Hippocampal ensembles regulate circuit-induced relapse of extinguished fear

Extinction learning is central to behavioral therapies for post-traumatic stress disorder (PTSD), but relapse poses a major challenge to this approach. Recent work has revealed a critical role for the thalamic nucleus reuniens (RE) in the suppression of extinguished fear memories. Silencing the RE yields a relapse of extinguished fear (i.e., "circuit-induced relapse"). Considerable work suggests that RE may contribute to extinction by inhibiting the retrieval of hippocampal (HPC)-dependent fear memories. To test this hypothesis, we first examined whether undermining the formation of contextual fear memories in the HPC would prevent circuit-induced relapse. Intra-hippocampal infusions of the NMDA receptor antagonist, APV, prior to auditory fear conditioning eliminated contextual fear memory and prevented the subsequent relapse of extinguished fear to the auditory conditioned stimulus (CS). In a second experiment, we used an activity-dependent labeling system (AAV-cFos-tTA; AAV-TRE-hM3Dq-mCherry) to express excitatory DREADDs in HPC neurons during fear conditioning. Chemogenetic reactivation of these ensembles after extinction was sufficient to drive relapse of fear to the extinguished CS. Lastly, in a third experiment, we expressed excitatory DREADDs in HPC ensembles captured during extinction learning and found that chemogenetic reactivation of this ensemble was sufficient to inhibit circuit-induced relapse. These results reveal that HPC-dependent ensembles play a critical role in regulating the expression and relapse of extinguished fear.