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Mahajan, P.

Publications and source records attributed to Mahajan, P..

11 recordsLinked to original sources

Entropy regularised reinforcement learning reconciles aversive and action prediction errors in the tail of the striatum

AO_SCPLOWBSTRACTC_SCPLOWDopamine activity in the tail of the striatum (TS) presents a novel challenge for reinforcement-learning theories of dopamine. Some studies suggest that TS-projecting dopamine signals encode aversive or threat prediction errors, whereas others argue that they encode action prediction errors involved in soft-habit formation. Here, we show that these accounts need not be mutually exclusive. We instantiate an entropy-regularised reinforcement-learning model in which TS-projecting dopamine neurons update both aversive values and the default policy. In this model, threat belief gates aversive value initialisations, producing TS-like activity during retreat from potentially threatening novel objects, while default-policy learning generates action prediction error signals that decline as actions become habitual. Our results further suggest why both of these signals may need to coexist in the temporal difference errors in our model, and qualitatively reproduce key response patterns and simulations from studies previously used to support both views. Beyond this descriptive reconciliation, our model simulations also highlight the normative role of the tail of the striatum in cautious behaviours in the context of potential threats and stable learning in the face of outcome uncertainty.

neuroscience↗

ARL15 promotes inflammatory fibroblast activation and disease severity in rheumatoid arthritis: integrated transcriptomic and collagen-induced arthritis model analyses

BackgroundADP-ribosylation factor-like protein 15 (ARL15) is a rheumatoid arthritis (RA) susceptibility gene identified through GWAS. Previous studies suggested a role for ARL15 in synovial fibroblast (SF) pathogenicity, but its contribution to inflammatory arthritis remains unclear. We investigated the inflammatory role of ARL15 and its therapeutic potential in RA. MethodsARL15 was overexpressed in MH7A cells followed by bulk RNA sequencing and pathway enrichment analyses. Therapeutic relevance was evaluated in collagen-induced arthritis (CIA) mouse model using anti-ARL15 monoclonal antibodies, ARL15-targeting siRNA, or isoquinoline. Arthritis scores, histopathology, micro-CT and serum cytokines were assessed. Publicly available single-cell RNA sequencing (scRNA-seq) datasets were analyzed to determine ARL15 expression in RASF subsets. ResultsARL15 overexpression induced a pro-inflammatory transcriptional program characterized by upregulation of IL1A, IL1B, IL6, IL8, CXCL1, CXCL10, and CCL20. Gene set enrichment analysis revealed activation of IL6-JAK-STAT, TNF, interferon-response, and KRAS signaling pathways, with suppression of oxidative phosphorylation, lipid metabolism, and mTORC1 signaling. In CIA mice, ARL15 inhibition significantly reduced arthritis severity, inflammatory infiltrates, and joint destruction while preserving cartilage and bone integrity. Serum TNF-, IL-6, and IL-1{beta} levels were markedly decreased following ARL15 blockade. Combination monoclonal antibody treatment demonstrated the greatest therapeutic benefit. scRNA-seq analysis showed broad ARL15 expression across RA fibroblast populations, with enrichment in inflammatory lining and SF subsets. ConclusionsARL15 is a pro-inflammatory regulator of SF activation and arthritis progression. Integrated transcriptomic, single-cell, and in vivo analyses identify ARL15 as a therapeutic target for RA and support further translational development of ARL15 based therapies.

immunology↗

Neurodevelopmental origin of seizures in Lowe syndrome

Lowe syndrome (LS) is a rare X-linked monogenic disorder resulting from mutations in the OCRL1 gene that encodes a phosphatidylinositol 4,5-bisphosphate 5 phosphatase enzyme. Patients with LS exhibit a range of neurological symptoms, including neurodevelopmental delays, hypotonia, febrile seizures, and behavioural abnormalities; however, the cellular and developmental origins of LS remain poorly understood. The Drosophila genome encodes a single homolog of OCRL (docrl). Here, we report that a germline null allele of docrl (docrlKO) shows heat induced seizures reminiscent of the febrile seizures in LS patients. Cell type specific deletion of docrl in neurons was sufficient to recapitulate the heat induced seizures seen in docrlKO indicating a cell autonomous requirement of docrl in neurons to prevent seizures. Temporally controlled deletion of docrl showed that heat induced seizure in adults were predetermined by a requirement of docrl in neural stem cells during embryonic neurogenesis. Collectively, our findings demonstrate the developmental origin of the neurological manifestations of LS highlighting the need to target potential therapeutic interventions during this developmental time window.

neuroscience↗

Optimal composition of multiple value functions for dopamine-mediated efficient, safe and stable learning

AO_SCPLOWBSTRACTC_SCPLOWThe seminal reward prediction error account of dopamine has been highly successful, but faces several key challenges. Most notable are the difficulty of learning multiple rewards simultaneously, inefficient on-policy learning, and accounting for the heterogeneous striatal responses observed across and within striatal targets. Here we address these issues with a normative entropy-regularised reinforcement-learning framework. We propose that dopamine optimises not just cumulative rewards, but a reward value function augmented by a penalty for deviating from a default behavioural policy. In simulations, this off-policy formulation provides a principled solution to composing multiple reward values, avoids the interference and unintended unlearning seen in multi-objective on-policy methods when priorities change, and adapts more efficiently than standard alternatives in environments with non-stationary rewards. More broadly, the framework offers a unified account of dopamine heterogeneity between and within striatal targets, including a normative way to understand why aversive and action prediction errors may coexist in the tail of the striatum. Together, these results suggest that dopamine-mediated learning may be better captured by prediction errors in composable, entropy-regularised value functions than by a single broadcast prediction error, and offer testable predictions for future experiments.

neuroscience↗

State or personality trait: Determinants of boldness and shoal size preference in adult zebrafish

Animals adjust their behavior in response to physiological states to optimize the trade-off between energy acquisition and survival. A key question in animal personality research is whether behavioral variation is driven by consistent physiological state differences or stable personality traits. This study evaluates boldness and shoal size discrimination in adult male zebrafish (Danio rerio) across three hunger states: same-day feeding (H0), 24-hour food deprivation (H1), and 48-hour food deprivation (H2). Behavioral assessments were conducted over two testing cycles, with each individual undergoing every test twice for each hunger state within each cycle. The assays comprised the Open Field Test (OFT), Emergence Test (ET), and Social Preference Test (SPT), with the SPT conducted under binary (4 vs. 2 fish) and ternary (4 vs. 2 vs. 1 fish) choice conditions. Hunger significantly reduced emergence latency, but did not affect exploratory behavior in the OFT. Hunger also enhanced preference for larger shoals above chance in the binary SPT during the second testing cycle, though this effect was absent in ternary choices. Testing cycle effects revealed habituation-driven increases in boldness in both the tests and a progressive shift toward larger shoal preferences in the binary SPT. Among all assays, only the OFT showed significant repeatability, making it a reliable measure of boldness. However, it did not show consistent individual differences in plasticity due to hunger. These results highlight the crucial role of labile physiological states, such as hunger and habituation, in driving behavioral variation and underscore the importance of designing studies that disentangle state-dependent behaviors from stable personality traits in animal personality research.

animal behavior and cognition↗

Homeostasis After Injury: How Intertwined Inference and Control Underpin Post-Injury Pain and Behaviour

Injuries are an unfortunate but inevitable fact of life, leading to an evolutionary mandate for powerful homeostatic processes of recovery and recuperation. The physiological responses of the body and the immune system must be coordinated with behaviour to allow protected time for this to happen, and to prevent further damage to the affected bodily parts. Reacting appropriately requires an internal control system that represents the nature and state of the injury and specifies and withholds actions accordingly. We bring the formal uncertainties embodied in this system into the framework of a partially observable Markov decision process. We discuss nociceptive phenomena in light of this analysis, noting particularly the counter-intuitive behaviours associated with injury investigation, and the propensity for transitions from normative, tonic, to pathological, chronic pain states. Importantly, these simulation results provide a quantitative account and enable us to sketch a much needed roadmap for future theoretical and experimental studies on injury, tonic pain, and the transition to chronic pain. AO_SCPLOWUTHORC_SCPLOW SO_SCPLOWUMMARYC_SCPLOWSeveral arguments suggest that the brain has a dedicated representation of the state of an injury. This provides an internal control system to modulate our behaviour, influencing the pain, anxiety, and mood changes appropriate to the need for heightened protection and recuperation during healing. Here, we propose a computational architecture for how this system might be constructed. We model the injury as a problem where its true state is only partially observable, requiring the brain to combine inference with optimal control to make decisions. We show how this framework offers an explanation of two core paradoxical observations: it explains behaviours such as rubbing or probing an injured area so as to gain information and reduce uncertainty, and it accounts for the high propensity of an injury to transition into a pathological, chronic pain state via information restriction. Overall, this provides a quantitative framework for mapping the bodys healing processes to their underlying neural substrates. This has the potential to help researchers identify novel targets for treating and possibly preventing chronic pain.

neuroscience↗

Enhanced behavioural and neural sensitivity to punishments in chronic pain and fatigue

Chronic pain and fatigue in musculoskeletal disease contribute significantly to disability, and recent studies suggest an association with reduced motivation and excessive fear avoidance. In this behavioural neuroimaging study in chronic inflammatory arthritis participants and healthy controls, we aimed to identify the specific behavioral and neural changes associated pain and fatigue during reward and loss decision-making. Computational modeling of behaviour identified a parametric signature, characterized most notably by increased punishment sensitivity. This signature is distinct from patterns previously reported in psychiatric conditions and it aligns with predictions of mechanistic models of chronic pain such as the fear avoidance model. Neural activity associated with the punishment prediction error was enhanced in the right posterior insular cortex, putamen, pallidum, and dorsolateral prefrontal cortex. Functional network connectivity analysis showed that insula centrality correlated with subjective reports of fatigue and pain. Overall, the findings show that pain and fatigue in chronic pain relate to objective behavioural changes, and can be mapped to a specific pattern of activity in brain circuits of motivation and decision-making.

neuroscience↗

Balancing safety and efficiency in human decision making

The safety-efficiency dilemma describes the problem of maintaining safety during efficient exploration and is a special case of the exploration-exploitation dilemma in the face of potential dangers. Conventional exploration-exploitation solutions collapse punishment and reward into a single feedback signal, whereby early losses can be overcome by later gains. However, the brain has a separate system for Pavlovian fear learning, suggesting a possible computational advantage to maintaining a specific fear memory during exploratory decision-making. In a series of simulations, we show this promotes safe but efficient learning and is optimised by arbitrating Pavlovian avoidance of instrumental decision-making according to uncertainty. We provide a basic test of this model in a simple human approach-withdrawal experiment in virtual reality, and show that this flexible avoidance model captures choice and reaction times. These results show that the Pavlovian fear system has a more sophisticated role in decision-making than previously thought, by shaping flexible exploratory behaviour in a computationally precise manner.

neuroscience↗

IDSL.GOA: Gene Ontology Analysis for Metabolomics

Biological interpretation of metabolomic datasets often ends at a pathway analysis step to find the over-represented metabolic pathways in the list of statistically significant metabolites. However, definitions of biochemical pathways and metabolite coverage vary among different curated databases, leading to missed interpretations. For the lists of genes, transcripts and proteins, Gene Ontology (GO) terms over-presentation analysis has become a standardized approach for biological interpretation. But, GO analysis has not been achieved for metabolomic datasets. We present a new knowledgebase (KB) and the online tool, Gene Ontology Analysis by the Integrated Data Science Laboratory for Metabolomics and Exposomics (IDSL.GOA) to conduct GO over-representation analysis for a metabolite list. The IDSL.GOA KB covers 2,393 metabolic GO terms and associated 3,144 genes, 1,492 EC annotations, and 2,621 metabolites. IDSL.GOA analysis of a case study of older vs young female brain cortex metabolome highlighted 82 GO terms being significantly overrepresented (FDR <0.05). We showed how IDSL.GOA identified key and relevant GO metabolic processes that were not yet covered in other pathway databases. Overall, we suggest that interpretation of metabolite lists should not be limited to only pathway maps and can also leverage GO terms as well. IDSL.GOA provides a useful tool for this purpose, allowing for a more comprehensive and accurate analysis of metabolite pathway data. IDSL.GOA tool can be accessed at https://goa.idsl.me/

bioinformatics↗

Doing what's not wanted: Conflict in incentives and misallocation of behavioural control lead to drug-seeking despite adverse outcomes

Despite being aware of negative consequences and wanting to quit, long-term addicts find it difficult to quit seeking and consuming drugs. This inconsistency between the (often compulsive) behavioural patterns and the explicit knowledge of negative consequences represents a cognitive conflict which is a central characteristic of addiction. Neurobiologically, differential cue-induced activity in distinct striatal subregions, as well as the dopamine connectivity spiraling from ventral striatal regions to the dorsal regions, play critical roles in compulsive drug seeking. The focus of this work is to illustrate the mechanisms that lead to a cognitive conflict and its impact on actions taken i.e. addictive choices. We propose an algorithmic model that captures how the action choices that the agent makes when reinforced with drug-rewards become incongruent with the presence of negative consequences that often follow those choices. We advance the understanding of having a decision hierarchy in representing "cognitive control" and how lack of such control at higher-level in the hierarchy could potentially lead to consolidated drug-seeking habits. We further propose a cost-benefit based arbitration scheme, which mediates the allocation of control across different levels of the decision-making hierarchy. Lastly, we discuss how our work on extending a computational model to an algorithmic one, could in turn also helps us improve the understanding of how drugs hijack the dopamine-spiralling circuit at an implementation level.

neuroscience↗

IDSL.CCDB: a database for exploring inter-chemical correlations in metabolomics and exposomics datasets

Inter-chemical correlations in metabolomics and exposomics datasets provide valuable information for studying relationships among reported chemicals measured in human specimens. With an increase in the size of these datasets, a network graph analysis and visualization of the correlation structure is difficult to interpret. While co-regulatory genes databases have been developed, a similar database for metabolites and chemicals have not been developed yet. We have developed the Integrated Data Science Laboratory for Metabolomics and Exposomics - Chemical Correlation Database (IDSL.CCDB), as a systematic catalogue of inter-chemical correlation in publicly available metabolomics and exposomics studies. The database has been provided via an online interface to create single compound-centric views that are clear, readable and meaningful. We have demonstrated various applications of the database to explore: 1) the chemicals from a chemical class such as Per- and Polyfluoroalkyl Substances (PFAS), polycyclic aromatic hydrocarbons (PAHs), polychlorinated biphenyls (PCBs), phthalates and tobacco smoke related metabolites; 2) xenobiotic metabolites such as caffeine and acetaminophen; 3) endogenous metabolites (acyl-carnitines); and 4) unannotated peaks for PFAS. The database has a rich collection of 36 human studies, including the National Health and Nutrition Examination Survey (NHANES) and high-quality untargeted metabolomics datasets. IDSL.CCDB is supported by a simple, interactive and user-friendly web-interface to retrieve and visualize the inter-chemical correlation data. The IDSL.CCDB has the potential to be a key computational resource in metabolomics and exposomics facilitating the expansion of our understanding about biological and chemical relationships among metabolites and chemical exposures in the human body. The database is available at www.ccdb.idsl.me site.

bioinformatics↗