Neural ensemble dynamics underlying a long-term associative memory

The brain’s ability to associate different stimuli is vital to long-term memory, but how neural ensembles encode associative memories is unknown. Here we studied how cell ensembles in the basal and lateral amygdala (BLA) encode associations between conditioned and unconditioned stimuli (CS, US). Using a miniature fluorescence microscope, we tracked BLA ensemble neural Ca2+ dynamics during fear learning and extinction over six days in behaving mice. Fear conditioning induced both up- and down-regulation of individual cells’ CS-evoked responses. This bi-directional plasticity mainly occurred after conditioning and reshaped the CS ensemble neural representation to gain similarity to the US-representation. During extinction training with repetitive CS presentations, the CS-representation became more distinctive without reverting to its original form. Throughout, the strength of the ensemble-encoded CS-US association predicted each mouse’s level of behavioral conditioning. These findings support a supervised learning model in which activation of the US-representation guides the transformation of the CS-representation.