{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T08:51:39Z","timestamp":1788511899689,"version":"build-2803163510"},"reference-count":38,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,12,10]],"date-time":"2025-12-10T00:00:00Z","timestamp":1765324800000},"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. Behav. Neurosci."],"abstract":"<jats:p>\n                    The dorsomedial striatum (DMS) is believed to promote action-outcome associations by integrating cortical and limbic afferents with nigrostriatal dopamine. This functional role for the DMS encompasses reinforcement learning processes traditionally ascribed to the ventral (outcome valuation) and lateral (action-selection) subdivisions of the striatum. Previous studies have shown that DMS dopamine signaling encodes actions and outcomes, often in a lateralized manner (e.g., dopamine release is greater for contralateral actions). To determine how these dynamics evolve with changing action-outcome contingencies, we recorded dopamine axon Ca\n                    <jats:sup>2+<\/jats:sup>\n                    activity in the DMS during a lateralized reversal learning task in mice. Using a miniaturized fluorescence microscope, we found that dopamine axon Ca\n                    <jats:sup>2+<\/jats:sup>\n                    activation in the DMS encoded actions and outcomes with a lateral bias, but only very early in reversal learning, immediately after the action-outcome contingency switch. Specifically, we found that dopamine axon activation during contralateral choices and the rewards associated with those choices were only greater than ipsilateral choices and their rewards in the first session of reversal. Over the course of reversal, reward- and choice-evoked dopamine axon activation subsided for contralateral, but not ipsilateral, choices, resulting in no lateral bias after learning the new action-outcome contingency. Consistent with a causal role for these lateralized dynamics, unilateral optogenetic inhibition of the nigrostriatal dopamine pathway impaired contralateral reversal by reducing \u201cwin-stay\u201d responses. However, this deficit was transient, occurring only during the first reversal session. Our results suggest that dopamine signaling in the DMS facilitates the exploration of new actions, specifically at the specific moment the previous action-outcome contingency becomes conflicted. In our lateralized reversal learning task, this facilitation was particularly important when the new action and resulting outcome were contralateral to the recorded hemisphere. These findings advance our understanding of how the DMS carries out its ascribed role in action-outcome learning.\n                  <\/jats:p>","DOI":"10.3389\/fnbeh.2025.1703094","type":"journal-article","created":{"date-parts":[[2025,12,10]],"date-time":"2025-12-10T07:14:57Z","timestamp":1765350897000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["Lateralized nigrostriatal dopamine pathway activation promotes early reversal learning"],"prefix":"10.3389","volume":"19","author":[{"given":"Stefan W.","family":"Fleps","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ben","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicolette A.","family":"Moya","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xunhui","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seongsik","family":"Yun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jones G.","family":"Parker","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,12,10]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"432","DOI":"10.1016\/j.neuron.2007.12.019","article-title":"Cocaine seeking habits depend upon dopamine-dependent serial connectivity linking the ventral with the dorsal striatum","volume":"57","author":"Belin","year":"2008","journal-title":"Neuron"},{"key":"ref2","doi-asserted-by":"publisher","first-page":"1272","DOI":"10.1038\/s41593-018-0211-4","article-title":"In vivo measurement of afferent activity with axon-specific calcium imaging","volume":"21","author":"Broussard","year":"2018","journal-title":"Nat. Neurosci."},{"key":"ref3","doi-asserted-by":"publisher","first-page":"51","DOI":"10.1016\/j.nlm.2014.05.003","article-title":"From ventral-medial to dorsal-lateral striatum: neural correlates of reward-guided decision-making","volume":"117","author":"Burton","year":"2015","journal-title":"Neurobiol. Learn. Mem."},{"key":"ref4","doi-asserted-by":"publisher","first-page":"74","DOI":"10.1016\/j.bbr.2010.02.017","article-title":"Selective lesions of the dorsomedial striatum impair serial spatial reversal learning in rats","volume":"210","author":"Casta\u00f1\u00e9","year":"2010","journal-title":"Behav. Brain Res."},{"key":"ref5","doi-asserted-by":"publisher","first-page":"e3003289","DOI":"10.1371\/journal.pbio.3003289","article-title":"Regulation of working memory switches from striatal dopamine D2-receptor to D1-receptor neurons under high cognitive load","volume":"23","author":"Chen","year":"2025","journal-title":"PLoS Biol."},{"key":"ref6","doi-asserted-by":"publisher","first-page":"10972","DOI":"10.1523\/jneurosci.1521-08.2008","article-title":"Lesions of the medial striatum in monkeys produce perseverative impairments during reversal learning similar to those produced by lesions of the orbitofrontal cortex","volume":"28","author":"Clarke","year":"2008","journal-title":"J. Neurosci."},{"key":"ref7","doi-asserted-by":"publisher","first-page":"63","DOI":"10.1016\/j.neuron.2019.08.036","article-title":"Learning from action: reconsidering movement signaling in midbrain dopamine neuron activity","volume":"104","author":"Coddington","year":"2019","journal-title":"Neuron"},{"key":"ref8","doi-asserted-by":"publisher","first-page":"276","DOI":"10.1126\/science.aap8586","article-title":"An amygdalar neural ensemble that encodes the unpleasantness of pain","volume":"363","author":"Corder","year":"2019","journal-title":"Science"},{"key":"ref9","doi-asserted-by":"publisher","first-page":"244","DOI":"10.1038\/nature25457","article-title":"Dopamine neuron activity before action initiation gates and invigorates future movements","volume":"554","author":"da Silva","year":"2018","journal-title":"Nature"},{"key":"ref10","doi-asserted-by":"publisher","first-page":"6455","DOI":"10.1073\/pnas.1404323111","article-title":"Aversive behavior induced by optogenetic inactivation of ventral tegmental area dopamine neurons is mediated by dopamine D2 receptors in the nucleus accumbens","volume":"111","author":"Danjo","year":"2014","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref11","doi-asserted-by":"publisher","first-page":"3086","DOI":"10.1016\/j.cub.2024.05.069","article-title":"Dopamine neurons drive spatiotemporally heterogeneous striatal dopamine signals during learning","volume":"34","author":"Engel","year":"2024","journal-title":"Curr. Biol."},{"key":"ref12","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1146\/annurev-psych-122414-033457","article-title":"Drug addiction: updating actions to habits to compulsions ten years on","volume":"67","author":"Everitt","year":"2016","journal-title":"Annu. Rev. Psychol."},{"key":"ref28","volume-title":"The Mouse Brain in Stereotaxic Coordinates. 3rd ed., Boston, 2008. Available online at:","author":"Franklin","year":"2001"},{"key":"ref13","doi-asserted-by":"publisher","first-page":"80","DOI":"10.1016\/j.neuroscience.2018.01.032","article-title":"Cognitive flexibility deficits following 6-OHDA lesions of the rat dorsomedial striatum","volume":"374","author":"Grospe","year":"2018","journal-title":"Neuroscience"},{"key":"ref14","doi-asserted-by":"publisher","first-page":"2733","DOI":"10.1016\/j.cell.2021.03.046","article-title":"Wave-like dopamine dynamics as a mechanism for spatiotemporal credit assignment","volume":"184","author":"Hamid","year":"2021","journal-title":"Cell"},{"key":"ref15","doi-asserted-by":"publisher","first-page":"113828","DOI":"10.1016\/j.celrep.2024.113828","article-title":"Striatal dopamine release tracks the relationship between actions and their consequences","volume":"43","author":"Hart","year":"2024","journal-title":"Cell Rep."},{"key":"ref16","doi-asserted-by":"publisher","first-page":"5350","DOI":"10.1016\/j.cub.2021.09.040","article-title":"Nigrostriatal dopamine signals sequence-specific action-outcome prediction errors","volume":"31","author":"Hollon","year":"2021","journal-title":"Curr. Biol."},{"key":"ref17","doi-asserted-by":"publisher","first-page":"505","DOI":"10.1038\/nature18942","article-title":"Rapid signalling in distinct dopaminergic axons during locomotion and reward","volume":"535","author":"Howe","year":"2016","journal-title":"Nature"},{"key":"ref18","doi-asserted-by":"publisher","first-page":"12","DOI":"10.1016\/j.neuroscience.2016.03.021","article-title":"The neural basis of reversal learning: an updated perspective","volume":"345","author":"Izquierdo","year":"2017","journal-title":"Neuroscience"},{"key":"ref19","doi-asserted-by":"publisher","first-page":"607","DOI":"10.1007\/s00213-011-2579-7","article-title":"Reversal learning as a measure of impulsive and compulsive behavior in addictions","volume":"219","author":"Izquierdo","year":"2012","journal-title":"Psychopharmacology"},{"key":"ref20","doi-asserted-by":"publisher","first-page":"1124","DOI":"10.1038\/s41593-022-01152-z","article-title":"Fiber photometry in striatum reflects primarily nonsomatic changes in calcium","volume":"25","author":"Legaria","year":"2022","journal-title":"Nat. Neurosci."},{"key":"ref21","doi-asserted-by":"publisher","first-page":"1621","DOI":"10.1016\/j.neuron.2021.03.013","article-title":"Efficient optogenetic silencing of neurotransmitter release with a mosquito rhodopsin","volume":"109","author":"Mahn","year":"2021","journal-title":"Neuron"},{"key":"ref22","doi-asserted-by":"publisher","first-page":"1034","DOI":"10.1016\/j.cub.2024.01.067","article-title":"Dopamine neuron activity encodes the length of upcoming contralateral movement sequences","volume":"34","author":"Mendon\u00e7a","year":"2024","journal-title":"Curr. Biol."},{"key":"ref23","doi-asserted-by":"publisher","first-page":"737","DOI":"10.1038\/s41593-023-01566-3","article-title":"Dopamine transients follow a striatal gradient of reward time horizons","volume":"27","author":"Mohebi","year":"2024","journal-title":"Nat. Neurosci."},{"key":"ref24","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1016\/j.neures.2012.09.002","article-title":"An optogenetic application of proton pump ArchT to C. elegans cells","volume":"75","author":"Okazaki","year":"2013","journal-title":"Neurosci. Res."},{"key":"ref25","doi-asserted-by":"publisher","first-page":"6235","DOI":"10.1523\/jneurosci.1478-05.2005","article-title":"Dopamine cells respond to predicted events during classical conditioning: evidence for eligibility traces in the reward-learning network","volume":"25","author":"Pan","year":"2005","journal-title":"J. Neurosci."},{"key":"ref26","doi-asserted-by":"publisher","first-page":"845","DOI":"10.1038\/nn.4287","article-title":"Reward and choice encoding in terminals of midbrain dopamine neurons depends on striatal target","volume":"19","author":"Parker","year":"2016","journal-title":"Nat. Neurosci."},{"key":"ref27","doi-asserted-by":"publisher","first-page":"177","DOI":"10.1038\/s41586-018-0090-6","article-title":"Diametric neural ensemble dynamics in parkinsonian and dyskinetic states","volume":"557","author":"Parker","year":"2018","journal-title":"Nature"},{"key":"ref29","doi-asserted-by":"publisher","first-page":"e58544","DOI":"10.7554\/eLife.58544","article-title":"Striatal direct and indirect pathway neurons differentially control the encoding and updating of goal-directed learning","volume":"9","author":"Peak","year":"2020","journal-title":"eLife"},{"key":"ref30","doi-asserted-by":"publisher","first-page":"355","DOI":"10.1196\/annals.1401.013","article-title":"The contribution of the medial prefrontal cortex, orbitofrontal cortex, and dorsomedial striatum to behavioral flexibility","volume":"1121","author":"Ragozzino","year":"2007","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref31","doi-asserted-by":"publisher","first-page":"70","DOI":"10.1101\/lm.65404","article-title":"Dynamic changes in acetylcholine output in the medial striatum during place reversal learning","volume":"11","author":"Ragozzino","year":"2004","journal-title":"Learn. Mem."},{"key":"ref32","doi-asserted-by":"publisher","first-page":"1593","DOI":"10.1126\/science.275.5306.1593","article-title":"A neural substrate of prediction and reward","volume":"275","author":"Schultz","year":"1997","journal-title":"Science"},{"key":"ref33","doi-asserted-by":"publisher","first-page":"275","DOI":"10.1016\/s0301-0082(96)00040-8","article-title":"The unilateral 6-hydroxydopamine lesion model in behavioral brain research. Analysis of functional deficits, recovery and treatments","volume":"50","author":"Schwarting","year":"1996","journal-title":"Prog. Neurobiol."},{"key":"ref34","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1109\/83.650848","article-title":"A pyramid approach to subpixel registration based on intensity","volume":"7","author":"Thevenaz","year":"1998","journal-title":"IEEE Trans. Image Process."},{"key":"ref35","doi-asserted-by":"publisher","first-page":"e62390","DOI":"10.7554\/eLife.62390","article-title":"Distinct temporal difference error signals in dopamine axons in three regions of the striatum in a decision-making task","volume":"9","author":"Tsutsui-Kimura","year":"2020","journal-title":"eLife"},{"key":"ref36","doi-asserted-by":"publisher","first-page":"4529","DOI":"10.1111\/ejn.15764","article-title":"Striatal mechanisms of turning behaviour following unilateral dopamine depletion in mice","volume":"56","author":"Yu","year":"2022","journal-title":"Eur. J. Neurosci."},{"key":"ref37","doi-asserted-by":"publisher","first-page":"e70011","DOI":"10.1002\/syn.70011","article-title":"Cellular-resolution and bulk-fluorescence recordings of calcium activity yield reciprocal readouts of in vivo drug efficacy","volume":"79","author":"Yun","year":"2025","journal-title":"Synapse"},{"key":"ref38","doi-asserted-by":"publisher","first-page":"1417","DOI":"10.1038\/s41593-023-01390-9","article-title":"Antipsychotic drug efficacy correlates with the modulation of D1 rather than D2 receptor-expressing striatal projection neurons","volume":"26","author":"Yun","year":"2023","journal-title":"Nat. Neurosci."}],"container-title":["Frontiers in Behavioral Neuroscience"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnbeh.2025.1703094\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,10]],"date-time":"2025-12-10T07:14:58Z","timestamp":1765350898000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnbeh.2025.1703094\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,12,10]]},"references-count":38,"alternative-id":["10.3389\/fnbeh.2025.1703094"],"URL":"https:\/\/doi.org\/10.3389\/fnbeh.2025.1703094","relation":{},"ISSN":["1662-5153"],"issn-type":[{"value":"1662-5153","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,12,10]]},"article-number":"1703094"}}