Hippocampal output influences memory formation in the neocortex, but this process is poorly understood because the precise anatomical location and the underlying cellular mechanisms remain elusive. Here, we show that perirhinal input, predominantly to sensory cortical layer 1 (L1), controls hippocampal-dependent associative learning in rodents. This process was marked by the emergence of distinct firing responses in defined subpopulations of layer 5 (L5) pyramidal neurons whose tuft dendrites receive perirhinal inputs in L1. Learning correlated with burst firing and the enhancement of dendritic excitability, and it was suppressed by disruption of dendritic activity. Furthermore, bursts, but not regular spike trains, were sufficient to retrieve learned behavior. We conclude that hippocampal information arriving at L5 tuft dendrites in neocortical L1 mediates memory formation in the neocortex.

Signals sent back to the neocortex from the hippocampus control the long-term storage of memories in the neocortex[1][1],[2][2], but the cellular mechanisms underlying this process remain elusive. Here, we show that learning is controlled by specific medial-temporal input to neocortical layer 1. To show this we used direct cortical microstimulation detection task that allowed the precise region of learning to be examined and manipulated. Chemogenetically suppressing the last stage of the medial temporal loop, i.e. perirhinal cortex input to neocortical layer 1, profoundly disrupted early memory formation but had no effect on behavior in trained animals. The learning involved the emergence of a small population of layer 5 pyramidal neurons (~10%) with significantly increased firing involving high-frequency bursts of action potentials that were also blocked by suppression of perirhinal input. Moreover, we found that dendritic excitability was correspondingly enhanced in a similarly-sized population of pyramidal neurons and suppression of dendritic activity via optogenetic activation of dendrite-targeting inhibitory neurons also suppressed learning. Finally, single-cell stimulation of cortical layer 5 pyramidal neurons showed that burst but not regular firing retrieved previously learned behavior. We conclude that the medial temporal input to the neocortex controls learning through a process in L1 that elevates dendritic calcium and promotes burst firing. [1]: #ref-1 [2]: #ref-2