Striatal endocannabinoid-long-term potentiation mediates one-shot learning

Abstract

One-shot learning, the ability to form memories after a single, brief salient event, is essential to adapt ones behaviour in a dynamic world. However, how one-shot learning unfolds in the brain remains unknown. Challenges to elucidate its neural underpinnings stem experimentally from the scarcity of behavioral assays recapitulating one-shot learning in the laboratory, and conceptually from the limited number of neuronal plasticity mechanisms that could support learning after a small number of action potentials, as is common during a one-shot experience. Here, we overcome these challenges and identify a new mechanism for one-shot learning in dorsal striatum that relies on a non-classical form of plasticity, the endocannabinoid-mediated long-term potentiation (eCB-LTP). To do so, we develop a novel one-shot behavioral test, in which mice learn to avoid a sticky tape after a single, spontaneous and brief contact with the uncomfortable substrate, and maintain this memory for more than one month. We use the sticky tape avoidance test to demonstrate that striatal LTP emerges in vivo after one-shot learning; the observed patterns of activity in vivo suggest that eCB-LTP mediates one-shot learning, which we corroborate both ex vivo and through computational modeling. Consistent with this hypothesis, conditional knock-out mice abolishing eCB-LTP show impaired one-shot learning. These results highlight the importance of non-classical plasticity mechanisms in supporting memory formation after a single brief experience.