design. Replicating the exact same Stroop paradigm within a larger sample is therefore crucial to robustly establish the mechanistic link between incentive motivation and cognitive control and advancing our understanding of who chokes under pressure and why, a topic of great societal relevance today. The present study did not reveal any correlation between reward effects on cognitive control and striatal dopamine synthesis capacity, indexed with [18F]FDOPA-PET. Future studies might consider putative differential sensitivity of the radiotracer [18F]FMT and [18F]FDOPA, while also addressing other indices of dopamine transmission.

neuroscience↗

bioRxiv2020

Striatal dopamine synthesis capacity reflects smartphone social activity

Striatal dopamine has been implicated in social behavior across humans, rodents, and non-human primates in artificial laboratory settings with highly-practiced tasks and fixed reward contingencies. Whether striatal dopamine drives naturalistic, spontaneous social behavior remains unclear. Here, we leverage day-to-day logs of unconstrained smartphone behavior and establish a novel link between smartphone social activity and individual differences in striatal dopamine synthesis capacity using [18F]-DOPA PET in (N=22) healthy adult humans. We find a strong relationship such that a higher proportion of social app interactions correlates with lower dopamine synthesis capacity in the bi-lateral putamen. Permutation tests and penalized regressions provide evidence that this link between dopamine synthesis capacity and social versus non-social smartphone taps is specific. These observations provide a key empirical grounding for current speculations about dopamines role in digital social behavior.

neuroscience↗