Biology subjects

Franklin, S.

Publications and source records attributed to Franklin, S..

16 recordsLinked to original sources

bioRxiv2026

Cardiomyocyte-specific loss of Smyd5 leads to a robust activation of inflammatory signaling and heart failure in mice.

Background: Cardiomyocytes respond to stress by undergoing hypertrophic growth driven by dynamic changes in gene expression. Epigenetic mechanisms, including histone methylation, play critical roles in regulating these transcriptional programs, yet the enzymes controlling these modifications during cardiac disease remain largely unknown. The SMYD family of histone methyltransferases regulates gene expression in multiple biological contexts, but the function of SMYD5 in the mammalian heart has never been investigated. Methods: SMYD5 expression was assessed in human heart failure samples and in a mouse model of cardiac hypertrophy. To define its functional role in vivo, we generated inducible cardiomyocyte-specific Smyd5 knockout mice and characterized their cardiac phenotype using molecular, histological, and functional analyses. Chromatin immunoprecipitation-quantitative PCR (ChIP-qPCR) was performed to examine histone H4 lysine 20 trimethylation (H4K20me3) at the Il-6 promoter. Results: SMYD5 expression was altered in diseased human and mouse hearts. Under basal conditions, cardiomyocyte-specific deletion of Smyd5 resulted in baseline structural cardiac remodeling and transcriptional signatures characteristic of pathological stress. Smyd5-deficient hearts exhibited marked inflammatory activation resembling a cytokine storm with immune cell infiltration and heart failure. Notably, Smyd5 knockout mice displayed a 100-fold increase in Il-6 expression, accompanied by a global reduction in H4K20me3. ChIP-qPCR analysis of the Il-6 promoter, together with loss- and gain-of-function analysis of SMYD5, supports a direct epigenetic role of SMYD5 in regulating Il-6 expression through H4K20me3 in cardiomyocytes. Conclusions: SMYD5 is a previously unrecognized epigenetic regulator of cardiac homeostasis that restrains inflammatory signaling in cardiomyocytes under normal conditions. Loss of Smyd5 disrupts H4K20me3, leading to derepression of Il-6 in cardiomyocytes and a robust inflammatory response characterized by immune cell recruitment and fibrosis, accompanied by rapid progression of cardiac remodeling and heart failure. These findings identify SMYD5 as a critical regulator of intrinsic cardiomyocyte inflammatory signaling and reveal a novel chromatin-based mechanism contributing to inflammatory cardiomyopathies.

molecular biology↗

bioRxiv2026

The SMYD1 p.Asn101Ser is a partial loss-of-function variant that impairs mitochondrial function and leads to early-onset cardiomyopathy.

Infantile cardiomyopathies are rare, life-threatening disorders for which genetic diagnosis has been accelerated by next-generation sequencing approaches, including gene panel, exome, and genome sequencing. However, determining the functional consequences of identified variants remains a major challenge. Variants in SMYD1, a striated muscle-specific lysine methyltransferase critical for cardiac development and mitochondrial function, have only recently been linked to human cardiomyopathy. Here, we functionally characterize a homozygous SMYD1 variant (c.302A>G; p.Asn101Ser) identified in a patient with severe early-onset cardiomyopathy requiring cardiac transplantation. Structural modeling predicts that the N101S substitution perturbs a highly conserved residue near the cofactor binding pocket within SMYD1s catalytic domain, disrupting local interactions and modestly destabilizing the protein. Consistent with these predictions, in vitro studies demonstrate that the N101S variant impairs mitochondrial respiratory capacity in myocytes. Quantification of SMYD1 protein levels in patient cardiac tissue revealed increased SMYD1 abundance, suggesting that the N101S variant results in functional impairment rather than protein instability and may trigger compensatory upregulation of SMYD1 expression. Together, these findings support a hypomorphic mechanism in which the N101S variant disrupts SMYD1 activity, leading to mitochondrial dysfunction and cardiomyopathy. This study provides mechanistic insight into SMYD1-associated cardiomyopathy and highlights the importance of integrating genetic, structural, and functional analyses to establish the pathogenicity of rare variants. New & NoteworthyThis study provides the first functional characterization of the cardiomyopathy-associated SMYD1 N101S variant identified in a child with severe infantile cardiomyopathy. Structural modeling predicts reduced protein stability, while cellular assays demonstrate impaired mitochondrial respiratory function, supporting a hypomorphic effect. These findings establish a mechanistic link between SMYD1 dysfunction and infantile cardiomyopathy and highlight the importance of integrating genomic and functional approaches in rare cardiovascular disease.

cell biology↗

bioRxiv2026

Independent Online Visuomotor Control to Cursor and Target Motion

Skilled control of visually-guided reaching is fundamental for many daily activities. Visual information about hand and target position are used for movement planning and online corrections through rapid visuomotor feedback responses. Such feedback control is generally believed to implicate a single error signal, representing a difference vector between hand and target position. Here, we directly assess whether shared or independent systems serve visually-guided feedback control. We tested whether feedback gains can be independently modulated by hand/cursor and target motion through manipulating the task-relevance of each signal during goal-directed reaching. Our results demonstrate that the gains of visuomotor feedback responses to perturbed hand and target motion can be set independently of one another, at the same time, as a function of task-relevance. By dissociating feedback control of cursor and target signals, our findings support the existence of two independent visuomotor feedback pathways, revealing a more flexible neural architecture for goal-directed action.

neuroscience↗

bioRxiv2026

Flexible neural encoding of dynamics allows precise tuning to the environment

To precisely control our movements, the sensorimotor control system builds representations of the external world. However, the neural encoding of these representations - whether we encode our control as a function of specific kinematic or kinetic variables - and how we might then use these representations to build up complex actions is still unknown. Each prior study has provided support for a different reference frame or proposed mixture models to explain the complex findings. Here, we propose a different framework in which the sensorimotor control system uses multiple representations, allowing it to flexibly tune its representations to task demands. We directly test this by showing that the representation of external forces is totally governed by the nature of the experienced forces. Participants form a global force representation based on the coordinate system that best explains the forces experienced at different arm postures. We suggest that when formalizing such global representation, the system decides on the representation by considering the level of uncertainty it has in each of the coordinate systems. This flexibility and redundancy in the representations allows the precise tuning to any specific task within our complex environment, explaining our expertise in a wide range of tasks.

neuroscience↗

bioRxiv2026

Perm1 Gene Therapy Mitigates PRDM16-Associated Cardiomyopathy

BackgroundPathogenic variants in PR domain containing 16 (PRDM16) cause pediatric and adult cardiomyopathies characterized by ventricular dilation, systolic dysfunction, and impaired metabolic maturation. Cardiac deficiency of PRDM16 alters metabolic gene expression and long-chain fatty acid (FA) metabolites. However, the downstream mediators involved are not well characterized. Furthermore, whether improving mitochondrial FA metabolism can prevent PRDM16-associated cardiomyopathy is currently unknown. MethodsIn vivo and in vitro approaches using patient-induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) and mouse models with Prdm16 deletion/mutation were employed. Transcriptomics and proteomics analyses were conducted, and adeno-associated virus (AAV)-mediated therapy was tested. ResultsHere, we show that a defect in FA metabolism is an early hallmark of PRDM16 cardiac deficiency. We show, for the first time, that PERM1 is a direct downstream target of PRDM16 and is involved in the regulation of FA metabolism through coordinated action with PGC1. Most importantly, neonatal delivery of AAV9-Perm1 in cardiac-specific Prdm16 knockout (Prdm16 cKO) mice markedly improved contractile parameters, reduced left ventricular (LV) dilation, and extended survival. These cardioprotective effects of PERM1 gene therapy occurred independent of restoring FA oxidation. Transcriptional and proteomic analyses of AAV-Perm1-treated Prdm16 cKO mice demonstrated significant improvements in mitochondrial cristae architecture, preservation of sarcomere organization, reduced cardiomyocyte apoptosis, attenuated myocardial fibrosis, and diminished cardiac remodeling. ConclusionsWe identify PERM1 as a direct downstream effector of PRDM16 and uncover a previously unrecognized PRDM16-PGC1-PERM1 axis essential for FA metabolic regulation in the heart. Perm1 gene therapy ameliorated PRDM16-associated cardiomyopathy through post-transcriptional mechanisms involving preservation of mitochondrial and sarcomere integrity. The current study provides preclinical evidence suggesting that Perm1 gene therapy may be a promising therapeutic target to improve the cardiac outcomes of patients affected by pathogenic PRDM16 variants.

physiology↗

bioRxiv2026

Excessive Ca2+-dependent ER-mitochondrial contact stabilization by EFHD1 drives liver injury

Metabolic-associated steatohepatitis (MASH) involves hepatocyte damage that cannot be explained solely by lipid accumulation. Here, to discover injury-specific pathways, we focused on a gene of uncertain function, EF-Hand Domain Family Member D1 (EFHD1), identified in human genome-wide association studies of liver injury but not liver fat. We show that EFHD1, a Ca2+-dependent actin crosslinker, stabilizes endoplasmic reticulum-mitochondria contact sites (ERMCS), detecting spatiotemporal coincidence of inter-organellar proximity and ER Ca2+ release. During MASH, EFHD1 upregulation drives pathological mitochondrial fragmentation via excessive contact persistence. This structural failure promotes mitochondrial double-stranded RNA escape and activation of a maladaptive antiviral PKR-dependent stress response, a causal relationship also supported by Mendelian randomization in humans. Consequently, inhibiting EFHD1 in human and mouse models blunts hepatocyte damage. These findings identify EFHD1 as a Ca2+-dependent ERMCS stabilizer, reveal a hepatocyte-intrinsic injury pathway, and suggest EFHD1 inhibition as a therapeutic strategy.

cell biology↗

bioRxiv2025

Long-term development of a motor memory

Human behavior is developed through continuous adaptation to our environment over a range of timescales. Extensive studies have investigated the mechanisms and computations underlying this process of sensorimotor adaptation using several hundred trials. However, most of our motor skills have had countless hours of practice. Here we study a simple motor adaptation task using thousands of training trials over multiple weeks to study the long-term development of a motor memory, and examine changes in adaptation, retention, inter-limb transfer, decay, spontaneous recovery and generalization. Unlike previous studies, participants showed complete compensation to the novel dynamics, along with long-term increases in retention and spontaneous recovery. Moreover, we find narrowing in the angular generalization, suggesting continual tuning of the motor memory to the task. This demonstrates the extensive changes occurring with longer training of motor tasks, highlighting their importance in studies of sensorimotor control, rehabilitation and training.

neuroscience↗

bioRxiv2024

A repository of Ogden syndrome (NAA10) and NAA15 patient derived iPSC lines and isogenic pairs by X-chromosome screening and genome-editing.

Amino-terminal (Nt-) acetylation (NTA) is a common protein modification, affecting 80% of cytosolic proteins in humans. The human essential gene, NAA10, encodes the enzyme NAA10, as the catalytic subunit for the N-terminal acetyltransferase A (NatA) complex, including the accessory protein, NAA15. The first human disease directly involving NAA10 was discovered in 2011, and it was named Ogden syndrome (OS), after the location of the first affected family residing in Ogden, Utah, USA. Since that time, other variants have been found in NAA10 and NAA15. Here we describe the generation of 31 iPSC lines, with 16 from females and 15 from males. This cohort includes CRISPR-mediated correction to the wild-type genotype in 4 male lines, along with editing one female line to generate homozygous wild-type or mutant clones. Following the monoclonalizaiton and screening for X-chromosome activation status in female lines, 3 additional pairs of female lines, in which either the wild type allele is on the active X chromosome (Xa) or the pathogenic variant allele is on Xa, have been generated. Subsets of this cohort have been successfully used to make cardiomyocytes and neural progenitor cells (NPCs). These cell lines are made available to the community via the NYSCF Repository.

genetics↗

bioRxiv2024

Kernels of Motor Memory Formation: Temporal Generalization in Bimanual Adaptation

In daily life, we coordinate both simultaneous and sequential bimanual movements to manipulate objects. Our ability to rapidly account for different object dynamics suggests there are neural mechanisms to quickly deal with them. Here we investigate how actions of one arm can serve as a contextual cue for the other arm, and facilitate adaptation. Specifically, we examine the temporal characteristics that underlie motor memory formation and recall, by testing the contextual effects of prior, simultaneous, and post contralateral arm movements in both male and female human participants. To do so, we measure their temporal generalization in three bimanual interference tasks. Importantly, the timing context of the learned action plays a pivotal role in the temporal generalization. While motor memories trained with post adaptation contextual movements generalize broadly, motor memories trained with prior contextual movements exhibit limited generalization, and motor memories trained with simultaneous contextual movements do not generalize to prior or post contextual timings. This highlights temporal tuning in sensorimotor plasticity: different training conditions yield substantially different temporal generalization characteristics. Since these generalizations extend far beyond any variability in training times, we suggest that the observed differences may stem from inherent differences in the use of prior, current and post-adaptation contextual information in the generation of natural behavior. This would imply differences in the underlying neural circuitry involved in learning and executing the corresponding coordinated bimanual movements. Significance StatementThis study addresses a fundamental question in the field of sensorimotor neuroscience of how multiple movements are temporally linked within a single motor memory. We examine the temporal generalization of motor memory formation by varying the timing of contextual movements associated with a learned motor memory across a range of prior, current, and post adaptation movement times using a bimanual motor learning task. We observed distinct patterns of temporal generalization based on whether the contextual movements occurred prior to, simultaneously with, or after the adaptation movement. For the first time, our findings reveal that the timing of contextual movements is crucial in the formation and generalization of motor memories.

neuroscience↗

bioRxiv2023

Congruent visual cues speed dynamic motor adaptation

Motor adaptation to novel dynamics occurs rapidly using sensed errors to update the current motor memory. This adaption is strongly driven by proprioceptive and visual signals, that indicate errors in the motor memory. Here we extend this previous work by investigating whether the presence of additional visual cues could increase the rate of motor adaptation, specifically when the visual motion cue is congruent with the dynamics. Six groups of participants performed reaching movements while grasping the handle of a robotic manipulandum while an additional cue (red object) was connected to the cursor. After a baseline, either a unidirectional (3 groups) or bidirectional (3 groups) velocity dependent force field was applied during the reach. For each group, the movement of the red object relative to the cursor was either congruent with the force field dynamics, incongruent with the force field dynamics or constant (fixed distance). Participants adapted more to the unidirectional force fields than to the bidirectional force field groups. However, across both force fields, groups in which the visual cues matched the type of force field (congruent visual cue) exhibited higher final adaptation level at the end of learning compared to either the control or incongruent conditions. In all groups, we observed an additional congruent cue assisted the formation of the motor memory of the external dynamics. We then demonstrate that a state estimation based model that integrates proprioceptive and visual information can successfully replicate the experimental data. New & NoteworthyWe demonstrate that adaptation to novel dynamics is stronger when additional online visual cues that are congruent with the dynamics are presented during adaptation, compared to either a constant or incongruent visual cue. This effect was found regardless of whether a bidirectional or unidirectional velocity dependent force field was presented to the participants. We propose that this effect might arise through the inclusion of this additional visual cue information within the state estimation process.

neuroscience↗

bioRxiv2022

Goal-directed modulation of stretch reflex gains is reduced in the non-dominant upper limb

Most individuals experience their dominant arm as being more dexterous than the non-dominant arm, but the neural mechanisms underlying this asymmetry in motor behaviour are unclear. Using a delayed reach task, we have recently demonstrated strong goal-directed tuning of stretch reflex gains in the dominant upper limb of human participants. Here, we used an equivalent experimental paradigm to address the neural mechanisms that underlie the preparation for reaching movements with the non-dominant upper limb. We found only minor goal-directed differences in the short latency stretch reflex of the non-dominant limb. There were consistent effects of load, preparatory delay duration and target direction on the long latency stretch reflex. However, by comparing stretch reflex responses in the non-dominant arm with those previously documented in the dominant arm, we demonstrate that goal-directed tuning of short and long latency stretch reflexes is markedly weaker in the non-dominant limb. The results indicate that the motor performance asymmetries across the two upper limbs is partly due to the more sophisticated control of reflexive stiffness in the dominant limb, likely facilitated by the superior goal-directed control of muscle spindle receptors. Our findings therefore suggest that independent fusimotor control plays a role in determining performance of complex motor behaviours and support existing proposals that the dominant arm is better supplied for executing more complex tasks, such as trajectory control. Key pointsO_LIMost of us routinely rely on the dominant arm to perform more complex and demanding motor tasks, but the mechanisms enabling the superior motor performance of the dominant limb are unclear. C_LIO_LIA better understanding of the motor asymmetry across the two arms might provide key insight into core sensorimotor principles. C_LIO_LIThis study shows that goal-directed tuning of short and long latency stretch reflexes in the non-dominant arm is markedly weaker than in the dominant arm. C_LIO_LIOur results suggest that the more sophisticated control of reflexive stiffness in the dominant limb, likely facilitated by superior fusimotor control, partly underpins the laterality of motor performance. C_LI

neuroscience↗

bioRxiv2022

Assistive loading promotes goal-directed tuning of stretch reflex gains

Voluntary movements are prepared before they are executed. Preparatory activity has been observed across the CNS and recently documented in first order neurons of the human PNS i.e., in muscle spindles. The changes seen in these sensory organs suggest that the independent modulation of stretch reflex gains may represent an important component of movement preparation. The aim of the current study was to further investigate the preparatory modulation of short- and long-latency stretch reflex responses ( SLR and LLR) of the dominant upper limb. Specifically, we investigated how different target parameters (target distance and direction) affect the preparatory tuning of stretch reflex gains in the context of goal-directed reaching, and whether any such tuning depends on preparation duration and the direction of background loads. We found that target distance produced only small variations in reflex gains. In contrast, both SLR and LLR gains were strongly modulated as a function of target direction, in a manner that facilitated the upcoming voluntary movement. This goal-directed tuning of SLR and LLR gains was present or enhanced when the preparatory delay was sufficiently long (>250 ms) and the homonymous muscle was unloaded i.e., when a background load was first applied in the direction of homonymous muscle action (assistive loading). The results extend further support for a relatively slow-evolving process in reach preparation that functions to modulate reflexive muscle stiffness, likely via the independent control of fusimotor neurons. Such control can augment voluntary goal-directed movement and is triggered or enhanced when the homonymous muscle is unloaded. Significance StatementIt is well-known that movement preparation improves motor performance. That is, briefly delaying the onset of a goal-directed movement can significantly benefit the overall quality of movement. However, the mechanisms underlying movement preparation remain unclear. In this study we examined the preparatory modulation of short- and long-latency stretch reflex responses in the dominant upper limb. We found that goal-directed tuning of stretch reflex gains is consistently triggered or enhanced in cases where preparation is sufficiently long (>250 ms) and a background - assistive- load is first applied in the direction of homonymous muscle action. A better understanding of movement preparation will likely also benefit the development of rehabilitation regimes and movement augmentation devices.

neuroscience↗

bioRxiv2022

Histone H4K20 Trimethylation is Decreased in Murine Models of Heart Disease

Heart disease is the leading cause of death in the developed world, and its comorbidities such as hypertension, diabetes, and heart failure are accompanied by major transcriptomic changes in the heart. During cardiac dysfunction, which leads to heart failure, there are global epigenetic alterations to chromatin that occur concomitantly with morphological changes in the heart in response to acute and chronic stress. These epigenetic alterations include the reversible methylation of lysine residues on histone proteins. Lysine methylation on histone H3K4 and H3K9 were among the first methylated lysine residues identified and have been linked to gene activation and silencing, respectively. However, much less is known regarding other methylated histone residues, including histone H4K20. Trimethylation of histone H4K20 has been shown to repressive gene expression, however this mark has never been examined in the heart. Here we utilized immunoblotting and mass spectrometry to quantify histone H4K20 trimethylation in three models of cardiac dysfunction. Our results show that lysine methylation at this site is regulated in a biphasic manner leading to increased H4K20 trimethylation during acute hypertrophic stress and decreased H4K20 trimethylation during sustained ischemic injury and cardiac dysfunction. In addition, we examined publicly available datasets to analyze enzymes that regulate H4K20 methylation and identified one demethylase (KDM7C) and two methyltransferases (KMT5A and SMYD5) which were all upregulated in heart failure patients. This is the first study to examine histone H4K20 trimethylation in the heart and to determine how this post-translational modification is differentially regulated in multiple models of cardiac disease. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=73 SRC="FIGDIR/small/479885v1_ufig1.gif" ALT="Figure 1"> View larger version (25K): org.highwire.dtl.DTLVardef@169abeorg.highwire.dtl.DTLVardef@94bb0org.highwire.dtl.DTLVardef@4812e8org.highwire.dtl.DTLVardef@1d16478_HPS_FORMAT_FIGEXP M_FIG C_FIG

biochemistry↗

bioRxiv2019

Molecular Architecture of the Bardet-Biedl Syndrome 2-7-9 Subcomplex

Bardet-Biedl syndrome (BBS) is a genetic disease caused by mutations that disrupt the function of the BBSome, an eight-subunit complex that plays an important role in transport of proteins in primary cilia. To better understand the molecular basis of the disease, we analyzed the structure of a BBSome subcomplex consisting of three homologous BBS proteins (BBS2, BBS7, and BBS9) by an integrative structural modeling approach using electron microscopy and chemical crosslinking coupled with mass spectrometry. The resulting molecular model revealed an overall structure that resembles a flattened triangle. Within the structure, BBS2 and BBS7 form a tight dimer based on a coiled-coil interaction, and BBS9 associates with the dimer via an interaction with the -helical domain of BBS2. Interestingly, a BBS-linked mutation of BBS2 (R632P) is located in the -helical domain at the interface between BBS2 and BBS9, and binding experiments showed that this mutation disrupted the interaction of BBS2 with BBS9. This finding suggests that BBSome assembly is disrupted by the R632P substitution, providing a molecular explanation for BBS in patients harboring this mutation.

biochemistry↗

bioRxiv2019

The effect of tongue-tie application on stress responses in resting horses

Tongue-ties (TT) are commonly applied to both Standardbred and Thoroughbred racehorses to increase control, by preventing them from getting their tongue over the bit, and as a conservative treatment for equine respiratory conditions, principally dorsal displacement of the soft palate. This study investigated responses to TT application in horses, at rest, using both behavioural (head-tossing, ear position, gaping and lip licking) and physiological (salivary cortisol concentrations, eye surface temperature and heart rate) indices. Twelve Standardbred horses (six of which were naive to TT) were used in a randomised crossover design. The study comprised 3 phases; Phase 1 (Baseline), Phase 2 (Treatment), and Phase 3 (Recovery). At phase 2, tongue tie application (TTA) was performed using a rubber band that was looped around the tongue and secured to the mandible for 20 minutes. The control treatment (C) incorporated 30 secs of tongue manipulation, at the start of the 20 min, however no TT was applied. Behaviours (head-tossing, ear position, mouth gaping and lip-licking) and heart rate (HR) were recorded for the duration of the study and analysed in ten minute intervals. Salivary samples were taken at the end of each phase for subsequent cortisol assays and infrared thermography images were taken of each eye at 5-minute intervals. Statistical analyses were performed in SPSS using linear mixed effects models and repeated measures general linear models, to determine differences between treatments and within treatments, over time. Compared to control, there was more head-tossing/shaking (p<0.001), gaping (p<0.001) and backwards ear position (p<0.001) and less forward ear position (p<0.001) during TTA, in Phase 2. Horses with previous experience of TT showed more head-tossing (p=0.040) and gaping (p=0.030) than naive horses. Lip-licking was more frequent after TTA treatment than control, during Phase 3 (p<0.001). Salivary cortisol concentrations increased after TTA (1846.1pg/mL {+/-} 478.3pg/mL vs 1253.6pg/mL {+/-} 491.6pg/mL, p=0.047). Mean HR, and mean right and left eye temperature did not differ significantly between treatments in any phase (all p> 0.05). The findings of this study suggest the application of a tongue-tie causes changes to both behavioural and physiological parameters suggestive of a stress-related response. Further research is needed that will enable racing and sport horse regulatory bodies to make informed decisions about the appropriate use of tongue-ties in horses.

animal behavior and cognition↗

bioRxiv2019

Asymmetry in kinematic generalisation between visual and passive lead-in movements are consistent with a forward model in the sensorimotor system

In our daily life we often make complex actions comprised of linked movements, such as reaching for a cup of coffee and bringing it to our mouth to drink. Recent work has highlighted the role of such linked movements in the formation of independent motor memories, affecting the learning rate and ability to learn opposing force fields. In these studies, distinct prior movements (lead-in movements) allow adaptation of opposing dynamics on the following movement. Purely visual or purely passive lead-in movements exhibit different angular generalization functions of this motor memory as the lead-in movements are modified, suggesting different neural representations. However, we currently have no understanding of how different movement kinematics (distance, speed or duration) affect this recall process and the formation of independent motor memories. Here we investigate such kinematic generalization for both passive and visual lead-in movements to probe their individual characteristics. After participants adapted to opposing force fields using training lead-in movements, the lead-in kinematics were modified on random trials to test generalization. For both visual and passive modalities, recalled compensation was sensitive to lead-in duration and peak speed, falling off away from the training condition. However, little reduction in force was found with increasing lead-in distance. Interestingly, asymmetric transfer between lead-in movement modalities was also observed, with partial transfer from passive to visual, but very little vice versa. Overall these tuning effects were stronger for passive compared to visual lead-ins demonstrating the difference in these sensory inputs in regulating motor memories. Our results suggest these effects are a consequence of state estimation, with differences across modalities reflecting their different levels of sensory uncertainty arising as a consequence of dissimilar feedback delays.

neuroscience↗