Examining the engram encoding specificity hypothesis in mice.

According to the encoding specificity hypothesis, memory is best recalled by retrieval cues that overlap with training cues. Human studies generally support this hypothesis. However, memories are thought to be stored in neuronal ensembles (engrams), and retrieval cues are thought to reactivate neurons in an engram to induce memory recall. Here, we visualized engrams in mice to test whether retrieval cues that overlap with training cues produce maximal memory recall via high engram reactivation (engram encoding specificity hypothesis). Using variations of cued threat conditioning (pairing conditioned stimulus [CS] with footshock), we manipulated encoding and retrieval conditions along multiple domains, including pharmacological state, external sensory cue, and internal optogenetic cue. Maximal engram reactivation and memory recall occurred when retrieval conditions closely matched training conditions. These findings provide a biological basis for the encoding specificity hypothesis and highlight the important interaction between stored information (engram) and cues available at memory retrieval (ecphory).