GLP-1 at the Metabolic-Cognitive Interface: Reward, Affect, and Memory.

Glucagon-like peptide-1 (GLP-1) is a nutrient-responsive hormone classically associated with glucose homeostasis and food intake control, yet its receptor is broadly expressed throughout the central nervous system (CNS) in circuits governing complex cognitive processes. Here, we synthesize emerging evidence from preclinical models and human studies demonstrating that GLP-1 receptor (GLP-1R) signaling modulates multiple cognitive domains, including reward and motivational processes relevant to obesity and substance use disorder, affective-related behaviors, and learning and memory. We propose a unifying framework in which GLP-1R 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-1R activation dampens effort-based seeking for palatable food and addictive drugs alike, exerts bidirectional effects on affective behavior (e.g., anxiety-like behavior), and promotes synaptic plasticity, learning, and neuroprotection. Clinical studies further indicate that GLP-1R agonists alter neural responses to reward-related cues, influence mood-related 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-1R signaling as a metabolic-cognitive 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-1-based interventions for psychiatric and cognitive disorders.