Noradrenergic signaling mediates cortical early tagging and storage of remote memory

The neocortical prefrontal memory engram generated during initial learning is critical for remote episodic memory storage, however, the nature of early cortical tagging remains unknown. Here we found that in mice, increased norepinephrine (NE) release from the locus coeruleus (LC) to the medial prefrontal cortex (mPFC) during contextual fear conditioning (CFC) was critical for engram tagging and remote memory storage, which was regulated by the ventrolateral periaqueductal grey. β-Blocker infusion, or knockout of β1-adrenergic receptor (β1-AR) in the mPFC, impaired the storage of remote CFC memory, which could not be rescued by activation of LC-mPFC NE projection. Remote memory retrieval induced the activation of mPFC engram cells that were tagged during CFC. Inhibition of LC-mPFC NE projection or β1-AR knockout impaired mPFC engram tagging. Juvenile mice had fewer LC NE neurons than adults and showed deficiency in mPFC engram tagging and remote memory of CFC. Activation of β1-AR signaling promoted mPFC early tagging and remote memory storage in juvenile mice. Our data demonstrate that activation of LC NEergic signaling during CFC memory encoding mediates engram early tagging in the mPFC and systems consolidation of remote memory.