Induction of Activity Synchronization among Primed Hippocampal Neurons out of Random Dynamics is Key for Trace Memory Formation and Retrieval

Memory is thought to be encoded by sparsely distributed neuronal ensembles in memory-related regions. However, it is unclear how memory-eligible neurons react incrementally during learning to encode trace fear memory, and how they respond to cues to retrieve the memory. We implemented fiber-optic confocal fluorescence endoscopy to directly visualize calcium dynamics of hippocampal CA1 neurons in freely behaving mice, which were subjected to trace fear conditioning. Here we report that the overall activity levels of CA1 principal neurons showed a right-skewed lognormal-like distribution. A small portion of highly active neurons (termed Primed Neurons) exhibited high sensitivity to sensory stimuli and marked activity plasticity. The Primed Neurons maintained random activity status for at least 5 hours in multiple contexts, including those prior to training and prior to recall. Repetitive training induced Primed Neurons to shift from random activity to a well-tuned synchronization. Importantly, the emergence of activity synchronization coincided with the appearance of mouse freezing behaviors. In recall, a partial synchronization among the same population of Primed Neurons was induced from originally random activity, which also coincided with mouse freezing behaviors. Additionally, training-induced synchronization facilitated robust calcium entry into individual Primed Neurons. In contrast, most CA1 neurons stayed silent and did not respond significantly to tone and foot-shock throughout the training and recall testing cycles. In conclusion, highly active Primed Neurons are preferably recruited to encode trace fear memory, and induction of activity synchronization among Primed Neurons out of random dynamics is critical for trace memory formation and memory retrieval.\n\nSignificance StatementO_LIThe overall activity levels of hippocampal principal CA1 neurons show a right-skewed lognormal-like distribution.\nC_LIO_LIA small portion of CA1 neurons (termed Primed Neurons) exhibit high activity and marked activity plasticity during learning and recall.\nC_LIO_LIPrimed Neurons in the hippocampus are preferably recruited to encode trace fear memory, whereas the majority of CA1 neurons show little activity and little activity change during fear conditioning and recall testing.\nC_LIO_LIInduction of activity synchronization among Primed Neurons out of random dynamics is critical for trace memory formation and memory retrieval.\nC_LIO_LITraining-induced synchronization drastically increases calcium entry into Primed Neurons, which may promote memory consolidation.\nC_LI