Laura Lee Colgin, Tobias Denninger, Marianne Fyhn, Torkel Hafting, Tora Bonnevie, Ole Jensen, May-Britt Moser & Edvard I. Moser. Frequency of gamma oscillations routes flow of information in the hippocampus. Nature 462, 353-357 (19 November 2009)
Gamma oscillations are thought to transiently link distributed cell assemblies that are processing related information1, 2… This ‘binding’ mechanism requires that spatially distributed cells fire together with millisecond range precision7, 8; however, it is not clear how such coordinated timing is achieved given that the frequency of gamma oscillations varies substantially across space and time, from 25 to almost 150 Hz1, 9, 10, 11, 12, 13. Here we show that gamma oscillations in the CA1 area of the hippocampus split into distinct fast and slow frequency components that differentially couple CA1 to inputs from the medial entorhinal cortex, an area that provides information about the animal’s current position14, 15, 16, 17, and CA3, a hippocampal subfield essential for storage of such information14, 18, 19. Fast gamma oscillations in CA1 were synchronized with fast gamma in medial entorhinal cortex, and slow gamma oscillations in CA1 were coherent with slow gamma in CA3. Significant proportions of cells in medial entorhinal cortex and CA3 were phase-locked to fast and slow CA1 gamma waves, respectively. The two types of gamma occurred at different phases of the CA1 theta rhythm and mostly on different theta cycles.
Hippocampal gamma oscillations are thought to arise from two sources, one in the entorhinal cortex (EC)9, 21 and another intrinsic to the hippocampus9, 10. The estimated current sources during hippocampal gamma oscillations closely match the currents that result from stimulation of the perforant path projection from EC to the hippocampus9, indicating that hippocampal gamma may be entrained by direct inputs from EC. Entorhinal gamma has been reported to be relatively fast (90 Hz)22, and high-frequency gamma (80 Hz) has been reported also in the hippocampus9. However, in animals with EC lesions, a slower gamma rhythm (40 Hz) becomes more apparent in the hippocampus. The pattern of current dipoles for this slower oscillation matches the current profile associated with activation of the Schaffer collateral/commissural pathway from CA3 to CA19. Collectively, these observations indicate that hippocampal gamma oscillations have multiple origins and raise the possibility that variations in gamma frequency in CA1 reflect alternating synchronization with slow gamma in CA3 and fast gamma in EC (Supplementary Fig. 1). To test this idea, we sampled neural activity simultaneously from CA1 and either CA3 or layer III of medial entorhinal cortex (MEC) in freely moving rats.
We recorded a total of 169 CA1 place cells and 17
putative CA1 interneurons… Only 6% of CA1 place cells showed significant phase-locking to both slow and fast gamma (Supplementary Table 1). The fast gamma-modulated place cells tended to spike near the gamma trough and the slow gamma-modulated place cells preferred to fire closer to the gamma peak (Fig. 4d, 4e; Supplementary Fig. 12). These observations indicate that slow and fast gamma-modulated place cells correspond to separate populations of CA1 neurons firing at different gamma phases and carrying different temporal codes23.
The data support the notion that direct input from layer III of MEC is important for activating CA1 place cells, particularly in the centre of their firing field. A significantly higher proportion of place cells in CA1 was driven by fast gamma from MEC than by slow gamma from CA3. Additionally, fast gamma power in CA1 was maximal near the theta trough, the theta phase when CA1 place cells are most likely to fire. These observations fit well with previous studies showing that place-selective firing in CA1 depends on direct inputs from layer III of MEC14, 17 and indicate that transmission of spatial information between these regions is facilitated by fast gamma oscillations. Considering that the power of fast gamma oscillations in the prefrontal and parietal cortices has recently been found to be modulated by CA1 theta phase13, the fast gamma-mediated coupling between CA1 and MEC may extend further to other cortical regions.
A significantly lower percentage of CA1 place cells was phase-locked to slow gamma than to fast gamma. Slow gamma occurs primarily at a theta phase when CA1 place cells fire with relatively low probability and is probably driven by feedforward inhibition from CA3 that transiently suppresses CA1 firing10. Perhaps more easily able to overcome inhibition during slow gamma are cell ensembles with synapses that had previously undergone long-term potentiation, a process that lastingly strengthens the responses of neurons to inputs and is believed to underlie memory storage25. During periods of slow gamma, CA1 place cells were activated across larger spatial regions, indicating that the cells fired at earlier stages of trajectories through the firing fields, possibly as a consequence of long-term potentiation of CA3–CA1 synapses26, 27. Together, these findings raise the possibility that slow gamma conveys information from memory stores in the CA3 or CA3–CA1 network18, 19. In line with such an idea, coherence between gamma activity in CA3 and CA1 is increased during retrieval of spatial information in a hippocampus-dependent memory task6.
The results are consistent with previous studies reporting that inputs from EC and CA3 arrive in CA1 at different phases of the theta cycle28. Long-term potentiation in CA1 is most easily induced at a particular phase of theta29, corresponding to the phase when EC input is maximal28. This indicates that the theta phase when EC inputs preferentially arrive may coincide with the time when memory encoding occurs optimally and raises the possibility that the EC-coupled CA1 fast gamma observed in the present study serves to facilitate memory encoding30. Retrieval of information is thought to occur at a different theta phase than memory encoding, during which time CA3 input to CA1 is maximal and incoming signals from EC are suppressed28. This idea fits well with the above-hypothesized memory retrieval function for slow gamma. Separation of afferent inputs to CA1 on different phases of theta is probably important for avoiding re-encoding of previously stored memories and also for reliably distinguishing perceptions of ongoing experiences from internally evoked memories. The present results raise the possibility that slow and fast gamma play an important role in this separation of inputs by filtering out improperly timed signals from one afferent while facilitating transfer of coherent activity from another. Considering that broadband gamma oscillations occur in other areas1, 2, 3, 4, 11, 24, separation of gamma oscillations into discrete frequency channels may be used throughout the brain to enhance interregional communication.