Noradrenergic signaling mediates cortical early tagging and storage of remote memory

Abstract

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.

Prefrontal modulation of anxiety through a lens of noradrenergic signaling

“…Supporting this claim, β agonists induced anxiogenic effects in rodents ( Hecht et al, 2014 ). Further, β activation impairs fear extinction ( Atzori et al, 2016 ) and remote footshock-induced memory ( Fan et al, 2022 ), which may lead to a more dramatic and persistent anxiogenic response upon bulk activation. Though research surrounding specific β-AR subtype modulation in the PFC is sparse, a recent study demonstrated β2 optogenetic activation in the mPFC resulted anxiogenic responses in the OFT and EZM.…”

Contextual memory engrams, and the neuromodulatory influence of the locus coeruleus

“…Blocking NE neurotransmission impairs this ability and is not easily rescued with LC activation. Moreover, the expression of freezing representing a CFC memory was regulated by the LC-PAG pathway ( Fan et al, 2022 ). It will be interesting to see how future studies explore these other coerulear projections in terms of engram dynamics as well as examine the similarities and differences between LC neuromodulatory actions in these regions as compared to the hippocampus.…”

Shining light on the noradrenergic system

“…75 These sensors have also been instrumental in demonstrating the link between NA temporal dynamics and learning, 26,99 as well as NA and memory consolidation. 8,100 By imaging NA sensors in combination with optogenetics, researchers have begun to reveal the link between LC neuronal activity and NA release in target regions. 22,93,94,96,101 When combining these tools, it is critical to select optically compatible molecules, to avoid any interference between the excitation wavelengths of the opsin and the sensor.…”

“…Using either fiber photometry or two-photon imaging, researchers have used these sensors to uncover the temporal dynamics of NA release associated with various behavioral states, such as sleep, 4 , 8 , 9 the default mode network, 97 arousal, 73 , 98 and the processing of aversive stimuli 75 . These sensors have also been instrumental in demonstrating the link between NA temporal dynamics and learning, 26 , 99 as well as NA and memory consolidation 8 , 100 …”

“… 75 These sensors have also been instrumental in demonstrating the link between NA temporal dynamics and learning, 26 , 99 as well as NA and memory consolidation. 8 , 100 …”