Hierarchical Replay of Multi-regional Sequential Spiking Associated with Working Memory

How do millisecond-scale neural activities mediate second-scale behaviors? We recorded brain-wide activity in mice performing an olfactory working-memory task to decipher the cross-region organization of activity. Spike-correlograms analysis revealed millisecond within- and cross-region spike couplings, which were enriched among memory-encoding neurons with similar odor preferences. Spike coupling linked neurons into motifs of chains, single loops, and nested loops, especially among hippocampal and prefrontal-cortex neurons. Spike-coupling direction and activity-chain propagation aligned with that of memory-associated activity waves. Intriguingly, activity motifs were replayed before and after task performance, and during inter-trial intervals. Motifs exhibited hierarchical organization, with progressively longer time constants and the number of participating neurons. Thus, hierarchically organized and replayed cross-region spiking motifs are modulated on demand during the delay period, providing a potential mechanism for perceptual working-memory maintenance.