{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T20:07:37Z","timestamp":1789157257318,"version":"build-2803163510"},"posted":{"date-parts":[[2026,9,8]]},"group-title":"Neuroscience","reference-count":70,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T00:00:00Z","timestamp":1788825600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,9,8]]},"abstract":"<jats:title>SUMMARY<\/jats:title>\n                <jats:p>\n                  Working memory capacity is poorly understood. The ability to control and extend working memory time-scales provides the potential to alleviate cognitive decline in disease and aging. Through an unbiased genetic search, we previously identified a thalamic orphan receptor Gpr12 as a potent enhancer of working memory, however its activation mechanism remains poorly understood. Here, we describe the CryoEM structure of Gpr12, revealing a lipidic regulatory site enabling an activated signaling state. By surveying the native lipidic environment in mouse thalamus we identified a class of 20 carbon:4 double bond fatty acid eicosanoids as potential ligands. Cell-based assays confirmed that the endogenous cannabinoid anandamide (AEA), but not other closely related family members or derivatives, robustly activates Gpr12.\n                  <jats:italic>In vivo<\/jats:italic>\n                  imaging during behavior revealed that Gpr12 activation produces a striking molecular state \u2013 the persistent suppression of cAMP in thalamus that tracks the duration of memory maintenance. Notably, genetic or pharmacological manipulations that enhance the AEA-Gpr12 signaling axis are sufficient to prolong cAMP suppression and extend the temporal window of memory maintenance. Furthermore, AEA-mediated cAMP suppressions in thalamus support sustained neural activity in PFC, specifically during memory maintenance. Thus, while cannabinoids often impair memory, here we identify an AEA-Gpr12 signaling axis in thalamus that enhances memory, including in primates. These findings identify a lipidic signaling mechanism in thalamus that is sufficient to control and extend working memory duration.\n                <\/jats:p>","DOI":"10.64898\/2026.09.03.749183","type":"posted-content","created":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T00:50:16Z","timestamp":1788915016000},"source":"Crossref","is-referenced-by-count":0,"title":["Lipid Activation of a Thalamic GPCR Extends Working Memory Time-scales"],"prefix":"10.64898","author":[{"given":"James Newton","family":"Brandt","sequence":"first","affiliation":[{"name":"Laboratory of Neural Dynamics & Cognition, The Rockefeller University, New York, NY 10065, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandra","family":"Bonito-Oliva","sequence":"additional","affiliation":[{"name":"Laboratory of Neural Dynamics & Cognition, The Rockefeller University, New York, NY 10065, 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