Biology subjects

Duque, J.

Publications and source records attributed to Duque, J..

30 records · Page 2Linked to original sources

bioRxiv2022

Tension at intercellular junctions is necessary for accurate orientation of cell division in the epithelium plane

The direction in which a cell divides is set by the orientation of its mitotic spindle and is important for determining cell fate, controlling tissue shape and maintaining tissue architecture. Division perpendicular to the plane of the substrate can promote tissue stratification during development or wound healing, but also metastasis when orientation is aberrant. Much is known about the molecular mechanisms involved in setting the spindle orientation. However, less is known about the contribution of mechanical factors, such as tissue tension, in ensuring spindle orientation in the plane of the epithelium, despite epithelia being continuously subjected to mechanical stresses. Here, we used suspended epithelial monolayers devoid of extracellular matrix and subjected to varying levels of tissue tension to study the orientation of division relative to the tissue plane. We found that decreasing tissue tension by compressing the monolayers or by inhibiting myosin contractility leads to a higher frequency of out-of-plane divisions. Reciprocally, accurate in-plane division can be restored by increasing tissue tension by increasing cell contractility or by tissue stretching. By considering the full three-dimensional geometry of the epithelium, we show that spindles are sensitive to tissue tension, independently of cell shape, through its impact on the tension at subcellular surfaces. Overall, our data suggest that accurate spindle orientation in the plane of the epithelium necessitates the presence of a sufficiently large tension at intercellular junctions. Significance statementIn growing epithelia, divisions are typically oriented in the plane of the tissue to drive expansion. In some organs, divisions are then re-oriented so that they occur perpendicular to the epithelium plane to drive tissue stratification and cell differentiation. When uncontrolled, this switch in orientation can lead to defects in tissue organisation and, in cancer, likely contribute to metastasis. While much is known about the molecular mechanisms controlling mitotic spindle orientation, less is known about the role of mechanical factors. Here we use mechanical and chemical perturbations to show that mechanics plays a role in controlling the plane of division. Overall, our data suggest that the orientation of spindles in the epithelium plane requires sufficient tension across intercellular junctions.

biophysics↗

bioRxiv2021

Post-error slowing reflects the joint impact of adaptive and maladaptive processes during decision making

Errors and their consequences are typically studied by investigating changes in decision speed and accuracy in trials that follow an error, commonly referred to as "post-error adjustments". Many studies have reported that subjects slow down following an error, a phenomenon called "post-error slowing" (PES). However, the functional significance of PES is still a matter of debate as it is not always adaptive. That is, it is not always associated with a gain in performance and can even occur with a decline in accuracy. Here, we hypothesized that the nature of PES is influenced by ones speed-accuracy tradeoff policy, which determines the overall level of choice accuracy in the task at hand. To test this hypothesis, we investigated post-error adjustments in subjects performing the same task while they were required to either emphasize speed (low accuracy) or cautiousness (high accuracy) in two distinct contexts (hasty and cautious contexts, respectively) experienced on separate days. Accordingly, our data indicate that post-error adjustments varied according to the context in which subjects performed the task, with PES being solely significant in the hasty context. In addition, we only observed a gain in performance after errors in a specific trial type, suggesting that post-error adjustments depend on a complex combination of processes that affect the speed of ensuing actions as well as the degree to which such PES comes with a gain in performance.

neuroscience↗

bioRxiv2021

Reward timing matters in motor learning

Reward can improve motor learning and the consolidation of motor memories. Identifying the features of reward feedback that are critical for motor learning is a necessary step for successful integration into rehabilitation programs. One central feature of reward feedback that may affect motor learning is its timing - that is, the delay after which reward is delivered following movement execution. In fact, research on associative learning has shown that short and long reward delays (e.g., 1 and 6 s following action execution) activate preferentially the striatum and the hippocampus, respectively, which both contribute with varying degrees to motor learning. Given the distinct functional role of these two areas, we hypothesized that reward timing could modulate how people learn and consolidate a new motor skill. In sixty healthy participants, we found that delaying reward delivery by a few seconds influenced motor learning dynamics. Indeed, training with a short reward delay (i.e., 1 s) induced slow, yet continuous gains in performance, while a long reward delay (i.e., 6 s) led to initially high learning rates that were followed by an early plateau in the learning curve and a lower endpoint performance. Moreover, participants who successfully learned the skill with a short reward delay displayed overnight consolidation, while those who trained with a long reward delay exhibited an impairment in the consolidation of the motor memory. Overall, our data show that reward timing affects motor learning, potentially by modulating the engagement of different learning processes, a finding that could be exploited in future rehabilitation programs.

neuroscience↗

bioRxiv2021

Overlapping influences shape motor activity during hasty sensorimotor decisions

Humans and other animals are able to adjust their speed-accuracy tradeoff (SAT) at will depending on the urge to act, favoring either cautious or hasty decision policies in different contexts. An emerging view is that SAT regulation relies on influences exerting broad changes on the motor system, tuning its activity up globally when hastiness is at premium. The present study aimed to test this hypothesis. Fifty subjects performed a task involving choices between left and right index fingers, in which incorrect choices led either to a high or to a low penalty in two contexts, inciting them to emphasize either cautious or hasty policies. We applied transcranial magnetic stimulation on multiple motor representations, eliciting motor evoked potentials (MEP) in nine finger and leg muscles. MEP amplitudes allowed us to probe activity changes in the corresponding finger and leg representations, while subjects were deliberating about which index to choose. Our data indicate that hastiness entails a broad amplification of motor activity, though this amplification was limited to the chosen side. On top of this effect, we identified a local suppression of motor activity, surrounding the chosen index representation. Hence, a decision policy favoring speed over accuracy appears to rely on overlapping processes producing a broad (but not global) amplification and a surround suppression of motor activity. The latter effect may help to increase the signal-to-noise ratio of the chosen representation, as supported by single-trial correlation analyses indicating a stronger differentiation of activity changes in finger representations in the hasty context.

neuroscience↗

bioRxiv2021

Molecular architecture determines brain delivery of a transferrin-receptor targeted lysosomal enzyme

Delivery of biotherapeutics across the blood-brain barrier (BBB) is a challenge. Many approaches fuse biotherapeutics to platforms that bind the transferrin receptor (TfR), a brain endothelial cell target, to facilitate receptor-mediated transcytosis across the BBB. Here, we characterized the pharmacological behavior of two distinct TfR-targeted platforms fused to iduronate 2-sulfatase (IDS), a lysosomal enzyme deficient in mucopolysaccharidosis type II (MPS II), and compared the relative brain exposures and functional activities of both approaches in mouse models. IDS fused to a moderate-affinity, monovalent TfR binding enzyme transport vehicle (ETV:IDS) resulted in widespread brain exposure, internalization by parenchymal cells, and significant substrate reduction in the CNS of an MPS II mouse model. In contrast, IDS fused to a standard high-affinity bivalent antibody (IgG:IDS) resulted in lower brain uptake, limited biodistribution beyond brain endothelial cells, and reduced brain substrate reduction. These results highlight important features likely to impact the clinical development of TfR-targeting platforms in MPS II and potentially other CNS diseases. SummaryBrain delivery, biodistribution and pharmacodynamics of a lysosomal enzyme fused to a moderate-affinity transferrin receptor-directed blood-brain barrier enzyme transport vehicle are superior to a traditional high-affinity anti-TfR monoclonal antibody fusion.

neuroscience↗

bioRxiv2021

Reward boosts reinforcement-based motor learning

Besides relying heavily on sensory and reinforcement feedback, motor skill learning may also depend on the level of motivation experienced during training. Yet, how motivation by reward modulates motor learning remains unclear. In 90 healthy subjects, we investigated the net effect of motivation by reward on motor learning while controlling for the sensory and reinforcement feedback received by the participants. Reward improved motor skill learning beyond performance-based reinforcement feedback. Importantly, the beneficial effect of reward involved a specific potentiation of reinforcement-related adjustments in motor commands, which concerned primarily the most relevant motor component for task success and persisted on the following day in the absence of reward. We propose that the long-lasting effects of motivation on motor learning may entail a form of associative learning resulting from the repetitive pairing of the reinforcement feedback and reward during training, a mechanism that may be exploited in future rehabilitation protocols.

neuroscience↗

bioRxiv2020

Dynamic changes in urgency over the course of a decision

Humans and other animals often need to balance the desire to gather sensory information (to make the best choice) with the urgency to act, facing a speed-accuracy tradeoff (SAT). Given the ubiquity of SAT across species, extensive research has been devoted to understanding the computational mechanisms allowing its regulation at different timescales, including from one context to another, and from one decision to another. However, animals must frequently change their SAT on even shorter timescales - i.e., over the course of an ongoing decision - and little is known about the mechanisms that allow such rapid adaptations. The present study aimed at addressing this issue. Human subjects performed a decision task with changing evidence. In this task, subjects received rewards for correct answers but incurred penalties for mistakes. An increase or a decrease in penalty occurring halfway through the trial promoted rapid SAT shifts, favoring speeded decisions either in the early or in the late stage of the trial. Importantly, these shifts were associated with stage-specific adjustments in the accuracy criterion exploited for committing to a choice. Those subjects who decreased the most their accuracy criterion at a given decision stage exhibited the highest gain in speed, but also the highest cost in terms of performance accuracy at that time. Altogether, the current findings offer a unique extension of previous work, by suggesting that dynamic changes in accuracy criterion allow the regulation of the SAT within the timescale of a single decision. New and noteworthyExtensive research has been devoted to understanding the mechanisms allowing the regulation of the speed-accuracy tradeoff (SAT) from one context to another and from one decision to another. Here, we show that humans can voluntarily change their SAT on even shorter timescales - i.e., over the course of a decision. These rapid SAT shifts are associated with dynamic adjustments in the accuracy criterion exploited for committing to a choice.

animal behavior and cognition↗

bioRxiv2020

Motor training strengthens corticospinal suppression during movement preparation

Training can improve motor skills and modify neural activity at rest and during movement execution. Learning-related modulations may also concern motor preparation but the neural correlates and the potential behavioral relevance of such adjustments remain unclear. In humans, preparatory processes have been largely investigated using transcranial magnetic stimulation (TMS) with several studies reporting decreased corticospinal excitability (CSE) relative to a baseline measure; a phenomenon called preparatory suppression. Here, we investigated the effect of motor training on preparatory suppression of CSE in humans, as compared to modulatory changes at rest. We trained participants to initiate quick movements in an instructed-delay reaction time (RT) task and used TMS to investigate changes in CSE over the practice blocks. Training on the task speeded up RTs, with no repercussion on error rates. Training also increased baseline CSE at rest. Most interestingly, we found that motor activity during action preparation did not mirror the training-related rise in resting CSE. Rather, the degree of preparatory suppression from the rising baseline strengthened with practice. This training-related change in preparatory suppression predicted RT gains (but not the changes in baseline CSE): subjects showing a stronger expansion of preparatory suppression were also those exhibiting larger gains in RTs. Finally, such relationship between RTs and preparatory suppression was also evident at the single-trial level: RTs were generally faster in trials where preparatory suppression was deeper. These findings suggest that training induces changes in motor preparatory processes that are linked to an enhanced ability to initiate fast movements. New and NoteworthyAny movement is preceded by a period of preparation, which involves a broad suppression of the corticospinal pathway, a phenomenon called preparatory suppression. Here, we show that motor training strengthens preparatory suppression and that this strengthening is associated with an acceleration of movement initiation. Our findings yield an extension of former work, highlighting a key role of preparatory suppression in training-driven behavioral improvements.

neuroscience↗

bioRxiv2019

Planning Face, Hand, and Leg Movements: Anatomical Constraints on Preparatory Inhibition.

Motor-evoked potentials (MEPs), elicited by Transcranial Magnetic Stimulation (TMS) over the motor cortex, are reduced during the preparatory period in delayed response tasks. Here we examine how MEP suppression varies as a function of the anatomical organization of the motor cortex. MEPs were recorded from a left index muscle while participants prepared a hand or leg movement in Experiment 1, or prepared an eye or mouth movement in Experiment 2. In this manner, we assessed if the level of MEP suppression in a hand muscle varied as a function of the anatomical distance between the agonist for the forthcoming movement and the muscle targeted by TMS. MEPs suppression was attenuated when the cued effector was anatomically distant from the hand (e.g., leg or facial movement compared to finger movement). A similar effect was observed in Experiment 3 in which MEPs were recorded from a muscle in the leg and the forthcoming movement involved the upper limb or face. These results demonstrate an important constraint on preparatory inhibition: It is sufficiently broad to be manifest in a muscle that is not involved in the task, but is not global, showing a marked attenuation when the agonist muscle belongs to a different segment of the body. New & NoteworthyUsing TMS, we examine changes in corticospinal excitability as people prepare to move. Consistent with previous work, we observe a reduction in excitability during the preparatory period, an effect observed in both task relevant and task irrelevant muscles. However, this preparatory inhibition is anatomically constrained, attenuated in muscles belonging to a different body segment than the agonist of the forthcoming movement.

neuroscience↗

bioRxiv2018

Challenging the function of motor inhibition: Does it really assist action selection?

By applying transcranial magnetic stimulation (TMS) over the primary motor cortex (M1) to elicit motor-evoked potentials (MEPs) in muscles of the contralateral hand during reaction time (RT) tasks, many studies have reported a strong suppression of MEPs during action preparation, a phenomenon called preparatory inhibition. Several hypotheses have been put forward regarding the role of this inhibition, with the predominant view suggesting that it would help action selection. However, this assumption is still a matter of debate. Here, we aimed at directly addressing this idea by comparing MEPs in a task that required subjects to select a finger response within a set of predefined options (choice RT task: left or right index finger abduction) or when subjects simply had to provide the same finger response on every trial, in the absence of choice (simple RT task). Moreover, we minimized any effect that could be associated with other forms of inhibition. In both versions of the task, TMS was applied on both M1 (double-coil protocol) at several time points between the go signal and the left or right index finger response, eliciting MEPs bilaterally in the prime mover (index finger agonist) and in an irrelevant muscle (pinky agonist). Overall, MEP suppression was moderate in this study; it was only found for the irrelevant muscle. As such, MEPs in the index agonist were facilitated when elicited in a responding hand (e.g. left MEPs preceding left responses) and remained mostly unchanged in a non-responding hand (e.g. left MEPs preceding right responses). In contrast, MEPs were almost always suppressed in the pinky muscle when elicited in the non-responding hand and sometimes also in the responding hand. Importantly, this effect was more consistent in the choice than in the simple RT task, supporting the view that preparatory inhibition may assist action selection. Moreover, the fact that it sometimes concerned the responding hand is coherent with the idea of a global process, suppressing broadly the motor system.\n\nHighlightsO_LIAddressed the debated idea that preparatory inhibition assists action selection\nC_LIO_LICompared MEPs in simple and choice RT tasks (no catch, no delay)\nC_LIO_LIDetected preparatory suppression of MEPs, although weaker than usual\nC_LIO_LIObserved a more consistent suppression of MEPs in the choice than simple setting\nC_LIO_LIProvided support for action selection hypothesis, with traces of broad inhibition\nC_LI

neuroscience↗

bioRxiv2018

M1 disruption delays motor processes but not deliberation about action choices

Decisions about actions typically involve a period of deliberation that ends with the commitment to a choice and the motor processes overtly expressing that choice. Previous studies have shown that neural activity in sensorimotor areas, including the primary motor cortex (M1), correlates with deliberation features during action selection. Yet, the causal contribution of these areas to the decision process remains unclear. Here, we investigated whether M1 determines choice commitment, or whether it simply reflects decision signals coming from upstream structures and instead mainly contributes to the motor processes that follow commitment. To do so, we tested the impact of a disruption of M1 activity, induced by continuous theta burst stimulation (cTBS), on the behavior of human subjects in (1) a simple reaction time (SRT) task allowing us to estimate the duration of the motor processes and (2) a modified version of the tokens task (Cisek et al., 2009), which allowed us to estimate subjects time of commitment as well as accuracy criterion. The efficiency of cTBS was attested by a reduction in motor evoked potential amplitudes following M1 disruption, as compared to those following a sham stimulation. Furthermore, M1 cTBS lengthened SRTs, indicating that motor processes were perturbed by the intervention. Importantly, all of the behavioral results in the tokens task were similar following M1 disruption and sham stimulation, suggesting that the contribution of M1 to the deliberation process is potentially negligible. Taken together, these findings favor the view that M1 contribution is downstream of the decision process.\n\nNew and noteworthyDecisions between actions are ubiquitous in the animal realm. Deliberation during action choices entails changes in the activity of the sensorimotor areas controlling those actions, but the causal role of these areas is still often debated. Using continuous theta burst stimulation, we show that disrupting the primary motor cortex (M1) delays the motor processes that follow instructed commitment but does not alter volitional deliberation, suggesting that M1 contribution may be downstream of the decision process.

neuroscience↗

bioRxiv2017

Theoretical Analysis of Inducer and Operator Binding for Cyclic-AMP Receptor Protein Mutants

Allosteric transcription factors undergo binding events both at their inducer binding sites as well as at distinct DNA binding domains, and it is often difficult to disentangle the structural and functional consequences of these two classes of interactions. In this work, we compare the ability of two statistical mechanical models - the Monod-Wyman-Changeux (MWC) and the Koshland-Nemethy-Filmer (KNF) models of protein conformational change - to characterize the multi-step activation mechanism of the broadly acting cyclic-AMP receptor protein (CRP). We first consider the allosteric transition resulting from cyclic-AMP binding to CRP, then analyze how CRP binds to its operator, and finally investigate the ability of CRP to activate gene expression. In light of these models, we examine data from a beautiful recent experiment that created a single-chain version of the CRP homodimer, thereby enabling each subunit to be mutated separately. Using this construct, six mutants were created using all possible combinations of the wild type subunit, a D53H mutant subunit, and an S62F mutant subunit. We demonstrate that both the MWC and KNF models can explain the behavior of all six mutants using a small, self-consistent set of parameters. In comparing the results, we find that the MWC model slightly outperforms the KNF model in the quality of its fits, but more importantly the parameters inferred by the MWC model are more in line with structural knowledge of CRP. In addition, we discuss how the conceptual framework developed here for CRP enables us to not merely analyze data retrospectively, but has the predictive power to determine how combinations of mutations will interact, how double mutants will behave, and how each construct would regulate gene expression.

biophysics↗