Abstract
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. Challenges in elucidating its neural underpinnings stem experimentally from the scarcity of behavioral assays that recapitulate one-shot learning in the laboratory, and conceptually from the limited number of neuronal plasticity mechanisms that could support learning from the small numbers of action potentials typical of one-shot experience. Here, we test whether a non-classical form of plasticity induced by a few paired stimulations in vitro, the endocannabinoid-mediated long-term potentiation (eCB-LTP), mediates one-shot learning in the dorsal striatum. To do so, we develop a novel oneshot behavioral test, the sticky tape avoidance test, in which mice learn to avoid a piece of sticky tape after a spontaneous single and brief contact, and maintain this memory for more than one month. We demonstrate that striatal potentiation emerges in vivo after one-shot learning only after brief contacts. The cortical and striatal patterns of activity in vivo during brief contacts suggest that one shot learning may be mediated by eCB-LTP, which we corroborate through ex vivo electrophysiology and computational modeling. Consistent with this hypothesis, conditional knockout and drug-infused mice abolishing eCB-LTP show impaired one-shot learning. These results highlight the essential role of non-classical plasticity mechanisms in supporting memory formation after a single brief experience.