To survive in a dynamic environment, animals need to identify and appropriately respond to stimuli that signal danger1,2. At the same time, animal survival also depends on suppressing the threat response during a stimulus that predicts absence of threat, i.e. safety3-5. Understanding the biological substrates of differential threat memories in which animals learn to flexibly switch between expressing and suppressing defensive responses to a threat-predictive cue and a safety cue, respectively, is critical for developing treatments for memory disorders such as PTSD6. A key brain area for processing and storing threat memories is the centrolateral amygdala (CeL), which receives convergent sensory inputs from the parabrachial nucleus and the basolateral amygdala and connects directly to the output nucleus of amygdala, the centromedial nucleus, to mediate defensive responses7-9. Despite a plethora of studies on the importance of neuronal activity in specific CeL neuronal populations during memory acquisition and retrieval10-12, little is known about regulation of their protein synthesis machinery. Consolidation of long-term, but not short-term, threat memories requires de novo protein synthesis, which suggests that the translation machinery in CeL interneurons is tightly regulated in order to stabilize associative memories. Herein, we have applied intersectional chemogenetic strategies in CeL interneurons to block cell type-specific translation initiation programs that are sensitive to depletion of eukaryotic initiation factor 4E (eIF4E) and phosphorylation of eukaryotic initiation factor 2α (p-eIF2α), respectively. We show that in a differential threat conditioning paradigm, de novo translation in somatostatin-expressing (SOM) interneurons in the CeL is necessary for long-term storage of conditioned threat response whereas de novo translation in protein kinase Cδ-expressing (PKCδ) interneurons in the CeL is essential for storing conditioned response inhibition to a safety cue. Further, we show that oxytocinergic neuromodulation of PKCδ interneurons during differential threat learning is important for long-lasting cued threat discrimination. Our results indicate that the molecular elements of a differential threat memory trace are compartmentalized in distinct CeL interneuron populations and provide new mechanistic insight into the role of de novo protein synthesis in consolidation of long-term memories.
Long-term structural remodeling in Aplysia sensory neurons requires de novo protein synthesis during a critical time period