The interactions between cortical and hippocampal circuits are critical for memory formation, yet their basic organization at the neuronal network level is not well understood. Here, we demonstrate that a significant portion of neurons in the medial prefrontal cortex of freely behaving rats are phase locked to the hippocampal theta rhythm. In addition, we show that prefrontal neurons phase lock best to theta oscillations delayed by approximately 50 ms and confirm this hippocampo-prefrontal directionality and timing at the level of correlations between single cells. Finally, we find that phase locking of prefrontal cells is predicted by the presence of significant correlations with hippocampal cells at positive delays up to 150 ms. The theta-entrained activity across cortico-hippocampal circuits described here may be important for gating information flow and guiding the plastic changes that are believed to underlie the storage of information across these networks.

Theta oscillations clock hippocampal activity during awake behaviour and rapid eye movement (REM) sleep. These oscillations are prominent in the local field potential, and they also reflect the subthreshold membrane potential and strongly modulate the spiking of hippocampal neurons. The prevailing view is that theta oscillations are synchronized throughout the hippocampus, despite the lack of conclusive experimental evidence. In contrast, here we show that in freely behaving rats, theta oscillations in area CA1 are travelling waves that propagate roughly along the septotemporal axis of the hippocampus. Furthermore, we find that spiking in the CA1 pyramidal cell layer is modulated in a consistent travelling wave pattern. Our results demonstrate that theta oscillations pattern hippocampal activity not only in time, but also across anatomical space. The presence of travelling waves indicates that the instantaneous output of the hippocampus is topographically organized and represents a segment, rather than a point, of physical space.Theta oscillations are a prominent 4-10-Hz rhythm in the hippocampal local field potential (LFP) of all mammals studied to date 1-3 , including humans 4 . During wakefulness they are associated with different speciesspecific behaviours, and they are invariably present during REM sleep 2,3 . In the rat, theta oscillations always accompany voluntary movement and active exploration 2,5 . Theta oscillations are essential for the normal functioning of the hippocampus, because manipulations that disrupt them produce behavioural impairments that mimic hippocampal lesions 6,7 . The importance of theta oscillations is underscored by the fact that they reflect subthreshold membrane potentials [8][9][10] and strongly modulate the spiking 5,11,12,13 of hippocampal neurons. Furthermore, theta oscillations gate synaptic plasticity, because the timing of stimulation with respect to the phase of theta is important in determining the magnitude and direction of synaptic change 14,15 . Theta oscillations therefore offer macroscopic access to the internal clock of the hippocampal circuit, responsible for temporally patterning its operation. Such clocking is essential for the temporal coding of spatial information by place cells 5,16 , as evidenced by theta phase precession [17][18][19] . In addition to coding position, theta phase precession ensures that the order of place-cell firing over behavioural timescales (seconds) is preserved and compressed within individual theta cycles and inside the window of plasticity 18 . In the presence of spike-timing-dependent plasticity 20 , the resulting compression of temporal sequences offers a mechanism for the formation of hippocampal memory traces 21 . Furthermore, theta oscillations modulate activity not only in the hippocampus, but also in several subcortical, limbic and cortical structures [22][23][24] .If theta oscillations can be thought of as a clock, what time is it in different parts of the hippocampus? In other words, how does the phase of theta oscillation...

Summary Cortico-hippocampal interactions during sleep are believed to reorganize neural circuits in support of memory consolidation. However, spike timing relationships across cortico-hippocampal networks, which are key determinants of synaptic changes, are not well understood. Here we show that cells in prefrontal cortex fire consistently within 100 ms after hippocampal cells in naturally sleeping animals. This provides evidence at the single cell-pair level for highly consistent directional interactions between these areas within the window of plasticity. Moreover, these interactions are state-dependent: they are driven by hippocampal sharp-wave/ripple (SWR) bursts in slow-wave sleep (SWS) and are sharply reduced during REM sleep. Finally, prefrontal responses are non-linear: as the strength of hippocampal bursts rises, short-latency prefrontal responses are augmented by increased spindle band activity and a secondary peak ~100 ms later. These findings suggest that SWR events serve as an atomic unit of hippocampal-prefrontal communication during SWS, and that the coupling between prefrontal and hippocampal areas is highly attenuated during REM sleep.

The level of synchronization in distributed systems is often controlled by the strength of the interactions between individual elements. In brain circuits the connection strengths between neurons are modified under the influence of spike-timing-dependent plasticity (STDP) rules. Here we show that when recurrent networks with conduction delays exhibit population bursts, STDP rules exert a strong decoupling force that desynchronizes activity. Conversely, when activity in the network is random, the same rules can have a coupling and synchronizing influence. The presence of these opposing forces promotes the self-organization of spontaneously active neuronal networks to a state at the border between randomness and synchrony. The decoupling force of STDP may be engaged by the synchronous bursts occurring in the hippocampus during slow-wave sleep, leading to the selective erasure of information from hippocampal circuits as memories are established in neocortical areas.

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