Biology subjects

Ahmed, A. A.

Publications and source records attributed to Ahmed, A. A..

At least 19 recordsLinked to original sources

bioRxiv2026

Locomotor adaptation can persistently reorganize stride-to-stride regulation of centre of mass error dynamics

Locomotor learning in novel environments relies on a gradual alteration of motor output to achieve a desired state. Changes in gait outcomes such as step-length asymmetry are typically used to describe this process. Recently, stability-relevant adaptations, quantified by scalar metrics such as the margin of stability, have also attracted interest. Yet humans, in part, regulate walking stability from stride-to-stride. Scalar metrics only provide instantaneous snapshots of stability and fail to capture rules governing fluctuations from one stride to the next. Here, we investigate whether locomotor adaptation changes how movement regulation evolves across strides using a multidimensional, dynamical systems model of centre-of-mass (CoM) based locomotion error. We apply this approach to split-belt locomotor adaptation, where participants walk on a treadmill with a separate belt for each foot. One belt moves faster than the other, driving participants to adapt compensatory gait patterns due to asymmetry. Using our stride-to-stride model, we find that, in addition to reducing CoM error while adapting, multidimensional error regulation dynamics are also adapted. This structural adaptation persists upon re-exposure to split-belt conditions. Our findings show that split-belt locomotor adaptation includes an adaptation of the structure of stride-to-stride CoM movement regulation and that this structure may be rapidly recalled.

neuroscience↗

bioRxiv2025

Development of a long-read high-throughput chromatin conformation capture method for evaluating both cis and trans interactions between integrated Hepatitis B Virus and host genomes.

High-throughput chromatin conformation capture (Hi-C) has been utilized for characterizing the 3-dimensional (3D) interactome of the genome. However, short-read sequencing approaches have limited the information it provides, especially for integrated proviral DNAs . Herein we describe the development of a pipeline to investigate the 3D interactome associated with integrated Hepatitis B Virus (HBV) DNAs (iDNAs) to further understand the role of HBV iDNA in liver carcinogenesis. We employed long-read DNA sequencing combined with a novel target-pull-down library construction approach that protects against DNA shearage resulting in greatly improved sensitivity and specificity for the targeted HBV iDNA. Most importantly, we successfully increased the length of captured Hi-C library to the multi-kilobase-level and report Hi-C contacts based on a custom-developed informatics pipeline. We anticipate this combined laboratory{-}informatics pipeline will provide a more comprehensive view of HBV iDNA-host genomic interactions associated with their role in liver carcinogenesis, but even more importantly that it should be generalizable for the study of the geno-topological effects associated with any type of integrated DNA. (word count: 164/250)

genomics↗

bioRxiv2025

Single cell functional immunogenomics of the fallopian tube reveals a precursor immune surveillance network for ovarian cancer prevention

The fallopian tube (FT) is increasingly recognized as the site of origin for high-grade serous ovarian cancer (HGSOC), yet its immune landscape and potential role in tumor surveillance remain poorly understood. Here, we employ single-cell RNA sequencing (scRNA-seq) and paired single-cell T-cell receptor sequencing (scTCR-seq) to profile tissue-resident memory-like T cells (TRMLs) from matched non- cancerous FT, metastatic omental tumors, and peripheral blood in HGSOC patients. Surprisingly, we identify a substantial clonal and functional overlap between TRMLs from non-cancerous FT and tumor- infiltrating TRMLs, with 18.4% of tumor TRML clonotypes being shared with FT TRMLs, significantly exceeding overlap with circulating T cells. Shared TCR clonotypes are preferentially enriched in exhausted CD8+ T cells (CD8-Tex) and proliferative exhausted CD8+ subsets, suggesting prior antigenic exposure. Notably, we identify a previously uncharacterized CD8+ SIK3-high subset enriched in tumors, with gene expression signatures implicating epigenetic plasticity and metabolic adaptation. Functionally, non-cancerous FT-derived TRMLs recognize autologous tumor antigens, as evidenced by robust IFN-{gamma} responses in tumor organoid co-culture assays and CD137 upregulation. Whole-genome and transcriptomic analyses reveal shared somatic mutations between the FT and tumor, supporting the FT as the tumors evolutionary origin. Predicted tumor neoantigens elicit TRML responses in the non-cancerous FT, and single-cell TCR profiling confirms that neoantigen-reactive T cells in FT share clonotypes with tumor-infiltrating TRMLs, further reinforcing their role in early immune surveillance. Importantly, FT-derived TRMLs exhibit lower exhaustion signatures than their tumor counterparts, suggesting their potential as a preferable source for adoptive T cell therapies. Our findings uncover a precursor immune surveillance network in the FT and provide a rationale for leveraging FT-resident T cells in cancer immunotherapy and prevention.

immunology↗

bioRxiv2025

The role of effort in adaptation to split-belt locomotion

In many motor learning tasks, the process of error reduction is mirrored in a process of effort reduction, where metabolic cost and or muscle co-contraction decrease gradually in tandem with error. Effort reduction may be incidental to the learning process, but high error movements can be more effortful and a drive to minimize effort costs could also play a role in motor learning. In this study, we focused on the effort requirements of the task, asking whether task (background) effort cost affects learning, aftereffects, or relearning in a split-belt walking task. We hypothesized that greater effort costs would amplify the need to reduce effort and accelerate learning. Alternatively, we hypothesized that greater effort requirement could compromise and slow the learning process. Participants in high, low, and control effort groups completed a split-belt walking task while wearing a weighted vest with 15% body mass, 5% body mass, or the vest only, and we assessed step length asymmetry throughout the protocol. Step length asymmetry changed similarly between groups, with similar rates and extent of learning and relearning and similar patterns of aftereffects when the split-belt perturbation was removed. We found no significant effect of task effort on the process of split-belt adaptation, suggesting that the brains response to gait asymmetry and ability to adapt to novel dynamics is relatively unchanged by background effort requirements of the task. NEW & NOTEWORTHYDespite the brains sensitivity to effort cost and willingness to adjust gait parameters to minimize cost, the process of split-belt adaptation was unaffected by increased effort requirements. This finding provides a foundation for further research into performance-dependent effort cost. Additionally, modest increases in effort should be further explored in rehabilitation applications where higher effort requirements may help build strength and fitness without impairing motor learning.

neuroscience↗

bioRxiv2025

Reaching vigor tracks learned prediction error

Movement vigor across multiple modalities increases with reward, suggesting that the neural circuits that represent value influence the control of movement. Dopaminergic neuron (DAN) activity has been suggested as the potential mediator of this response. If DAN activity is the bridge between value and vigor, then vigor should track canonical mediators of DAN activity, namely learning signals in the form of reward expectation and reward prediction error. Here we ask if a similar time-locked response is present in vigor of reaching movements. We explore this link by leveraging the known phasic dopaminergic response to stochastic rewards, where activity is modulated by both reward expectation at cue and the reward prediction error at feedback. We used probabilistic rewards to create a reaching task rich in reward expectation, reward prediction error, and learning. In one experiment, target reward probabilities were explicitly stated, and in the other, were left unknown and to be learned by the participants. We included two stochastic rewards (probabilities 33% and 66%) and two deterministic ones (probabilities 100% and 0%). In both experiments, outgoing peak velocity increased with increasing reward expectation. Furthermore, we observed a short-latency response in the vigor of the ongoing movement, that tracked reward prediction error: either invigorating or enervating velocity consistent with the sign and magnitude of the error. Reaching kinematics also revealed the value-update process in a trial-to-trial fashion, similar to the effect of prediction error signals typical in dopamine-mediated striatal phasic activity. Lastly, reach vigor increased with reward history over trials, mirroring the motivational effects often linked to fluctuating dopamine levels. Taken together, our results highlight the link between known short-latency dopaminergic learning signals and the invigoration of movement, not only at the time of cue presentation and movement initiation, but during an ongoing movement immediately after feedback is provided. NEW & NOTEWORTHYPrevious research has demonstrated the invigorating effects of reward on movement. Growing evidence suggests this is causally explained by midbrain dopamine transients. Here, we demonstrate that reach vigor tracks canonical variables of learning and motivation across time scales ranging from milliseconds to minutes. Velocity was modulated by reward expectation, reward prediction error and reward rate, key variables that have also been associated with striatal dopaminergic fluctuations. These results point to a potential neural mechanism by which dopamine can influence both decision making and movement control and support the proposition that reward-based invigoration of movement is in part influenced by dopaminergic circuits.

neuroscience↗

bioRxiv2024

Reward invigorates isometric gripping actions

Individuals exhibit a propensity to move faster toward more rewarding stimuli. While this phenomenon has been observed in movements, the effect of reward on implicit control of isometric actions, like gripping or grasping, is relatively unknown. How reward-related invigoration generalizes to other effortful actions is an important question. Reward invigorates reaching movements and saccades, supporting the idea that reward pays the additional effort cost of moving faster. Effort in isometric force generation is less understood, so here we ask whether and how reward-related invigoration generalizes to isometric force gripping. And if so, what implicit characteristics of gripping change when there is a prospect of reward? Participants (N=19) gripped a force transducer and the force applied was mapped to radial position of an onscreen cursor. Each trial, a target appeared in one of four locations; increasing grip force moved the cursor toward the target. The gripping action was interchangeable for all target positions. In each block of 100 trials, one target was consistently rewarded, while the other targets were not. When gripping to acquire the rewarded target, participants reacted faster, generated force more rapidly and to a greater extent, while intriguingly maintaining the same accuracy and integral of force over time. These findings support the generalization of reward-related invigoration in isometric force tasks, and that the brain exquisitely trades-off reward and effort costs to obtain reward more rapidly without compromising accuracy or more effort costs than necessary. NEW & NOTEWORTHYGripping actions are important for day-to-day tasks, for medical diagnostics like strength and force control, and for choice selection in decision-making experiments. Comparing isometric gripping responses to reward and nonreward cues, we observed reward-based invigoration mediated by selective increases in effort. These findings can be leveraged to provide additional insight into the decision making process, and better understand the effect of reward on movement vigor and the implicit control of accuracy.

neuroscience↗

bioRxiv2024

Long-read sequencing to detect full-length protein-protein interactions

Given the increased predictions on interactome size and demand for protein function information, methods for detecting protein-protein interactions remain a significant development area. The all-vs.-all sequencing (AVA-Seq) method utilizes a convergent fusion plasmid design to make two-hybrid technology amenable to next-generation sequencing. Here, we further innovate to take advantage of synthetic DNA technologies and Oxford Nanopore Technologies long-read sequencing improvements to allow us to determine full-length protein-protein interactions. Here, using this approach we recovered 159 protein-protein interactions from a set of 57 human proteins using multiple forms of validation. Further, when referencing a human gold standard set of interactions, eight full-length protein-protein interactions were recovered from an expected 28 interaction pairs (28.6%), a typical recovery rate for two-hybrid technologies. The AVA-Seq, in combination with the ease of synthetic DNA production and the MinION platform, offers a low-cost, high-throughput alternative for determining protein-protein interactions, which can be utilized in research labs at all stages. 3 Key PointsO_LIFirst application of long-read sequencing for full-length protein-protein interaction studies. C_LIO_LIThe recovery rate of the AVA-Seq method using full-length proteins is on par with other leading methods. C_LIO_LIAdvances in synthetic biology and sequencing technologies make full-length protein interactomes affordable and accessible. C_LI GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=74 SRC="FIGDIR/small/586447v1_ufig1.gif" ALT="Figure 1"> View larger version (23K): org.highwire.dtl.DTLVardef@1d81412org.highwire.dtl.DTLVardef@10dbb19org.highwire.dtl.DTLVardef@76a04borg.highwire.dtl.DTLVardef@15baf0_HPS_FORMAT_FIGEXP M_FIG C_FIG

molecular biology↗

bioRxiv2024

Physical Effort Pre-Crastination Determines Preference in an Isometric Task

How the brain decides when to invest effort is a central question in neuroscience. When asked to walk a mile to a destination, would you choose a path with a hill at the beginning or the end? The traditional view of effort suggests we should be indifferent--all joules are equal so long as it does not interfere with accomplishing the goal. Yet when total joules are equal, the brains sensitivity to the temporal profile of effort investment throughout a movement remains poorly understood. Here, we sought to parse out the interaction of time and physical effort by comparing subjective preferences in an isometric arm-pushing task that varied the duration and timing of high and low effort. Subjects were presented with a series of two-alternative forced choices, where they chose the force profile they would rather complete. Subjects preferred to pre-crastinate physical effort but were idiosyncratic about preference for task timing. A model of subjective utility that includes physical effort costs, task costs, and independent temporal sensitivity factors described subject preferences best. Interestingly, deliberation time and response vigor are best described by the same subjective utility model that won for preference, further validating this model of subjective utility. These results suggest physical effort costs are temporally sensitive, with earlier investment of effort preferred to later investment. These findings demonstrate that the representation of effort is based not only on the total energy required but its timing as well, and offer an alternative hypothesis for why animals pre-crastinate in physical tasks. NEW & NOTEWORTHYThis research utilizes a novel paradigm that differentiates between physical effort costs, task costs, and time, where subjects choose between isometric arm-pushing tasks. Here, subjects prefer high physical effort earlier, independent of task timing. We find that deliberation time and response vigor reflect subjective preferences. This research proposes a generalizable subjective utility model that includes independent time-sensitivity factors on physical effort and task costs and offers an alternative hypothesis for why animals may pre-crastinate.

neuroscience↗

bioRxiv2023

Effort cost of reaching prompts vigor reduction in older adults

As people age, they move slower. Is age-related reduction in vigor a reflection of a reduced valuation of reward by the brain, or a consequence of increased effort costs by the muscles? Here, we quantified cost of movements objectively via the metabolic energy that young and old participants consumed during reaching and found that in order reach at a given speed, older adults expended more energy than the young. We next quantified how reward modulated movements in the same populations and found that like the young, older adults responded to increased reward by initiating their movements earlier. Yet, their movements were less sensitive to increased reward, resulting in little or no modulation of reach speed. Lastly, we quantified the effect of increased effort on how reward modulated movements in young adults. Like the effects of aging, when faced with increased effort the young adults responded to reward primarily by reacting faster, with little change in movement speed. Therefore, reaching required greater energetic expenditure in the elderly, suggesting that the slower movements and reactions exhibited in aging are partly driven by an adaptive response to an elevation in the energetic landscape of effort. That is, moving slower appears to be a rational economic consequence of aging. Significance statementHealthy aging coincides with a reduction in speed, or vigor, of walking, reaching, and eye movements. Here we focused on disentangling two opposing sources of aging-related movement slowing: reduced reward sensitivity due to loss of dopaminergic tone, or increased energy expenditure movements related to mitochondrial or muscular inefficiencies. Through a series of three experiments and construction of a computational model, here we demonstrate that transient changes in reaction time and movement speed together offer a quantifiable metric to differentiate between reward- and effort-based alterations in movement vigor. Further, we suggest that objective increases in the metabolic cost of moving, not reductions in reward valuation, are driving much of the movement slowing occurring alongside healthy aging.

neuroscience↗

bioRxiv2023

Complex synaptic and intrinsic interactions disrupt input/output functions in the hippocampus of Scn1b knockout mice

Mutations in the SCN1B gene have been linked to severe developmental epileptic encephalopathies including Dravet syndrome. Scn1b knockout (KO) mice model SCN1B loss of function disorders, demonstrating seizures, developmental delays, and early death.SCN1B encodes the protein {beta}1, an ion channel auxiliary subunit that also has roles in cell adhesion, neurite outgrowth, and gene expression. The goal of this project is to better understand of how loss of {beta}1 alters information processing in the brain, resulting in seizures and associated cognitive dysfunction. Using slice electrophysiology in the CA1 region of the hippocampus from male and female Scn1b KO mice and wild-type (WT) littermates, we found that processing of physiologically relevant patterned Schaffer collateral (SC) stimulation produces larger, prolonged depolarizations and increased spiking in KO neurons compared to WTs. KO neurons exhibit enhanced intrinsic excitability, firing more action potentials with current injection. Interestingly, SC stimulation produces smaller, more facilitating excitatory and inhibitory postsynaptic currents in KO pyramidal neurons, but larger postsynaptic potentials with the same stimulation. We also found reduced intrinsic firing of parvalbumin-expressing interneurons and disrupted recruitment of both parvalbumin- and somatostatin-expressing interneurons in response to patterned synaptic stimulation. Neuronal information processing relies on the interplay between synaptic properties, intrinsic properties that amplify or suppress incoming synaptic signals, and firing properties that produce cellular output. We found changes at each of these levels in Scn1b KO pyramidal neurons, resulting in fundamentally altered information processing in the hippocampus that likely contributes to the complex phenotypes of SCN1B-linked epileptic encephalopathies. Significance statementGenetic developmental epileptic encephalopathies have limited treatment options, in part due to our lack of understanding of how genetic changes result in dysfunction at the cellular and circuit levels. SCN1B is a gene linked to Dravet syndrome and other epileptic encephalopathies, and Scn1b knockout mice phenocopy the human disease, allowing us to study underlying neurophysiological changes. Here we found changes at all levels of neuronal information processing in brains lacking {beta}1, including intrinsic excitability, synaptic properties, and synaptic integration, resulting in greatly enhanced input/output functions of the hippocampus. Our study shows that loss of {beta}1 results in a complex array of cellular and network changes that fundamentally alters information processing in the hippocampus.

neuroscience↗

bioRxiv2023

Disentangling the effects of metabolic cost and accuracy on movement vigor

AO_SCPLOWBSTRACTC_SCPLOWOn any given day, we make countless reaching movements to objects around us. While such ubiquity may suggest uniformity, each movement is unique in the speed with which it is made. Some movements are slow, while others are fast. These variations in reach speed have long been known to be influenced by accuracy constraints; we slow down when accuracy demands are high. However, in other forms of movement like walking, metabolic cost is the primary determinant of movement speed. Here we ask, how do metabolic cost and accuracy interact to determine speed of reaching movements? First we systematically measure the effect of increasing mass on the metabolic cost of reaching across a range of movement speeds. Next, in a sequence of three experiments, we examine how added mass affects preferred movement speeds in a simple reaching task with increasing accuracy requirements. We find that mass consistently increased metabolic cost and led to slower movements. Yet, intriguingly, preferred reach speeds were slower than metabolically optimal. We then demonstrate how a single model that, critically, considers both accuracy and metabolic cost can explain preferred movement speeds across the range of accuracy and effort requirements tested. Together, these findings provide a unifying framework to explain the combined effects of metabolic cost and accuracy on movement speed, and also highlight the integral role metabolic cost plays in determining reach speed.

neuroscience↗

bioRxiv2022

The E2 SUMO-conjugating enzyme UBE2I coordinates the oocyte and zygotic transcriptional programs

In mammals, meiotically competent oocytes develop cyclically during ovarian folliculogenesis. During folliculogenesis, prophase I arrested oocytes are transcriptionally active, producing and storing transcripts required for their growth and for early stages of embryogenesis prior to the maternal to zygotic transition. Defective oocyte development during folliculogenesis leads to meiotic defects, aneuploidy, follicular atresia, or non-viable embryos. Here we generated a novel oocyte-specific knockout of the SUMO E2 ligase, Ube2i, using Zp3-cre to test its function during folliculogenesis. Ube2i Zp3-cre+ female mice are sterile with oocytes that arrest in meiosis I with defective spindles and chromosome alignment. Fully grown mutant oocytes abnormally maintain transcription but downregulate maternal effect genes and prematurely activate the zygotic transcriptional program. Thus, this work uncovers UBE2i as a novel orchestrator of chromatin and transcriptional regulation in mouse oocytes. TeaserOocyte-specific deletion of Ube2i causes loss of transcriptional repression and premature activation of the zygotic genome.

cell biology↗

bioRxiv2022

LARP1 regulates metabolism and mTORC1 activity in cancer

The protein mammalian target of rapamycin (mTOR) is a master regulator of cell homeostasis. Although mTOR is aberrantly overactivated in 70% ovarian cancers, mTOR cascade inhibitors (such as those blocking the kinase activity of mTOR itself or upstream kinases PI3K/AKT) have demonstrated disappointing activity in ovarian cancer clinical trials. These findings indicate that, despite its pivotal role in normal cells, hyperactivated mTOR does not act as a master regulator of metabolism in this cancer context. Surprisingly, we have identified that the RNA binding protein LARP1, a known phospho-target of mTORC1 and activator of ribosomal biogenesis, is responsible for metabolic reprogramming in mTOR-dysregulated cancers. LARP1 post-transcriptionally regulates the expression of several hundred rate-limiting enzymes involved in multiple aspects of metabolism, including glycolysis and oxidative phosphorylation. Through this mechanism LARP1 sustains ATP production and mTORC1 localisation on the lysosome, thereby activating cell proliferation despite the scarcity of extracellular nutrients. Our findings show that, by sustaining global cellular metabolism in response to growth factor signalling, LARP1 has a central post-transcriptional role in controlling mTORC1 localisation and driving cancer progression, a key cancer hallmark.

cancer biology↗

bioRxiv2022

Single Cell Transcriptomics identifies a WNT7A-FZD5 Signaling Axis that maintains Fallopian Tube Stem Cells in Patient-derived Organoids

Despite its significance to reproduction, fertility, sexually transmitted infections and various pathologies, the fallopian tube (FT) is relatively understudied. Strong evidence points to the FT as the tissue-of-origin of high grade serous ovarian cancer (HGSOC), the most fatal gynaecological malignancy. HGSOC precursor lesions arise specifically in the distal FT (fimbria) which is reported to be enriched in stem-like cells. Investigation of the role of FT stem cells in health and disease has been hampered by a lack of characterization of FT stem cells and lack of models that recapitulate stem cell renewal and differentiation in vitro. Using optimized organoid culture conditions to address these limitations, we found that FT stem cell renewal is highly dependent on WNT/{beta}-catenin signaling and engineered endogenous WNT/{beta}-catenin signaling reporter organoids to biomark, isolate and characterize putative FT stem cells. Using functional approaches as well as bulk and single cell transcriptomic analyses, we show that an endogenous hormonally-regulated WNT7A-FZD5 signaling axis is critical for self-renewal of human FT stem cells, and that WNT/{beta}-catenin pathway-activated FT cells form a distinct transcriptomic cluster of cells enriched in ECM remodelling and integrin signaling pathways. In addition, we find that the WNT7A-FZD5 signaling axis is dispensable for mouse oviduct regeneration. Overall, we provide a deep characterization of FT stem cells and their molecular requirements for self-renewal, paving the way for mechanistic work investigating the role of stem cells in FT health and disease. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=165 SRC="FIGDIR/small/502319v3_ufig1.gif" ALT="Figure 1"> View larger version (31K): org.highwire.dtl.DTLVardef@124d8a0org.highwire.dtl.DTLVardef@9f92borg.highwire.dtl.DTLVardef@c57b33org.highwire.dtl.DTLVardef@11b5bec_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2022

The vigor paradox: saccade velocity during deliberation encodes utility of effortful actions

During deliberation, as the brain considers its options, the neural activity representing the goodness of each option rises toward a threshold, and the choice is often dictated by the option for which the rise is fastest. Here we report a surprising correlate of these activities: saccade vigor. We engaged human subjects in a decision-making task in which they considered effortful options, each requiring walking various durations and inclines. As they deliberated, they made saccades between the symbolic representations of those options. These saccades had no bearing on the effort that they would later expend, yet as they deliberated, saccade velocities increased. The rate of rise in vigor was faster for saccades toward the option that they later indicated as their choice, and encoded the difference in the subjective value of the two effortful options. Once deliberation ended, following a brief delay the subjects indicated their choice by making another saccade. Remarkably, vigor for this saccade dropped to baseline and no longer encoded subjective value. These results are consistent with an urgency model of decision-making in which a global signal in the brain drives both the neural circuits that make decisions, and the neural circuits that make movements. Paradoxically, this common drive is shared between the oculomotor circuits and the decision-making circuits, even when the decision involves effortful expenditure during a future event. SignificanceThere is a link between the decisions we make and the movements that follow. Not only do we prefer options of greater value, but we also move faster to acquire them. When deliberating between options, neural activity rises to a threshold and the option that wins this race is the one chosen. We report a potential correlate of this in the motor control circuits; during deliberation, saccade vigor to both options rise, but faster for the option ultimately chosen. Thus, our movements appear to mirror the neural activity conducting the decision-making process. Paradoxically, this is true even when the movements have no direct bearing on the decision at hand.

neuroscience↗

bioRxiv2022

Learning vs. minding: How subjective costs can mask motor learning

When learning new movements some people make larger kinematic errors than others, interpreted as a reduction in motor-learning ability. Consider a learning task where error-cancelling strategies incur higher effort costs, specifically where subjects reach to targets in a force field. Concluding that those with greater error have learned less has a critical assumption: everyone uses the same error-canceling strategy. Alternatively, it could be that those with greater error may be choosing to sacrifice error reduction in favor of a lower effort movement. Here, we test this hypothesis in a dataset that includes both younger and older adults, where older adults exhibited greater kinematic errors. Utilizing the framework of optimal control theory, we infer subjective costs (i.e., strategies) and internal model accuracy (i.e., proportion of the novel dynamics learned) by fitting a model to each populations trajectory data. Our results demonstrate trajectories are defined by a combination of the amount learned and strategic differences represented by relative cost weights. Based on the model fits, younger adults could have learned between 65-90% of the novel dynamics. Critically, older adults could have learned between 60-85%. Each model fit produces trajectories that match the experimentally observed data, where a lower proportion learned in the model is compensated for by increasing costs on kinematic errors relative to effort. This suggests older and younger adults could be learning to the same extent, but older adults have a higher relative cost on effort compared to younger adults. These results call into question the proposition that older adults learn less than younger adults and provide a potential explanation for the equivocal findings in the literature. Importantly, our findings suggest that the metrics commonly used to probe motor learning paint an incomplete picture, and that to accurately quantify the learning process the subjective costs of movements should be considered. Author SummaryHere we show that how a person values effort versus error in their movements has an impact on their overall strategy for performing those movements and adapting to a novel environment. When error alone is considered as a measure of learning, it appears that certain populations such as older adults are significantly worse at learning new motor tasks. However, using an optimal control framework, we are able to parse out differences in how much a population or person has learned, as well as how they subjectively value factors such as effort and error. In the case of older adults, we show that they could be learning as much as younger adults but exhibit larger errors because they care more about expending extra effort to reduce them.

neuroscience↗

bioRxiv2021

Effects of reward history on decision-making and movement vigor

During foraging, animals explore a site and harvest reward, and then abandon that site and travel to the next opportunity. One aspect of this behavior involves decision-making, while the other involves movement control. We recently proposed that control of decision-making and movements may be linked via a desire to maximize a single normative utility: the sum of all rewards acquired, minus all efforts expended, divided by time. If this is the case, then the history of rewards, and not just its immediate availability, should dictate how long one decides to stay and harvest reward, and how fast one travels to the next opportunity. We tested this theory in a series of experiments in which humans used their hand to harvest tokens at a reward patch, and then used their arm to reach toward a subsequent opportunity. Experiencing a history of poor rewards not only led people to forage longer, but they also reached slower toward the next reward site. Thus, reward history had a consistent effect on both the decision-making process regarding when to abandon a reward site, and the motor control process regarding how fast to move to the next opportunity.

neuroscience↗

bioRxiv2021

An interpretable meta-clustering framework for single-cell RNA-Seq data integration and evaluation

Single-cell RNA sequencing (scRNA-Seq) datasets that are produced from clinical samples are often confounded by batch effects and inter-patient variability. Existing batch effect removal methods typically require strong assumptions on the composition of cell populations being near identical across patients. Here we present a novel meta-clustering workflow, CIDER, based on inter-group similarity measures. We demonstrate that CIDER outperforms other scRNA-Seq clustering methods and integration approaches in both simulated and real datasets. Moreover, we show that CIDER can be used to assess the biological correctness of integration in real datasets, while it does not require the existence of prior cellular annotations.

bioinformatics↗