Learning to learn persistently modifies an entorhinal-hippocampal excitatory-inhibitory subcircuit

SUMMARY Cognitive control, the judicious use of relevant information while ignoring distractions, is a feature of everyday cognitive experience, but its neurobiology is understudied. We investigated whether cognitive control training (CCT) changes hippocampal neural circuit function in mice, beyond the changes caused by place learning and memory formation. Mice learned and remembered a conditioned place avoidance during CCT that required ignoring irrelevant locations of shock. They were compared to controls that learned the same place avoidance under lower cognitive control demands. Weeks after CCT, mice learn new tasks in novel environments faster than controls; they learned to learn. We investigated entorhinal cortex-to-dentate gyrus neural circuit changes and report that CCT rapidly changes synaptic circuit function, resulting in an excitatory-inhibitory subcircuit change that persists for months. CCT increases inhibition that attenuates the dentate response to medial entorhinal cortical input, and through disinhibition, potentiates the response to strong inputs, pointing to overall signal-to-noise enhancement. These neurobiological findings support a neuroplasticity hypothesis that, beyond storing item/event associations, CCT persistently optimizes neural circuit information processing.