PLoS Biology最新文献

{"title":"Decreased SynMuv B gene activity in response to viral infection leads to activation of the antiviral RNAi pathway in C. elegans.","authors":"Ashwin Seetharaman, Himani Galagali, Elizabeth Linarte, Mona H X Liu, Jennifer D Cohen, Kashish Chetal, Ruslan Sadreyev, Alex J Tate, Taiowa A Montgomery, Gary Ruvkun","doi":"10.1371/journal.pbio.3002748","DOIUrl":"10.1371/journal.pbio.3002748","url":null,"abstract":"<p><p>RNA interference (RNAi) mediates antiviral defense in many eukaryotes. Caenorhabditis elegans mutants that disable RNAi are more sensitive to viral infection. Many mutants that enhance RNAi have also been identified; these mutations may reveal genes that are normally down-regulated in antiviral defense. About one-third of the score of mutants that enhance RNAi are in synMuv B genes, identified 30 years ago in unrelated screens for increased growth factor signaling. Many synMuv B genes encode dREAM complex chromatin-regulatory proteins found in nearly all animals and plants. We show that mRNAs which are highly induced in synMuv B mutants are congruent with those induced by Orsay RNA virus infection, suggesting that the enhanced RNAi of synMuv B mutants may also be triggered by down-regulation of synMuvB gene activity in an Orsay virus infection of wild type. The multivulval (Muv) phenotype of synMuv B mutants requires the presence of a second nematode-specific synMuv A gene mutation, but the enhanced RNAi of synMuv B mutants does not require a second synMuv A mutation. To test if Orsay viral infection down-regulates synMuv B gene activity, we infected a single synMuv A mutant with Orsay virus and found that a Muv phenotype could be induced. Thus, decreased synMuv B gene activity is part of the normal C. elegans viral defense response. In support of the model that decreased syn- Muv B gene activity enhances antiviral response, we found that synMuv B mutants have 50 to 100× lower viral RNA levels during an Orsay virus infection than wild type. Thus down-regulation of synMuv B activity to enhance RNAi is a key component in the defense response to viral infection. Small RNA deep sequencing analysis of dREAM complex mutants revealed siRNA profiles indicative of such a response. Thus, the pan-eukaryotic synMuv B genes constitute an element in C. elegans antiviral defense which is conserved across many eukaryotes where it also may act in viral defense. The enhanced RNAi and conservation of the dREAM complex mutants suggests new therapeutic avenues to boost antiviral defenses.</p>","PeriodicalId":49001,"journal":{"name":"PLoS Biology","volume":"23 1","pages":"e3002748"},"PeriodicalIF":9.8,"publicationDate":"2025-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11778786/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143069131","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Lineage tracing studies suggest that the placenta is not a de novo source of hematopoietic stem cells.","authors":"Xiaowen Chen, Joanna Tober, Martin Dominguez, Alan T Tang, Jenna Bockman, Jisheng Yang, Sneha Mani, Chin Nien Lee, Mei Chen, Triloshan Thillaikumaran, Patricia Mericko-Ishizuka, Monica Mainigi, Nancy A Speck, Mark L Kahn","doi":"10.1371/journal.pbio.3003003","DOIUrl":"10.1371/journal.pbio.3003003","url":null,"abstract":"<p><p>Definitive hematopoietic stem and progenitor cells (HSPCs) arise from a small number of hemogenic endothelial cells (HECs) within the developing embryo. Understanding the origin and ontogeny of HSPCs is of considerable interest and potential therapeutic value. It has been proposed that the murine placenta contains HECs that differentiate into HSPCs. However, during human gestation HSPCs arise in the aorta considerably earlier than when they can first be detected in the placenta, suggesting that the placenta may primarily serve as a niche. We found that the Runx1 transcription factor, which is required to generate HSPCs from HECs, is not expressed by mouse placental ECs. To definitively determine whether the mouse placenta is a site of HSPC emergence, we performed lineage tracing experiments with a Hoxa13Cre allele that specifically labels ECs in the placenta and umbilical cord (UC), but not in the yolk sac or embryo. Immunostaining revealed Hoxa13Cre lineage-traced HECs and HSPCs in the UC, a known site of HECs, but not the placenta. Consistent with these findings, ECs harvested from the E10.5 aorta and UC, but not the placenta, gave rise to hematopoietic cells ex vivo, while colony forming assays using E14.5 fetal liver revealed only 2% of HSPCs arose from Hoxa13-expressing precursors. In contrast, the pan-EC Cdh5-CreERT2 allele labeled most HSPCs in the mouse placenta. Lastly, we found that RUNX1 and other HEC genes were not expressed in first-trimester human placenta villous ECs, suggesting that human placenta is not hemogenic. Our findings demonstrate that the placenta functions as a site for expansion of HSPCs that arise within the embryo proper and is not a primary site of HSPC emergence.</p>","PeriodicalId":49001,"journal":{"name":"PLoS Biology","volume":"23 1","pages":"e3003003"},"PeriodicalIF":9.8,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11774391/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143061147","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The neurohormone tyramine stimulates the secretion of an insulin-like peptide from the Caenorhabditis elegans intestine to modulate the systemic stress response.","authors":"Tania Veuthey, Jeremy T Florman, Sebastián Giunti, Stefano Romussi, María José De Rosa, Mark J Alkema, Diego Rayes","doi":"10.1371/journal.pbio.3002997","DOIUrl":"10.1371/journal.pbio.3002997","url":null,"abstract":"<p><p>The DAF-2/insulin/insulin-like growth factor signaling (IIS) pathway plays an evolutionarily conserved role in regulating reproductive development, life span, and stress resistance. In Caenorhabditis elegans, DAF-2/IIS signaling is modulated by an extensive array of insulin-like peptides (ILPs) with diverse spatial and temporal expression patterns. However, the release dynamics and specific functions of these ILPs in adapting to different environmental conditions remain poorly understood. Here, we show that the ILP, insulin-3 (INS-3), plays a crucial role in modulating the response to various environmental stressors in C. elegans. ins-3 mutants display increased resistance to heat, oxidative stress, and starvation; however, this advantage is countered by slower reproductive development under favorable conditions. We find that ins-3 expression is downregulated in response to environmental stressors, whereas, the neurohormone tyramine, which is released during the acute flight response, increases ins-3 expression. We show that tyramine induces intestinal calcium (Ca2+) transients through the activation of the TYRA-3 receptor. Our data support a model in which tyramine negatively impacts environmental stress resistance by stimulating the release of INS-3 from the intestine via the activation of a TYRA-3-Gαq-IP3 pathway. The release of INS-3 systemically activates the DAF-2 pathway, resulting in the inhibition of cytoprotective mechanisms mediated by DAF-16/FOXO. These studies offer mechanistic insights into a brain-gut communication pathway that weighs adaptive strategies to respond to acute and long-term stressors.</p>","PeriodicalId":49001,"journal":{"name":"PLoS Biology","volume":"23 1","pages":"e3002997"},"PeriodicalIF":9.8,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11774402/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143061153","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Supraspinal facilitation of painful stimuli by glutamatergic innervation from the retrosplenial to the anterior cingulate cortex.","authors":"Shun Hao, Man Xue, Qi-Yu Chen, Jinjin Wan, Yu-Jie Ma, Wantong Shi, Xuanying Chen, Xu-Hui Li, Jing-Shan Lu, Fang Xu, Guo-Qiang Bi, Wucheng Tao, Min Zhuo","doi":"10.1371/journal.pbio.3003011","DOIUrl":"10.1371/journal.pbio.3003011","url":null,"abstract":"<p><p>The anterior cingulate cortex (ACC) is recognized as a pivotal cortical region involved in the perception of pain. The retrosplenial cortex (RSC), located posterior to the ACC, is known to play a significant role in navigation and memory processes. Although the projections from the RSC to the ACC have been found, the specifics of the synaptic connections and the functional implications of the RSC-ACC projections remain less understood. In this study, we employed a combination of whole-brain imaging, in vitro electrophysiology, and two-photon calcium imaging techniques to confirm the presence of direct excitatory glutamatergic projections from the RSC to the ACC in mice. This excitatory transmission is predominantly mediated by the postsynaptic AMPA receptors. Furthermore, the activation of the RSC-ACC projections through opto-/chemogenetics significantly facilitated the behavioral responses to both mechanical and thermal nociceptive stimuli in adult mice. Notably, this activation did not influence spinal nociceptive responses in the tail-flick test, nor did it affect anxiety-like or aversive behaviors. These findings indicate that the RSC-ACC glutamatergic pathway modulates nociceptive perception primarily at the supraspinal cortical level. We have identified a novel cortico-cortical facilitatory pathway that contributes to nociceptive processing in the cingulate cortex. The RSC-ACC pathway probably serves to integrate memory engrams with pain perception in both humans and animals.</p>","PeriodicalId":49001,"journal":{"name":"PLoS Biology","volume":"23 1","pages":"e3003011"},"PeriodicalIF":9.8,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11801709/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143053989","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Trithorax regulates long-term memory in Drosophila through epigenetic maintenance of mushroom body metabolic state and translation capacity.","authors":"Nicholas Raun, Spencer G Jones, Olivia Kerr, Crystal Keung, Emily F Butler, Kumari Alka, Jonathan D Krupski, Robert A Reid-Taylor, Veyan Ibrahim, MacKayla Williams, Deniz Top, Jamie M Kramer","doi":"10.1371/journal.pbio.3003004","DOIUrl":"10.1371/journal.pbio.3003004","url":null,"abstract":"<p><p>The role of epigenetics and chromatin in the maintenance of postmitotic neuronal cell identities is not well understood. Here, we show that the histone methyltransferase Trithorax (Trx) is required in postmitotic memory neurons of the Drosophila mushroom body (MB) to enable their capacity for long-term memory (LTM), but not short-term memory (STM). Using MB-specific RNA-, ChIP-, and ATAC-sequencing, we find that Trx maintains homeostatic expression of several non-canonical MB-enriched transcripts, including the orphan nuclear receptor Hr51, and the metabolic enzyme lactate dehydrogenase (Ldh). Through these key targets, Trx facilitates a metabolic state characterized by high lactate levels in MBγ neurons. This metabolic state supports a high capacity for protein translation, a process that is essential for LTM, but not STM. These data suggest that Trx, a classic regulator of cell type specification during development, has additional functions in maintaining underappreciated aspects of postmitotic neuron identity, such as metabolic state. Our work supports a body of evidence suggesting that a high capacity for energy metabolism is an essential cell identity characteristic for neurons that mediate LTM.</p>","PeriodicalId":49001,"journal":{"name":"PLoS Biology","volume":"23 1","pages":"e3003004"},"PeriodicalIF":9.8,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11835295/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143053991","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Diverse neuronal activity patterns contribute to the control of distraction in the prefrontal and parietal cortex.","authors":"Panagiotis Sapountzis, Alexandra Antoniadou, Georgia G Gregoriou","doi":"10.1371/journal.pbio.3003008","DOIUrl":"10.1371/journal.pbio.3003008","url":null,"abstract":"<p><p>Goal-directed behavior requires the effective suppression of distractions to focus on the task at hand. Although experimental evidence suggests that brain areas in the prefrontal and parietal lobe contribute to the selection of task-relevant and the suppression of task-irrelevant stimuli, how conspicuous distractors are encoded and effectively ignored remains poorly understood. We recorded neuronal responses from 2 regions in the prefrontal and parietal cortex of macaques, the frontal eye field (FEF) and the lateral intraparietal (LIP) area, during a visual search task, in the presence and absence of a salient distractor. We found that in both areas, salient distractors are encoded by both response enhancement and suppression by distinct neuronal populations. In FEF, a larger proportion of units displayed suppression of responses to the salient distractor compared to LIP, with suppression effects in FEF being correlated with search time. Moreover, in FEF but not in LIP, the suppression for the salient distractor compared to non-salient distractors that shared the target color could not be accounted for by an enhancement of target features. These results reveal a distinct contribution of FEF in the suppression of salient distractors. Critically, we found that in both areas, the population level representations of the target and singleton locations were not orthogonal, suggesting a mechanism of interference from salient stimuli.</p>","PeriodicalId":49001,"journal":{"name":"PLoS Biology","volume":"23 1","pages":"e3003008"},"PeriodicalIF":9.8,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11801722/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143053987","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ParSite is a multicolor DNA labeling system that allows for simultaneous imaging of triple genomic loci in living cells.","authors":"Xiaohui He, Yadong Sun, Hanhui Ma","doi":"10.1371/journal.pbio.3003009","DOIUrl":"10.1371/journal.pbio.3003009","url":null,"abstract":"<p><p>The organization of the human genome in space and time is critical for transcriptional regulation and cell fate determination. However, robust methods for tracking genome organization or genomic interactions over time in living cells are lacking. Here, we developed a multicolor DNA labeling system, ParSite, to simultaneously track triple genomic loci in the U2OS cells. The tricolor ParSite system is derived from the T. thermophilus ParB/ParSc (TtParB/ParSc) system by rational design. We mutated the interface between TtParB and ParSc and generated a new pair of TtParBm and ParSm for genomic DNA labeling. The insertions of 16 base-pair palindromic ParSc and ParSm into genomic loci allow dual-color DNA imaging in living cells. A pair of genomic loci labeled by ParSite could be colocalized with p53-binding protein 1 (53BP1) in response to CRISPR/Cas9-mediated double-strand breaks (DSBs). The ParSite permits tracking promoter and terminator dynamics of the APP gene, which spans 290 kilobases in length. Intriguingly, the hybrid ParS (ParSh) of half-ParSc and half-ParSm enables for the visualization of a third locus independent of ParSc or ParSm. We simultaneously labeled 3 loci with a genomic distance of 36, 89, and 352 kilobases downstream the C3 repeat locus, respectively. In sum, the ParSite is a robust DNA labeling system for tracking multiple genomic loci in space and time in living cells.</p>","PeriodicalId":49001,"journal":{"name":"PLoS Biology","volume":"23 1","pages":"e3003009"},"PeriodicalIF":9.8,"publicationDate":"2025-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11798528/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143034325","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Rspo3-mediated metabolic liver zonation regulates systemic glucose metabolism and body mass in mice.","authors":"Kenji Uno, Takuya Uchino, Takashi Suzuki, Yohei Sayama, Naoki Edo, Kiyoko Uno-Eder, Koji Morita, Toshio Ishikawa, Miho Koizumi, Hiroaki Honda, Hideki Katagiri, Kazuhisa Tsukamoto","doi":"10.1371/journal.pbio.3002955","DOIUrl":"10.1371/journal.pbio.3002955","url":null,"abstract":"<p><p>The unique architecture of the liver consists of hepatic lobules, dividing the hepatic features of metabolism into 2 distinct zones, namely the pericentral and periportal zones, the spatial characteristics of which are broadly defined as metabolic zonation. R-spondin3 (Rspo3), a bioactive protein promoting the Wnt signaling pathway, regulates metabolic features especially around hepatic central veins. However, the functional impact of hepatic metabolic zonation, regulated by the Rspo3/Wnt signaling pathway, on whole-body metabolism homeostasis remains poorly understood. In this study, we analyze the local functions of Rspo3 in the liver and the remote actions of hepatic Rspo3 on other organs of the body by using murine models. Rspo3 expression analysis shows that Rspo3 expression patterns are spatiotemporally controlled in the murine liver such that it locates in the pericentral zones and converges after feeding, and the dynamics of these processes are disturbed in obesity. We find that viral-mediated induction of Rspo3 in hepatic tissue of obesity improves insulin resistance and prevents body weight gain by restoring attenuated organ insulin sensitivities, reducing adipose tissue enlargement and reversing overstimulated adaptive thermogenesis. Denervation of the hepatic vagus suppresses these remote effects, derived from hepatic Rspo3 induction, toward adipose tissues and skeletal muscle, suggesting that signals are transduced via the neuronal communication consisting of afferent vagal and efferent sympathetic nerves. Furthermore, the non-neuronal inter-organ communication up-regulating muscle lipid utilization is partially responsible for the ameliorations of both fatty liver development and reduced skeletal muscle quality in obesity. In contrast, hepatic Rspo3 suppression through Cre-LoxP-mediated recombination system exacerbates diabetes due to glucose intolerance and insulin resistance, promotes fatty liver development and decreases skeletal muscle quality, resulting in obesity. Taken together, our study results reveal that modulation of hepatic Rspo3 contributes to maintaining systemic glucose metabolism and body composition via a newly identified inter-organ communication mechanism.</p>","PeriodicalId":49001,"journal":{"name":"PLoS Biology","volume":"23 1","pages":"e3002955"},"PeriodicalIF":9.8,"publicationDate":"2025-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11759367/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143034450","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ventral hippocampus to nucleus accumbens shell circuit regulates approach decisions during motivational conflict.","authors":"Dylan Patterson, Nisma Khan, Emily A Collins, Norman R Stewart, Kian Sassaninejad, Dylan Yeates, Andy C H Lee, Rutsuko Ito","doi":"10.1371/journal.pbio.3002722","DOIUrl":"10.1371/journal.pbio.3002722","url":null,"abstract":"<p><p>Successful resolution of approach-avoidance conflict (AAC) is fundamentally important for survival, and its dysregulation is a hallmark of many neuropsychiatric disorders, and yet the underlying neural circuit mechanisms are not well elucidated. Converging human and animal research has implicated the anterior/ventral hippocampus (vHPC) as a key node in arbitrating AAC in a region-specific manner. In this study, we sought to target the vHPC CA1 projection pathway to the nucleus accumbens (NAc) to delineate its contribution to AAC decision-making, particularly in the arbitration of learned reward and punishment signals, as well as innate signals. To this end, we used pathway-specific chemogenetics in male and female Long Evans rats to inhibit the NAc shell projecting vHPC CA1 neurons while rats underwent a test in which cues of positive and negative valence were presented concurrently to elicit AAC. Additional behavioral assays of social preference and memory, reward and punishment cue processing, anxiety, and novelty processing were administered to further interrogate the conditions under which the vCA1-NAc shell pathway is recruited. Chemogenetic inhibition of the vCA1-NAc shell circuit resulted in animals exhibiting increased decision-making time and avoidance bias specifically in the face of motivational conflict, as the same behavioral phenotype was absent in separate conditioned cue preference and avoidance tests. vCA1-NAc shell inhibition also led to a reduction in seeking social interaction with a novel rat but did not alter anxiety-like behaviors. The vCA1-NAc shell circuit is therefore critically engaged in biasing decisions to approach in the face of social novelty and approach-avoidance conflict. Dysregulation of this circuit could lead to the precipitation of addictive behaviors in substance abuse, or maladaptive avoidance in situations of approach-avoidance conflict.</p>","PeriodicalId":49001,"journal":{"name":"PLoS Biology","volume":"23 1","pages":"e3002722"},"PeriodicalIF":9.8,"publicationDate":"2025-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11761569/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143034451","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cost-benefit tradeoff mediates the transition from rule-based to memory-based processing during practice.","authors":"Guochun Yang, Jiefeng Jiang","doi":"10.1371/journal.pbio.3002987","DOIUrl":"10.1371/journal.pbio.3002987","url":null,"abstract":"<p><p>Practice not only improves task performance but also changes task execution from rule- to memory-based processing by incorporating experiences from practice. However, how and when this change occurs is unclear. We test the hypothesis that strategy transitions in task learning can result from decision-making guided by cost-benefit analysis. Participants learn 2 task sequences and are then queried about the task type at a cued sequence and position. Behavioral improvement with practice can be accounted for by a computational model implementing cost-benefit analysis and the model-predicted strategy transition points align with the observed behavioral slowing. Model comparisons using behavioral data show that strategy transitions are better explained by a cost-benefit analysis across alternative strategies rather than solely on memory strength. Model-guided fMRI findings suggest that the brain encodes a decision variable reflecting the cost-benefit analysis and that different strategy representations are double-dissociated. Further analyses reveal that strategy transitions are associated with activation patterns in the dorsolateral prefrontal cortex and increased pattern separation in the ventromedial prefrontal cortex. Together, these findings support cost-benefit analysis as a mechanism of practice-induced strategy shift.</p>","PeriodicalId":49001,"journal":{"name":"PLoS Biology","volume":"23 1","pages":"e3002987"},"PeriodicalIF":9.8,"publicationDate":"2025-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11793810/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143030146","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}