The connectivity of the hippocampal trisynaptic circuit, formed by the dentate gyrus, the CA3 and the CA1 region, is well characterized anatomically and functionally in vitro. The functional connectivity of this circuit in vivo remains to be understood. Toward this goal, we investigated the influence of the spontaneous, synchronized oscillations in the neocortical local field potential, reflecting up-down states (UDS) of cortical neurons, on the hippocampus. We simultaneously measured the extracellular local field potential in association cortex and the membrane potential of identified hippocampal excitatory neurons in anesthetized mice. Dentate gyrus granule cells showed clear UDS modulation that was phase locked to cortical UDS with a short delay. In contrast, CA3 pyramidal neurons showed mixed UDS modulation, such that some cells were depolarized during the cortical up state and others were hyperpolarized. CA1 pyramidal neurons, located farther downstream, showed consistent UDS modulation, such that when the cortical and dentate gyrus neurons were depolarized, the CA1 pyramidal cells were hyperpolarized. These results demonstrate the differential functional connectivity between neocortex and hippocampal subfields during UDS oscillations.consolidation ͉ hippocampus ͉ neocortex ͉ oscillation ͉ sleep C ortico-hippocampal interaction, especially during quiet wakefulness and sleep, is thought to be important for the formation of long-term memories by a process of consolidation (1-12). During these behavioral states and under anesthesia, neocortical neurons are spontaneously active, and their activity is modulated by slow, 0.3-to 1.5-Hz oscillations called up-down states (UDS) characteristic of slow wave sleep (SWS) oscillations. Both the local field potential (LFP) and the membrane potential (MP) show that UDS are synchronized across large areas of the cortex (13-17). Although neocortex is the major source of input to the hippocampal formation (18), the hippocampal LFP shows large-irregular activity during SWS that seems uncorrelated with the neocortical activity (19,20). This is indicative of minimal cortico-hippocampal interaction during UDS. However, recent studies have shown cortico-hippocampal interaction during various behavioral states including SWS (6,11,(21)(22)(23)(24)(25)(26). The mechanisms underlying this interaction and the contribution of different parts of the hippocampal circuit to this interaction remain to be understood.Each area of the hippocampal trisynaptic circuit sends glutamatergic projections to both excitatory and inhibitory neurons in the next stage (27). Hence, the net output of any hippocampal region would be a complex and, presumably, state-dependent function of the strength and timing of excitatory and inhibitory inputs (28). The functional connectivity of cortico-hippocampal circuits has been extensively investigated by using electrical stimulation [see e.g., special issue of Hippocampus (1995) 5:101-146], whereas its interrelations with spontaneous activity such as UDS have receiv...