A critical role of hippocampus for formation of remote cued fear memory

A unique feature of fear memory is its persistence that is highly relevant to fear and anxiety-related mental disorders. Recurrent reactivation of neural representations acquired from a traumatic event is thought to contribute to the indelibility of fear memory. Given a well-established role of hippocampus for memory reactivation, hippocampus is likely involved in consolidation process of fear memory. However, evidence suggests that formation of fear memory to a discrete sensory cue is hippocampus-independent. Here, using a pharmacological reversible inactivation of dorsal hippocampus in auditory cued fear conditioning by local infusion of muscimol, we demonstrate in mice that hippocampus is critical for remote memory formation of learned fear to the discrete sensory cue. Muscimol infusion before conditioning did not affect formation of recent auditory fear memory as previously reported. Same muscimol infusion, however, impaired remote auditory fear memory. Muscimol infusion before remote test of auditory fear memory did not affect memory retrieval, indicating hippocampus is not a brain site for storage of remote cued fear memory. Moreover, memory reactivation enforced by re-exposure to the conditioned tone could compensate for hippocampal inactivation, as memory-reactivated mice showed normal remote auditory fear memory despite hippocampal inactivation. Our findings support that hippocampus may have a general role for consolidation of remote associative memory through reactivation of memory trace, giving an insight into how learned fear persists over time.