STRIATAL SIGNALING PATHWAYS AT PLAY FROM ONE- TO MULTIPLE-SHOT LEARNING​​​​​

The ability to rapidly adapt to novel situations relies on learning mechanisms operating after a single experience. One-shot learning refers to such learning experiences that involve both a unique and brief exposure to a stimulus. To examine how learning mechanisms engaged after a one-shot experience evolve upon repetition, we have developed a novel one-shot behavioral test, the sticky tape avoidance test, in which mice learn to avoid a sticky tape after a spontaneous single and brief contact (Piette et al., BioRxiv). We found that, in the dorsolateral striatum, an endocannabinoid-mediated LTP drove one-shot learning. Here, we examined how the signaling pathways evolves from one-shot to multiple-shot learning. To do so, we used a combination of in vivo electrophysiology, fiber photometry, conditional knock-out and pharmacological approaches and ex vivo occlusion patch-clamp experiments. We found that upon repetition of the one-shot learning task, NMDA-mediated plasticity gradually replaces the endocannabinoid-mediated LTP. To link synaptic plasticity with neuromodulatory dynamics, we monitored, dopamine, calcium and endocannabinoid transients in the dorsolateral striatum using fiber photometry and found profound remodeling of the dynamics of those transients. Our results suggest that distinct forms of synaptic plasticity are differentially engaged as a function of experience, with endocannabinoid-mediated-LTP enabling one-shot learning, while NMDA-mediated-LTP contributes to the gradual stabilization and proceduralization of behavior.