The prefrontal cortex controls memory organization in the hippocampus

Prior memories can be integrated with novel experiences during learning to facilitate memory organization. This process must be tightly regulated to prevent inappropriate integration of unrelated memories. However, the biological mechanisms underlying such control are currently unknown. Using multiple imaging, chemogenetic and optogenetic techniques in mice, we demonstrate that the ventromedial prefrontal cortex is recruited over time to control memory integration in the hippocampus according to contextual similarities between experiences. This control is achieved through direct projections to the medial entorhinal cortex that modulate entorhinal activity, ensemble overlap in the dorsal hippocampus, memory linking, activity of neurogliaform cells in the dorsal CA1 and memory allocation. Together, our results provide new insights into the mechanisms controlling crucial processes of memory organization in the mammalian brain.