Hippocampus shapes entorhinal cortical output through a direct feedback circuit

Abstract

Our brains integrate sensory, cognitive and internal state information with memories to extract behavioral relevance. Cortico–hippocampal interactions likely mediate this interplay, but underlying circuit mechanisms remain elusive. Unlike the entorhinal cortex-to-hippocampus pathway, we know little about the organization and function of the hippocampus-to-cortex feedback circuit. Here we report in mice, two functionally distinct parallel hippocampus-to-entorhinal cortex feedback pathways: the canonical disynaptic route via layer 5 and a novel monosynaptic input to layer 2/3. Circuit mapping reveals that hippocampal input predominantly drives excitation in layer 5 but feed-forward inhibition in layer 2/3. Upon repetitive pairing with cortical layer 1 inputs, hippocampal inputs undergo homosynaptic potentiation in layer 5, but induce heterosynaptic plasticity and spike output in layer 2/3. Behaviorally, hippocampal inputs to layer 5 and layer 2/3 support object memory encoding versus recall, respectively. Two-photon imaging during navigation reveals hippocampal suppression reduces spatially tuned cortical axonal activity. We present a model, where hippocampal feedback could iteratively shape ongoing cortical processing. Distinct hippocampal feedback pathways to deep and superficial layers of the cortex in mice differentially modulate excitation–inhibition dynamics, plasticity and cognitive behavioral output.