Astrocytes Contribute to Remote Memory Formation by Modulating Hippocampal-Cortical Communication During Learning

Remote memories depend on coordinated activity in the hippocampus and frontal cortices, but the timeline of these interactions is debated. Astrocytes sense and modify neuronal activity, but their role in remote memory was scarcely explored. We expressed the Gi-coupled receptor hM4Di in CA1 astrocytes, and discovered that astrocytic manipulation during learning specifically impaired remote, but not recent, memory recall, and decreased activity in the anterior cingulate cortex (ACC) during retrieval. We revealed massive recruitment of ACC-projecting CA1 neurons during memory acquisition, accompanied by activation of ACC neurons. Astrocytic Gi activation disrupted CA3 to CA1 communication in-vivo, and reduced the downstream response in ACC. In behaving mice, it induced a projection-specific inhibition of CA1-to-ACC neurons during learning, consequently preventing ACC recruitment. Finally, direct inhibition of CA1-to-ACC projecting neurons spared recent and impaired remote memory. Our findings suggest that remote memory acquisition involves projection-specific functions of astrocytes in regulating CA1-to-ACC neuronal communication.