Complex spatial working memory (WM) tasks have been shown to require both hippocampal sharp wave ripple (SWR) activity and dentate gyrus (DG) neuronal activity. We therefore asked whether DG inputs to CA3 contribute to spatial WM by promoting SWR generation. Recordings from DG and CA3 while rats performed a dentate-dependent WM task on an 8-arm radial maze revealed that the activity of dentate neurons and the incidence rate of SWRs both increased during reward consumption. We then found reduced reward-related CA3 SWR generation without direct input from dentate granule neurons. Furthermore, CA3 cells with place fields in not-yet visited arms preferentially fired during SWRs at reward locations, and these prospective CA3 firing patterns were more pronounced for correct trials and were dentate dependent. These results indicate that coordination of CA3 neuronal activity patterns by DG is necessary for the generation of neuronal firing patterns that support goal-directed behavior and memory.

Highlights d Neuron loss in the mEC results in an impairment in the delayed alternation task d Hippocampal sequential cell activity during delay intervals is not required for WM d CA1 spatial discrimination during WM encoding is disrupted by mEC lesions d CA3 cells distinguish contexts despite the loss of mEC inputs

SummaryThe hippocampal CA3 subregion is a densely connected recurrent circuit that supports memory consolidation and retrieval by generating and storing sequential neuronal activity patterns that reflect recent experience. While theta phase precession is thought to be critical for generating sequential activity during memory encoding, the circuit mechanisms that support this computation across hippocampal subregions are unknown. By analyzing CA3 network activity in the absence of each of its theta modulated excitatory inputs, we show necessary and unique contributions of the dentate gyrus (DG) and the medial entorhinal cortex (MEC) to phase precession. DG inputs are essential for generating the preferential spiking of CA3 cells during late theta phases and for organizing the temporal order of neuronal firing, while MEC inputs modulate the general precision of phase precession. A computational model that accounts for the empirical findings suggests that DG inputs affect the phase and MEC inputs affect the amplitude of inhibitory subnetworks. Our results thus identify a novel and unique functional role of the DG for the generation of sequence coding in the CA3 recurrent circuit.