Biased synaptic activation of dentate granule cells by exercise reflects inputs from the lateral entorhinal cortex

Hippocampal dentate granule cells receive multisensory information from the entorhinal cortex in a laminated and functionally segregated manner. We previously reported that brief periods of voluntary exercise in mice increased EPSCs and dendritic spines for inputs from the lateral, but not the medial, entorhinal cortex. Here we asked whether laminar specificity was due to molecular changes specific to distal granule cell dendrites or rather was dependent on upstream drive from the entorhinal cortex. Selective chemogenetic stimulation of either lateral entorhinal cortex (LEC) or the medial entorhinal cortex (MEC) increased granule cell dendritic spine density in the selected pathway. However, the preponderance of exercise-activated cells originated from LEC based on expression of an activity-dependent retrograde virus in Fos-TRAP mice. Our results indicate that the preferential activation by exercise reflects the drive of locomotor-related inputs from the lateral entorhinal cortex rather than selective molecular mechanisms in distal dendrites of dentate granule cells. How this activation pattern affects other salient stimuli involving contextual or spatial cues may underlie the benefits of exercise on learning and memory.