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Here, we synthesize emerging evidence from preclinical models and human studies demonstrating that GLP\u20101 receptor (GLP\u20101R) signaling modulates multiple cognitive domains, including reward and motivational processes relevant to obesity and substance use disorder, affective\u2010related behaviors, and learning and memory. We propose a unifying framework in which GLP\u20101R signaling acts as a key interoceptive indicator of energy status, dynamically modulating cognitive and behavioral output in accordance with metabolic state. In animal models, GLP\u20101R activation dampens effort\u2010based seeking for palatable food and addictive drugs alike, exerts bidirectional effects on affective behavior (e.g., anxiety\u2010like behavior), and promotes synaptic plasticity, learning, and neuroprotection. Clinical studies further indicate that GLP\u20101R agonists alter neural responses to reward\u2010related cues, influence mood\u2010related outcomes, and are associated with reduced risk of cognitive decline, although results pertaining to benefits in neurodegenerative disease remain mixed. Collectively, these data position GLP\u20101R signaling as a metabolic\u2010cognitive interface linking internal energy status to reward processing, affective regulation, and memory, and highlight the importance of disentangling direct central actions from indirect secondary metabolic effects when evaluating the therapeutic potential of GLP\u20101\u2010based interventions for psychiatric and cognitive disorders.<\/jats:p>","DOI":"10.1002\/cph4.70129","type":"journal-article","created":{"date-parts":[[2026,3,25]],"date-time":"2026-03-25T04:16:43Z","timestamp":1774412203000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["GLP\u20101 at the Metabolic\u2013Cognitive Interface: Reward, Affect, and Memory"],"prefix":"10.1002","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-6438-9192","authenticated-orcid":false,"given":"Serena X.","family":"Gao","sequence":"first","affiliation":[{"name":"Department of 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