Striatal endocannabinoids drive one-shot learning.

One-shot learning-the ability to form memories after a single, brief salient event-is essential for behavioral flexibility in a dynamic world. However, how one-shot learning unfolds in the brain and whether it relies on distinct plasticity mechanisms remains unknown. Here we show that a nonclassical plasticity mechanism requiring only a few stimulations-endocannabinoid-mediated long-term potentiation (eCB-LTP)-underlies one-shot learning in the striatum. To do so, we developed a one-shot behavioral paradigm-the sticky tape avoidance test-in which mice learn to avoid a piece of sticky tape after a spontaneous single and brief contact. Brief, but not prolonged, contacts drive striatal potentiation in vivo and engage coordinated cortical-striatal activity patterns consistent with eCB-LTP induction, as corroborated by ex vivo electrophysiology and computational modeling. Finally, genetic and pharmacological disruptions of eCB-LTP impaired one-shot learning. These results highlight the essential role of nonclassical plasticity mechanisms in supporting memory formation after a single experience.