Semaglutide modulates consolidation and updating of inhibitory avoidance memory

Semaglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist widely prescribed for metabolic disease, also acts on central neural circuits. However, its effects on the formation and long-term stabilization of emotional memories remain poorly understood. We tested whether systemic semaglutide modulates different aversive memory processes. Adult CF-1 mice underwent one-trial step-through inhibitory avoidance training and received a single subcutaneous injection of semaglutide (0.1 mg/kg) or vehicle immediately after training, before testing, or after memory reactivation. Memory was assessed up to seven days later. Post-training semaglutide increased step-through latencies at both 48 hours and 7 days, and this enhancement persisted at a second test 24 hours later. The effect was time-dependent: semaglutide given 3 hours after training was ineffective. Pre-test administration did not alter memory expression, indicating that the effect was not due to an acute modulation of retrieval. Semaglutide given immediately after memory reactivation also strengthened subsequent retention. These findings indicate that a single systemic dose of semaglutide strengthens the consolidation and post-retrieval updating of inhibitory avoidance memory without detectable effects on memory retrieval. They identify GLP-1 signaling as a modulator of long-term aversive memory and raise important translational questions about the cognitive effects of this widely used medication.