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

Abstract

Recent and remote memories are encoded throughout the brain in Engrams: cell ensembles formed during acquisition, and upon their reactivation, a specific memory can be recalled. The maturation of engrams from recent to remote time points involves the recruitment of CA1 neurons projecting to the anterior cingulate cortex (CA1[->]ACC). Various modifications to CA1 astrocytes, to the Gq- or Gi-GPCR pathways, during memory acquisition 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[->]ACC cells during recent and remote recall in the same animals. The behavioral results were coupled with changes in the recruitment of CA1[->]ACC projection cells to the engram, demonstrated by the number of CA1[->]ACC projecting cells in 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[->]ACC projecting cells to the engram. In contrast, when activating the Gi pathway in astrocytes during acquisition, only remote recall was impaired, and CA1[->]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[->]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 their implications on recent and remote recall.