Astrocytes Control Recent and Remote Memory Strength by Affecting the Recruitment of the CA1 to ACC Projection to Engrams

Description

Recent and remote memories are encoded throughout the brain in 'engrams': cell ensembles formed during acquisition, and a specific memory can be recalled upon their reactivation. The maturation of engrams from recent to remote time points involves the recruitment of dorsal CA1 neurons projecting to the anterior cingulate cortex (CA1to ACC). Various modifications to CA1 astrocytes during memory acquisition, specifically to the Gq- or Gi- GPCR pathways, were shown to affect recent and remote recall in seemingly contradictory ways. To address the inconsistency, we applied transgenic approaches for ensemble identification, CLARITY, retro-AAV virus for circuit mapping, and chemogenetics in astrocytes for functional investigation. We manipulated the activity of either Gq- or Gi- pathways in CA1 astrocytes during memory acquisition and tagged cFos+ engram cells and CA1 to ACC cells during recent and remote recall in the same animals. The behavioral results were coupled with changes in the recruitment of CA1toACC projection cells to the engram, demonstrated by the number of CA1toACC projecting cells within the engram as well as the number of axons projecting from the CA1 engram toward the ACC: Gq pathway activation in astrocytes caused enhancement of recent recall alone and was accompanied by earlier recruitment of CA1toACC projecting cells to the engram. In contrast, Gi pathway activation in astrocytes during acquisition resulted in impairment of only remote recall, and CA1toACC projecting cells were not recruited during remote memory. Finally, we provide a simple working model, hypothesizing that astrocytes control behavioral performance by targeting the CA1toACC projection. Specifically, that Gq- and Gi- pathway activation affect memory differently, but do so by modulating the same mechanism. These findings illuminate the importance of astrocytes in the acquisition of fear memory and the implications on recent and remote recall.

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