Top-down prefrontal cortex inputs to the hippocampus have been hypothesized to be important in memory consolidation, retrieval, and the pathophysiology of major psychiatric diseases; however, no such direct projections have been identified and functionally described. Here we report the discovery of a monosynaptic prefrontal cortex (predominantly anterior cingulate) to hippocampus (CA3 to CA1 region) projection in mice, and find that optogenetic manipulation of this projection (here termed AC–CA) is capable of eliciting contextual memory retrieval. To explore the network mechanisms of this process, we developed and applied tools to observe cellular-resolution neural activity in the hippocampus while stimulating AC–CA projections during memory retrieval in mice behaving in virtual-reality environments. Using this approach, we found that learning drives the emergence of a sparse class of neurons in CA2/CA3 that are highly correlated with the local network and that lead synchronous population activity events; these neurons are then preferentially recruited by the AC–CA projection during memory retrieval. These findings reveal a sparsely implemented memory retrieval mechanism in the hippocampus that operates via direct top-down prefrontal input, with implications for the patterning and storage of salient memory representations. Here, a sparse neuronal projection from a part of the prefrontal cortex, the anterior cingulate, to the hippocampus is identified that, when activated, can elicit memory retrieval in mice. Recent work has begun to explore how neural ensembles in the hippocampus encode and reactivate a memory, but relatively little is known about how hypothesized 'top-down' inputs arising in the cortex could potentially influence memory processes. Here Karl Deisseroth and colleagues develop new tools and strategies to identify a sparse neuronal projection from the anterior cingulate (part of the prefrontal cortex) to the hippocampus. When activated, these projections can elicit memory retrieval in mice.

Projections from neocortex mediate top-down control of memory retrieval