Mechanisms of contextual fear memory suppression and extinction by the Nucleus Reuniens-CA1 pathway

Remembering and responding to aversive events is a crucial evolutionarily conserved behavior. In mammals, regulation of contextual fear memories depends on both medial prefrontal cortex (mPFC), key for extinguishing non-salient fear responses, and dorsal hippocampal CA1 (dCA1), key for encoding contextual memories. However, there is no direct mPFC to CA1 path, leaving unclear how these regions coordinate. A potential route is through the Nucleus Reuniens (NR), a higher-order thalamic region well-connected to emotional regulation areas. NR is driven by mPFC and sends an excitatory monosynaptic input to the Stratum Lacunosum Moleculare (SLM) of CA1, where CA1 pyramidal cell apical tuft dendrites reside. Both the mPFC-NR pathway and NR itself are necessary for contextual fear memory extinction, but the NR-CA1 pathway’s role is unknown. Our experiments uncover its role in a virtual reality contextual fear memory paradigm at the behavioral and circuit level. We used mild tail shocks to induce context-dependent fear (freezing). Using in-vivo 2-photon calcium imaging of NR-CA1 axons, we discovered the NR-CA1 pathway selectively activates during fear-induced freezing (fear memory recall), but not during non-fearful pausing prior to fear induction. Supporting this, NR axonal activity was well predicted by behavioral information using a gradient boosted decision trees model following fear induction, but poorly predicted before. By selectively inactivating CA1-projecting NR neurons following fear induction, we extended the length of fear-induced freezing epochs, both during inactivation and on the following day when NR was no longer inactivated, revealing a disruption in fear extinction. Population activity recordings of SLM dendrites revealed an increase in the frequency of dendritic transients during fearful freezing, but not during non-fearful pausing epochs. These findings reveal a novel role for Nucleus Reuniens in suppressing contextual fear memories by increasing apical tuft dendritic excitability of CA1 pyramidal cells during contextual fear memory recall, inducing fear extinction.