Biology subjects

Kumar, A. D.

Publications and source records attributed to Kumar, A. D..

4 recordsLinked to original sources

bioRxiv2025

Contextual Cues and Transition Statistics Drive Expression of Competing Motor Memories

Learning multiple motor skills without interference and expressing the correct one in a changing environment is a fundamental challenge. Contextual cues are known to help separate these memories, but how they interact during retrieval is not well understood. We investigated how the stability, recency, and transitional statistics of learning environments influence this process. Across six visuomotor adaptation experiments, participants learned opposing rotations (Tasks A and B) tagged with distinct contextual cues under different schedules (blocked or interleaved) and were tested in stable or dynamic environments. We found that while contextual cues can successfully separate memories, expression is systematically biased by learned transition statistics: towards more stable memories after imbalanced training, and towards more recent memories when stabilities are matched. Critically, when the stable statistics of training mismatched the volatile statistics of testing, cue-based retrieval collapsed, and behavior was dominated by these stability or recency biases. Conversely, learning in a high-entropy, interleaved environment enabled precise, cue-appropriate expression regardless of the testing schedule. These results demonstrate that memory retrieval is not cue-driven but arises from an arbitration process between cues and transition priors. Our findings reveal that memory retrieval involves weighting sensory information against latent priors derived from the history of context transitions. This work provides a unifying theoretical framework for understanding adaptive memory expression, positing that the brain leverages the learned statistical structure of the environment to infer which memory to recall, thereby balancing cue-driven selection with the stability and predictability of past experience. This principle offers a unifying explanation for interference, spontaneous recovery, and the benefits of variable practice, providing a more holistic model of adaptive motor behavior. Statement of SignificanceHow does a tennis player instantly switch between a forehand and a backhand? Our work reveals a fundamental principle of how the brain organizes and retrieves memories. We demonstrate that recalling a skill is not just about recognizing a contextual cue, but about an internal process of integrating that cue with the learned statistics of the environment, such as the stability and recency of past experiences. This finding provides a unifying framework for phenomena like interference and spontaneous recovery. It has significant implications for designing more effective training in sports and rehabilitation, where structuring practice around environmental statistics can optimize learning and promote flexible skill application.

neuroscience↗

bioRxiv2025

Structure-guided engineering of CCL27 enhances natural ligand CAR T-cells against CCR10 for multiple myeloma

Despite the success of BCMA CAR-Ts, many multiple myeloma patients relapse and require additional therapeutic options. Our group previously identified the chemokine receptor CCR10 as a potential alternate target to address this need. Here, we validated CCR10 expression on primary myeloma tumors and sought to develop CAR T-cells against CCR10, utilizing its natural ligand CCL27 as a CAR binding element. However, CARs based on the native CCL27 sequence were ineffective. We thus utilized computational modeling and structure-guided engineering to inform rational mutations along the CCL27-CCR10 interface, exploiting a hydrophobic pocket on CCR10. This effort identified CCL27 mutants with an additional N-terminal aromatic amino acid that dramatically improved the efficacy of CCL27-based CAR-Ts to near that of current anti-BCMA CAR-Ts. We validated key amino acid contacts at the CCL27-CCR10 interface, which contribute to increased CAR binding avidity, predicted to be influenced by increased Van der Waals interactions. Lastly, we found that the CCL27 mutants have no toxicity in the hematopoietic compartment. This work illustrates the potential of engineering natural ligand CAR-Ts beyond their wild-type sequences and underscores the translational potential of engineered CCL27 mutant CAR-Ts.

cancer biology↗

bioRxiv2025

Neural Mechanisms Underlying Approach and Avoidance Tendencies in Alcohol Use: An Electrophysiological Investigation

Background: A growing body of research highlights the differential role of approach and avoidance tendencies toward alcohol cues in the development and maintenance of harmful drinking behavior. Some individuals involved in alcohol consumption show an automatic approach towards alcohol-related stimuli, whereas others demonstrate avoidance, suggesting the need to understand the neurocognitive mechanisms underlying these automatic tendencies. Methods: The current study employed an Alcohol Approach-Avoidance Task (A-AAT) with electroencephalography (EEG) to investigate neural responses among individuals with alcohol approach and avoidance tendencies. Alcohol group participants were categorized into approach and avoidance subgroups based on their behavioral tendencies following A-AAT administration. Findings: Results revealed significant attenuation in P3 and FN400 amplitudes at frontal and parietal sites, respectively, in the alcohol-approach participants compared to both the alcohol-avoidance and non-alcohol participants. These findings suggest weakened controlled cue processing and impaired stimulus-response conflict resolution in individuals with stronger approach tendencies. Notably, right prefrontal activity exhibited prominent differences between the approach and avoidance groups, highlighting its potential role in regulating automatic alcohol-related responses. Implications: The identified ERP markers provide clinical utility for assessing alcohol approach tendencies and monitoring the progress of intervention. Findings further emphasize the importance of individually tailored targeted interventions aimed at reducing harmful alcohol consumption behavior by altering alcohol approach tendencies.

neuroscience↗

bioRxiv2025

Interaction between Model-based and Model-free Mechanisms in Motor Learning

Motor learning can be driven by distinct mechanisms--habitual, model-free processes, and strategic, model-based processes--depending on the magnitude and context of movement errors. Although small and large errors are known to engage distinct motor learning mechanisms--model-free (implicit) or model-based (explicit), respectively--it remains unclear whether successfully deploying one mechanism might hamper the engagement of the other in subsequent learning tasks. Here, we investigated how prior engagement of a particular mechanism biases future adaptations, even when the new task context typically favours the alternative strategy. Across three experiments (N=82), participants performed reaching movements to targets that either remained fixed or "jumped" mid-movement by small (15{degrees}) or large (30{degrees}, 45{degrees}, or 60{degrees}) angles. When first exposed to small errors (15{degrees}), participants exhibited persistent aftereffects in subsequent catch trials and stable reaction times (RTs), hallmarks of a model-free, habitual process. Surprisingly, even when switching to larger error magnitudes later, these participants continued to show robust aftereffects and did not elevate RTs-- indicating a carryover of model-free learning. Conversely, participants who initially experienced large errors showed minimal aftereffects and flexible RT modulation consistent with model-based strategies; this bias persisted in later sessions with smaller errors, leading to reduced habitual aftereffects. Notably, inserting a washout phase to reset baseline performance did not abolish these mechanistic biases, highlighting that the initial engagement of either model-free or model-based processes leaves a durable imprint on subsequent adaptations. Taken together, these findings demonstrate that motor learning is shaped not only by ongoing task demands (e.g., error magnitude) but also by an individuals prior learning history. Understanding how initial learning experiences constrain future adaptations has broad implications for designing interventions and training protocols in motor rehabilitation and skill acquisition. Statement of SignificanceMotor learning involves distinct mechanisms: habitual, model-free processes (driven by gradual stimulus-response associations) and strategic, model-based processes (guided by explicit adjustments). This study demonstrates that initial engagement of one mechanism biases subsequent adaptations, even when task demands shift to favor the alternative. The findings suggest that motor learning is a hierarchical process shaped by cumulative contextual experiences. Our results have highlighted how early learning establishes neural or cognitive frameworks that constrain future adaptations, prioritizing efficiency over flexibility. This has implications for designing motor training or rehabilitation protocols: initiating learning with model-based strategies (via large errors) may preserve adaptability, while model-free training (via small errors) risks anchoring rigid habits. By elucidating how prior mechanisms bias ongoing learning, this work advances our understanding of motor memory interactions and their real-world applications in skill acquisition and recovery.

neuroscience↗