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. ß-Blocker infusion, or knockout of ß1-adrenergic receptor (ß1-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 ß1-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 ß1-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.

Rac1 Signaling in Amygdala Astrocytes Regulates Fear Memory Acquisition and Retrieval.

The importance of astrocytes in behavior control is increasingly appreciated, but little is known about the effects of their dynamic activity in regulating learning and memory. In the present study, we constructed AAVs of photoactivatable and photoinactivatable Ras-related C3 botulinum toxin substrate 1 (Rac1) under the mGFAP promoter, which enabled the manipulation of Rac1 activity in astrocytes by optical stimulation in free-moving mice. We found that both up-regulation and down-regulation of astrocytic Rac1 activity in the basolateral amygdala (BLA) attenuated memory acquisition in a fear conditioning mouse model. Meanwhile, neuronal activation in the BLA induced by memory acquisition was inhibited under both the up- and down-regulation of astrocytic Rac1 activity during training. In terms of the impact on fear memory retrieval, we found both up- and down-regulation of BLA astrocytic Rac1 activity impaired memory retrieval of fear conditioning and memory retrieval-induced neuronal activation. Notably, the effect of astrocytic Rac1 on memory retrieval was reversible. Our results demonstrate that the normal activity of astrocytic Rac1 is necessary for the activation of neurons and memory formation. Both activation and inactivation of astrocytic Rac1 activity in the BLA reduced the excitability of neurons, and thereby impaired fear memory acquisition and retrieval.