Hippocampal reactivation of aversive experience enables safety learning and slow-breathing state for recovery from stress

Adaptive threat responses require both defensive behaviours to minimize danger and recovering from the induced physiological stress. However, the behavioural and neural basis of these recuperative strategies are still elusive. Using a novel two-location fear conditioning paradigm in mice, we have identified a slow-breathing immobility state of recovery that emerges when animals identify safe environments after threat avoidance. This immobile state was characterized by a 2-4 Hz breathing profile and replay of the aversive experience in the hippocampus. Suppressing hippocampal sharp-wave ripples (SWRs) inhibited the emergence of this recovery state, suggesting their role in learning safe locations. Anxiolysis with diazepam directly promoted the recovery state while suppressing SWRs, showing this treatment to be a double-edged sword that facilitates immediate relief but impairs long-term safety learning. These results demonstrate the importance of hippocampal replay for emotional resilience through its role in recovery.