{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T13:11:38Z","timestamp":1789132298720,"version":"build-2803163510"},"reference-count":37,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T00:00:00Z","timestamp":1787270400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell. Neurosci."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Animals must learn not only which cues predict reward, but also when to act to obtain it. Although the orbitofrontal cortex (OFC) encodes reward-related information, whether reward contingency is sufficient to reorganize the temporal alignment of OFC activity remains unclear.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We recorded calcium signals from lateral OFC pyramidal neurons (lOFC-PNs) in wild-type (WT) and\n                      <jats:italic>Sapap3<\/jats:italic>\n                      knockout (KO) mice using fiber photometry, during sequential learning of Pavlovian and instrumental contingencies in a single-odor reward association task. We further used a cue-free lick test and linear mixed-effects modeling to dissociate the contribution of reward contingency from that of licking behavior.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Licking behavior and lOFC-PN activity were comparable between WT and KO mice, supporting pooled analysis. Under Pavlovian contingencies, licking and lOFC-PN activity were concentrated around reward delivery. Under instrumental contingencies, both shifted to the pre-reward delay period, and the timing of lOFC-PN activity became progressively coupled to anticipatory licking as learning advanced. A cue-free lick test and linear mixed-effects modeling confirmed that these contingency-related differences reflected reward contingency rather than licking\n                      <jats:italic>per se<\/jats:italic>\n                      .\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>These findings indicate that reward contingency dynamically reorganizes the temporal alignment of lOFC-PN activity and its coupling with behavior, shifting from reward-aligned under Pavlovian learning to action-aligned under instrumental learning. This contingency-dependent temporal reorganization may support flexible adaptation of neural processing to changing reward contingencies during associative learning.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fncel.2026.1850197","type":"journal-article","created":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T05:36:53Z","timestamp":1787290613000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Reward contingency reorganizes lateral orbitofrontal cortex pyramidal neuron activity from reward-aligned to action-aligned during associative learning"],"prefix":"10.3389","volume":"20","author":[{"given":"Zicheng","family":"Yang","sequence":"first","affiliation":[{"name":"School of Basic Medical Sciences, Beijing Key Laboratory of Neural Regeneration and Repair, Key Laboratory for Neurodegenerative Diseases of the Ministry of Education, Laboratory for Clinical Medicine, Capital Medical University","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaolan","family":"Chen","sequence":"additional","affiliation":[{"name":"School of Basic Medical Sciences, Beijing Key Laboratory of Neural Regeneration and Repair, Key Laboratory for Neurodegenerative Diseases of the Ministry of Education, Laboratory for Clinical Medicine, Capital Medical University","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaohong","family":"Sun","sequence":"additional","affiliation":[{"name":"School of Basic Medical Sciences, Beijing Key Laboratory of Neural Regeneration and Repair, Key Laboratory for Neurodegenerative Diseases of the Ministry of Education, Laboratory for Clinical Medicine, Capital Medical University","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huimeng","family":"Lei","sequence":"additional","affiliation":[{"name":"School of Basic Medical Sciences, Beijing Key Laboratory of Neural Regeneration and Repair, Key Laboratory for Neurodegenerative Diseases of the Ministry of Education, Laboratory for Clinical Medicine, Capital Medical University","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,8,21]]},"reference":[{"key":"ref1","volume-title":"Neurobiology of Sensation and Reward","author":"Balleine","year":"2011"},{"key":"ref2","doi-asserted-by":"publisher","first-page":"407","DOI":"10.1016\/S0028-3908(98)00033-1","article-title":"Goal-directed instrumental action: contingency and incentive learning and their cortical substrates","volume":"37","author":"Balleine","year":"1998","journal-title":"Neuropharmacology"},{"key":"ref3","doi-asserted-by":"publisher","first-page":"48","DOI":"10.1038\/npp.2009.131","article-title":"Human and rodent homologies in action control: corticostriatal determinants of goal-directed and habitual action","volume":"35","author":"Balleine","year":"2010","journal-title":"Neuropsychopharmacology"},{"key":"ref4","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1038\/s42003-020-01611-y","article-title":"A cross-species assessment of behavioral flexibility in compulsive disorders","volume":"4","author":"Benzina","year":"2021","journal-title":"Commun. Biol."},{"key":"ref5","doi-asserted-by":"publisher","first-page":"4675","DOI":"10.1016\/j.cub.2022.09.022","article-title":"Orbitofrontal cortex populations are differentially recruited to support actions","volume":"32","author":"Cazares","year":"2022","journal-title":"Curr. Biol."},{"key":"ref6","doi-asserted-by":"publisher","first-page":"eadi0645","DOI":"10.1126\/sciadv.adi0645","article-title":"Dissociable components of attention exhibit distinct neuronal signatures in primate visual cortex","volume":"10","author":"Chandrasekaran","year":"2024","journal-title":"Sci. Adv."},{"key":"ref7","doi-asserted-by":"publisher","first-page":"4","DOI":"10.1111\/gbb.12191","article-title":"Behavioral flexibility in rats and mice: contributions of distinct frontocortical regions","volume":"14","author":"Hamilton","year":"2015","journal-title":"Genes Brain Behav."},{"key":"ref8","doi-asserted-by":"publisher","first-page":"490","DOI":"10.1016\/j.cub.2019.12.007","article-title":"Targeted stimulation of human orbitofrontal networks disrupts outcome-guided behavior","volume":"30","author":"Howard","year":"2020","journal-title":"Curr. Biol."},{"key":"ref9","doi-asserted-by":"publisher","first-page":"10529","DOI":"10.1523\/JNEUROSCI.1678-17.2017","article-title":"Functional heterogeneity within rat orbitofrontal cortex in reward learning and decision making","volume":"37","author":"Izquierdo","year":"2017","journal-title":"J. Neurosci."},{"key":"ref10","doi-asserted-by":"publisher","first-page":"441","DOI":"10.1007\/s00213-022-06265-8","article-title":"Medial orbitofrontal cortical regulation of different aspects of Pavlovian and instrumental reward seeking","volume":"240","author":"Jenni","year":"2023","journal-title":"Psychopharmacology"},{"key":"ref11","doi-asserted-by":"publisher","first-page":"e1005753","DOI":"10.1371\/journal.pcbi.1005753","article-title":"Flexibility to contingency changes distinguishes habitual and goal-directed strategies in humans","volume":"13","author":"Lee","year":"2017","journal-title":"PLoS Comput. Biol."},{"key":"ref12","doi-asserted-by":"publisher","first-page":"425","DOI":"10.1007\/s12264-019-00379-4","article-title":"Long-term Fiber photometry for neuroscience studies","volume":"35","author":"Li","year":"2019","journal-title":"Neurosci. Bull."},{"key":"ref13","doi-asserted-by":"publisher","first-page":"2990","DOI":"10.1016\/j.cub.2026.05.004","article-title":"Multi-timescale motor circuit dynamics underlie adaptive and efficient exploratory behavior","volume":"36","author":"Li","year":"2026","journal-title":"Curr. Biol."},{"key":"ref14","doi-asserted-by":"publisher","first-page":"5549","DOI":"10.1016\/j.cub.2025.10.007","article-title":"Distinct contributions of anterior and posterior orbitofrontal cortex to outcome-guided behavior","volume":"35","author":"Liu","year":"2025","journal-title":"Curr. Biol."},{"key":"ref15","doi-asserted-by":"publisher","first-page":"12","DOI":"10.1016\/j.ynstr.2014.09.003","article-title":"Behavioral control blunts reactions to contemporaneous and future adverse events: medial prefrontal cortex plasticity and a corticostriatal network","volume":"1","author":"Maier","year":"2015","journal-title":"Neurobiol. Stress"},{"key":"ref16","doi-asserted-by":"publisher","first-page":"1494","DOI":"10.1038\/s41386-018-0307-2","article-title":"Impaired instrumental reversal learning is associated with increased medial prefrontal cortex activity in Sapap3 knockout mouse model of compulsive behavior","volume":"44","author":"Manning","year":"2019","journal-title":"Neuropsychopharmacology"},{"key":"ref17","doi-asserted-by":"publisher","first-page":"989","DOI":"10.1016\/j.biopsych.2021.11.018","article-title":"Distinct patterns of abnormal lateral orbitofrontal cortex activity during compulsive grooming and reversal learning normalize after fluoxetine","volume":"93","author":"Manning","year":"2023","journal-title":"Biol. Psychiatry"},{"key":"ref18","doi-asserted-by":"publisher","first-page":"1677","DOI":"10.1038\/s41593-019-0502-4","article-title":"Single-trial neural dynamics are dominated by richly varied movements","volume":"22","author":"Musall","year":"2019","journal-title":"Nat. Neurosci."},{"key":"ref19","doi-asserted-by":"publisher","first-page":"1110","DOI":"10.1038\/s41593-019-0408-1","article-title":"Single-cell activity tracking reveals that orbitofrontal neurons acquire and maintain a long-term memory to guide behavioral adaptation","volume":"22","author":"Namboodiri","year":"2019","journal-title":"Nat. Neurosci."},{"key":"ref20","doi-asserted-by":"publisher","first-page":"116687","DOI":"10.1016\/j.celrep.2025.116687","article-title":"Locus coeruleus norepinephrine neurons facilitate orbitofrontal cortex remapping and behavioral flexibility","volume":"44","author":"Ogg","year":"2025","journal-title":"Cell Rep."},{"key":"ref21","doi-asserted-by":"publisher","first-page":"4819","DOI":"10.1523\/JNEUROSCI.5443-06.2007","article-title":"Orbitofrontal cortex mediates outcome encoding in Pavlovian but not instrumental conditioning","volume":"27","author":"Ostlund","year":"2007","journal-title":"J. Neurosci."},{"key":"ref22","doi-asserted-by":"publisher","first-page":"e0078242024","DOI":"10.1523\/JNEUROSCI.0078-24.2024","article-title":"Adaptive responding to stimulus-outcome associations requires noradrenergic transmission in the medial prefrontal cortex","volume":"44","author":"Piccin","year":"2024","journal-title":"J. Neurosci."},{"key":"ref23","doi-asserted-by":"publisher","first-page":"151","DOI":"10.1037\/h0024475","article-title":"Two-process learning theory: relationships between Pavlovian conditioning and instrumental learning","volume":"74","author":"Rescorla","year":"1967","journal-title":"Psychol. Rev."},{"key":"ref24","doi-asserted-by":"publisher","first-page":"2010","DOI":"10.1523\/JNEUROSCI.2951-16.2016","article-title":"Orbitofrontal cortex signals expected outcomes with predictive codes when stable contingencies promote the integration of reward history","volume":"37","author":"Riceberg","year":"2017","journal-title":"J. Neurosci."},{"key":"ref25","doi-asserted-by":"publisher","first-page":"8931","DOI":"10.1038\/s41467-025-63866-5","article-title":"Neural coding of choice and outcome are modulated by uncertainty in orbitofrontal but not secondary motor cortex","volume":"16","author":"Romero-Sosa","year":"2025","journal-title":"Nat. Commun."},{"key":"ref26","doi-asserted-by":"publisher","first-page":"1143","DOI":"10.1016\/j.neuron.2014.10.049","article-title":"The orbitofrontal oracle: cortical mechanisms for the prediction and evaluation of specific behavioral outcomes","volume":"84","author":"Rudebeck","year":"2014","journal-title":"Neuron"},{"key":"ref27","doi-asserted-by":"publisher","first-page":"R1083","DOI":"10.1016\/j.cub.2018.07.018","article-title":"Orbitofrontal cortex","volume":"28","author":"Rudebeck","year":"2018","journal-title":"Curr. Biol."},{"key":"ref28","doi-asserted-by":"publisher","first-page":"885","DOI":"10.1038\/nrn2753","article-title":"A new perspective on the role of the orbitofrontal cortex in adaptive behaviour","volume":"10","author":"Schoenbaum","year":"2009","journal-title":"Nat. Rev. Neurosci."},{"key":"ref29","doi-asserted-by":"publisher","first-page":"104464","DOI":"10.1016\/j.neuint.2019.104464","article-title":"Neural circuits in goal-directed and habitual behavior: implications for circuit dysfunction in obsessive-compulsive disorder","volume":"129","author":"Simmler","year":"2019","journal-title":"Neurochem. Int."},{"key":"ref30","doi-asserted-by":"publisher","first-page":"620","DOI":"10.1038\/nn.3982","article-title":"What the orbitofrontal cortex does not do","volume":"18","author":"Stalnaker","year":"2015","journal-title":"Nat. Neurosci."},{"key":"ref31","doi-asserted-by":"publisher","first-page":"255","DOI":"10.1126\/science.aav7893","article-title":"Spontaneous behaviors drive multidimensional, brainwide activity","volume":"364","author":"Stringer","year":"2019","journal-title":"Science"},{"key":"ref32","volume-title":"Reinforcement Learning: An Introduction","author":"Sutton","year":"1998"},{"key":"ref33","doi-asserted-by":"publisher","first-page":"e12557","DOI":"10.1111\/gbb.12557","article-title":"Behavioral flexibility in a mouse model for obsessive-compulsive disorder: impaired Pavlovian reversal learning in SAPAP3 mutants","volume":"18","author":"Van den Boom","year":"2019","journal-title":"Genes Brain Behav."},{"key":"ref34","doi-asserted-by":"publisher","first-page":"7078","DOI":"10.1523\/JNEUROSCI.3860-09.2010","article-title":"Theta-band phase locking of orbitofrontal neurons during reward expectancy","volume":"30","author":"Van Wingerden","year":"2010","journal-title":"J. Neurosci."},{"key":"ref35","doi-asserted-by":"publisher","first-page":"31","DOI":"10.1146\/annurev.neuro.30.051606.094334","article-title":"Orbitofrontal cortex and its contribution to decision-making","volume":"30","author":"Wallis","year":"2007","journal-title":"Annu. Rev. Neurosci."},{"key":"ref36","doi-asserted-by":"publisher","first-page":"927","DOI":"10.1016\/j.neuron.2010.02.027","article-title":"Separable learning systems in the macaque brain and the role of orbitofrontal cortex in contingent learning","volume":"65","author":"Walton","year":"2010","journal-title":"Neuron"},{"key":"ref37","doi-asserted-by":"publisher","first-page":"381","DOI":"10.1016\/j.cub.2020.10.045","article-title":"Dysfunction of orbitofrontal GABAergic interneurons leads to impaired reversal learning in a mouse model of obsessive-compulsive disorder","volume":"31","author":"Yang","year":"2021","journal-title":"Curr. Biol."}],"updated-by":[{"DOI":"10.3389\/fncel.2026.1987114","type":"correction","label":"Correction","source":"publisher","updated":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T00:00:00Z","timestamp":1789084800000}}],"container-title":["Frontiers in Cellular Neuroscience"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fncel.2026.1850197\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T12:58:03Z","timestamp":1789131483000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fncel.2026.1850197\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,21]]},"references-count":37,"alternative-id":["10.3389\/fncel.2026.1850197"],"URL":"https:\/\/doi.org\/10.3389\/fncel.2026.1850197","relation":{},"ISSN":["1662-5102"],"issn-type":[{"value":"1662-5102","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,21]]},"article-number":"1850197"}}