{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,1,16]],"date-time":"2026-01-16T02:32:59Z","timestamp":1768530779419,"version":"3.49.0"},"posted":{"date-parts":[[2025,10,31]]},"group-title":"Neuroscience","reference-count":87,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,10,31]],"date-time":"2025-10-31T00:00:00Z","timestamp":1761868800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"name":"Fondazione Istituto Italiano di Tecnologia","award":["Core Funding"],"award-info":[{"award-number":["Core Funding"]}]},{"name":"NKFIH EXCELLENCE","award":["151377"],"award-info":[{"award-number":["151377"]}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["P30DA056410"],"award-info":[{"award-number":["P30DA056410"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"name":"National Center for Gene Therapy and Drug based on RNA Technology","award":["CN00000041"],"award-info":[{"award-number":["CN00000041"]}]},{"name":"NextGenerationEU PNRR MUR \u2013 M4C2 \u2013 Action 1.4-Call \u201cPotenziamento strutture di ricerca e di campioni nazionali di R&S\u201d","award":["CUP J33C22001130001"],"award-info":[{"award-number":["CUP J33C22001130001"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,10,31]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Synaptic plasticity is a fundamental substrate of behavioral adaptation, yet the underlying molecular dynamics remain poorly defined. We tested the hypothesis that, within striatal circuits, flexibility relies on nanoscale remodeling of synaptic machinery coupling anterograde glutamatergic transmission to retrograde endocannabinoid signaling, a process disrupted in states of rigidity and aging. In the dorsolateral striatum, we found cell-type-specific facilitation of metabotropic glutamate receptor 5 (mGlu\n                  <jats:sub>5<\/jats:sub>\n                  )-dependent, endocannabinoid-mediated long-term depression at cortico-striatal synapses of indirect pathway neurons in flexible goal-directed behavior, but not after training promoting inflexibility. Stochastic Optical Reconstruction Microscopy (STORM) super-resolution imaging revealed that behavioral adaptation, but not rigidity, is accompanied by increased postsynaptic abundance of mGlu\n                  <jats:sub>5<\/jats:sub>\n                  and diacylglycerol lipase-\u03b1 (DAGL\u03b1), an endocannabinoid-synthesizing enzyme, and presynaptic CB\n                  <jats:sub>1<\/jats:sub>\n                  cannabinoid receptors. In parallel, the nanoscale distance between mGlu\n                  <jats:sub>5<\/jats:sub>\n                  and DAGL\u03b1 is reduced in postsynaptic spine heads. These nanoscale changes emerged within the time window required for behavioral updating. Intriguingly, the molecular densities of mGlu5, DAGL\u03b1, and CB1 receptors predict the strength of behavioral adaptation. In aging mice, these nanoscale changes were absent in association with behavioral rigidity. These findings identify a nanoscale synaptic remodeling mechanism that enables behavioral flexibility and reveal how its failure contributes to rigidity, including that observed in aging.\n                <\/jats:p>","DOI":"10.1101\/2025.10.30.684628","type":"posted-content","created":{"date-parts":[[2025,10,31]],"date-time":"2025-10-31T09:50:12Z","timestamp":1761904212000},"source":"Crossref","is-referenced-by-count":0,"title":["Nanoscale synaptic remodeling at corticostriatal circuits predicts flexible action control"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8773-3538","authenticated-orcid":false,"given":"Vincent","family":"Paget-Blanc","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mikl\u00f3s","family":"Z\u00f6ldi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anna","family":"Cavaccini","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vivien","family":"Micz\u00e1n","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Barna","family":"Dudok","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Istv\u00e1n","family":"Katona","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Raffaella","family":"Tonini","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2025110303551211000_2025.10.30.684628v1.1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.neuro.29.051605.112851"},{"key":"2025110303551211000_2025.10.30.684628v1.2","doi-asserted-by":"crossref","first-page":"R1200","DOI":"10.1016\/j.cub.2017.09.060","article-title":"Habits","volume":"27","year":"2017","journal-title":"Curr. 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